U.S. flag

An official website of the United States government

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Noebels JL, Avoli M, Rogawski MA, et al., editors. Jasper's Basic Mechanisms of the Epilepsies. 5th edition. New York: Oxford University Press; 2024. doi: 10.1093/med/9780197549469.003.0028

Cover of Jasper's Basic Mechanisms of the Epilepsies

Jasper's Basic Mechanisms of the Epilepsies. 5th edition.

Show details

Chapter 28Inflammatory Astrocytic TGFβ Signaling Induced by Blood–Brain Barrier Dysfunction Drives Epileptogenesis

, , and .

Abstract

Under healthy conditions, the brain is protected by the blood–brain barrier (BBB), a selective barrier function of the central nervous system vasculature restricting the passage of most macromolecules and cells from the blood into the brain. BBB dysfunction (BBBD) occurs in various epileptogenic conditions including stroke, traumatic injury, status epilepticus, and aging. This chapter summarizes recent findings which demonstrate that BBBD is sufficient to induce epileptogenesis, and identifies the epileptogenic cascade triggered by BBBD. This cascade includes (1) cross-BBB influx of albumin from the serum into the brain neuropil, (2) albumin binding to and activating astrocytic transforming growth factor beta (TGFβ) receptor ALK5, (3) mounting of inflammatory signaling and TGFβ1 positive feedback, (4) transcriptional changes in astrocytes that induce astrocytic decoupling and downregulation of K+ and glutamate buffering capacity, (5) degradation of extracellular matrix, and (6) growth of new excitatory synapses and reorganization of neural networks to favor excitatory activity. These changes epitomize the major hallmarks of epileptogenesis across animal models of acquired epilepsy and in tissue samples from patients, providing a “missing link” for how epileptogenic injuries trigger these pathological changes. Inhibition of TGFβR signaling blocks this cascade of events and prevents epileptogenesis. These findings highlight the potential of BBB-stabilizing treatments as an epilepsy-preventive therapeutic approach, and BBBD quantification as a biomarker for predicting postinjury epilepsy outcomes.

Introduction

Epileptogenesis is a process of maladaptive plasticity, where a cascade of events in a healthy functional brain leads to development of the pathological epileptic brain, characterized by generation of abnormal paroxysmal electrical activity. Injuries including stroke, traumatic brain injury (TBI), or exposure to status epilepticus (SE), can lead to neural network rewiring that supports hyperexcitability, epileptiform activity, and finally chronic seizures. No drugs exist to date that are successful at modifying disease progression and preventing epilepsy before seizures emerge. Even after decades of research, the underlying mechanisms driving the process of epileptogenesis are not fully resolved. Classically, the research has followed the process in neuronal and network components. However, more recently, multiple lines of evidence documented roles for glial cells (particularly astrocytes), inflammation, and BBBD in epileptogenesis. In this chapter, we put together findings from the last decade that led to an emergent parsimonious model that connects these dots and describes a plausible step-by-step progression from the disruption of the BBB, to activation of astrocytic TGFβ signaling, inflammation, changes in perineuronal nets (PNN), network-level pathological plasticity, and ultimately leading to the development of epilepsy. This mechanism highlights the importance of brain environment and microvasculature health in the pathogenesis of epilepsy. Furthermore, this mechanistic understanding offers novel therapeutic targets as well as biomarkers for identifying patients at risk for the development of epilepsy.

The Blood–Brain Barrier

The blood–brain barrier (BBB) is a complex and dynamic system that not only strictly regulates the movement of molecules between blood and the brain parenchyma but also plays a critical role in mediating immunological processes in the central nervous system (CNS). Specialized CNS endothelial cells (ECs), brain vascular smooth muscle cells, pericytes, and astrocytes all form a cellular interface with the circulating blood to maintain and regulate the homeostatic environment of the brain parenchyma (Ballabh, Braun, and Nedergaard, 2004; Daneman and Prat, 2015; Giannoni et al., 2020).

Physiological BBB Function

These barrier cells contribute unique properties to the neurovasculature, including secreting distinct layers of basement membrane (BM), a critical component of the BBB composed of extracellular matrix (ECM) that reduces vascular permeability and provides anchor points and structure for signaling processes that occur within the neurovascular unit (Abbott, Rönnbäck, and Hansson, 2006). On the luminal side of CNS ECs, the glycocalyx component of the BBB is comprised of a network of negatively charged glycoproteins, proteoglycans, and glycolipids that coat the CNS ECs to prevent leukocyte adhesion and vascular permeability (Ando et al., 2018; Kutuzov, Flyvbjerg, and Lauritzen, 2018). Furthermore, CNS ECs exhibit tight and adherens junctions that are appreciatively more complex than peripheral vasculature, with high expressions of various claudins, occludins, and cell adhesion molecules that greatly limit paracellular transport (Tietz and Engelhardt, 2015). To restrict transcellular movement of solutes, CNS ECs lack fenestra and are highly polarized cells with extremely low rates of vesicle-mediated transcytosis (De Bock et al., 2016; Ayloo and Gu, 2019). Highly active efflux transporters and nutrient transporters are distinctly localized to the luminal side of CNS ECs, and both pericytes and astrocytes have been shown to be critical regulators of CNS EC polarity and contribute to BBB robustness (Armulik et al., 2010; Armulik, Genové, and Betsholtz, 2011; Obermeier, Daneman, and Ransohoff, 2013; Sweeney, Ayyadurai, and Zlokovic, 2016) The healthy brain with an intact BBB is typically impermeable to large serum proteins such as albumin and fibrinogen, with the exception of the naturally permeable capillary regions of the choroid plexus and circumventricular organs (Wilhelm et al., 2016; Kaur and Ling, 2017).

The BBB also serves a critical role in limiting the passage of blood-borne immune cells in the brain. To this end, leukocyte infiltration and other immune cell surveillance processes are highly restricted in the brain under nonpathological conditions rendering the brain an “immune privileged site” (Marchetti and Engelhardt, 2020). Microglia are the brain’s resident immune cells, and although passage of other blood-derived immune cells is limited in healthy CNS tissue, the BBB also serves as an interface for communication between microglia and immune cells from the periphery (da Fonseca et al., 2014; Negi and Das, 2018).

Dysfunctional BBB

A change in the selectivity of BBB function can occur when various components of the BBB are compromised and accordingly allow different blood proteins or cells to gain access into the brain parenchyma. BBBD has been documented in patients and animal models in a myriad of pathological scenarios following TBI (Hay et al., 2015; Salehi, Zhang, and Obenaus, 2017); concussion and blast injuries (Shlosberg et al., 2010; Marchi et al., 2013; Weissberg et al., 2014; Tagge et al., 2018; Veksler et al., 2020); ischemic injuries (Schoknecht et al., 2014; Kassner and Merali, 2015; Villringer et al., 2017; Lublinsky et al., 2019; Serlin et al., 2019); brain tumors; brain inflammation; and neurodegenerative disorder (Sweeney, Sagare, and Zlokovic, 2018). Indicators of BBBD include leukocyte infiltration, accumulation of proteins from the blood such as albumin and fibrinogen, and subsequent microglial activation and astrogliosis (Profaci et al., 2020). Detection and quantification of serum proteins in the brain parenchyma has long been used as a measure of increased BBB permeability (Saunders et al., 2015). However, depending on the precipitating event that causes BBBD, deleterious responses from the various neurovascular and neuroimmune elements may vary. Comparative transcriptomic studies in murine models of CNS injury and disease have begun to elucidate core profiles of BBBD response (Kim et al., 2017; Munji et al., 2019), enabling the potential discovery of underlying shared therapeutic targets. The detailed unique mechanisms underlying BBBD are not yet fully understood, but it appears that paracellular leakage, resulting from dysfunction or downregulation of tight-junction proteins, and enhanced transcellular transport across the endothelial barrier can both play significant roles depending on the pathological circumstances inducing BBBD (Krueger et al., 2013; Knowland et al., 2014; De Bock et al., 2016; Nahirney, Reeson, and Brown, 2016; Andreone et al., 2017; Yang et al., 2020).

BBBD in Epileptogenesis

Studies in epilepsy patients document consistent BBBD (Tomkins et al., 2008). This is also reflected in naturally occurring epilepsies in dogs (Hanael et al., 2019) and in experimental models of induced seizures in rats, mice, and pigs (Oby and Janigro, 2006; van Vliet et al., 2006; Marchi et al., 2007; Tomkins et al., 2008; Raabe et al., 2012; Boux et al., 2021). Furthermore, in experimental animals, the induction of seizures (Sokrab, Kalimo, and Johansson, 1989; Seiffert et al., 2004; Oby and Janigro, 2006; van Vliet et al., 2006; Marchi et al., 2007; Tomkins et al., 2008; Vezzani et al., 2011; Raabe et al., 2012; van Vliet, Aronica, and Gorter, 2014; Hanael et al., 2019) and especially SE (Zucker, Wooten, and Lothman, 1983; van Vliet et al., 2006) leads to a rapid BBBD lasting for several days to weeks, suggesting that BBBD does not represent a transient seizure-related event but may indicate prominent vascular pathology within the epileptic tissue. A role for BBBD was proposed in refractory epilepsies (Liu et al., 2012), and recently quantification of BBBD was suggested as a potential biomarker predicting posttraumatic epilepsy outcome (Bar-Klein et al., 2017; Kamintsky et al., 2019; Lublinsky et al., 2019; Serlin et al., 2019). Intriguingly, the extent of BBBD was shown to be correlated with the number of subsequent seizures in the pilocarpine model of temporal lobe epilepsy (TLE) (van Vliet et al., 2006).

Does BBBD play a causative role in epileptogenesis? Longitudinal assessment of BBB using magnetic resonance imaging (MRI) demonstrated BBBD in the amygdala, hippocampus, entorhinal cortex, and piriform cortex during early stages of epileptogenesis in a rat model of kainic-acid-induced SE (van Vliet, Aronica, and Gorter, 2014). These are intriguing correlations, but to tackle the question of causality, gain-of-function experiments are required. Several lines of evidence support the idea that BBBD leads to epileptogenesis: induction of local transient perturbation of the BBB by exposure to the chemical deoxycholate led to delayed development of spontaneous seizures (Ivens et al., 2007); mimicking BBBD by perfusion of the blood-borne protein albumin directly onto the cortex or by injection into the ventricles was sufficient to cause delayed development of spontaneous seizures (Bar-Klein et al., 2014; Weissberg et al., 2015) and reduce the threshold for seizures in naïve and epileptic animals (Frigerio et al., 2012; van Vliet, Aronica, and Gorter, 2014) and in animals with pentylenetetrazole (PTZ)-induced seizures (Senatorov et al., 2019; Friedman, Kaufer, and Heinemann, 2009; Friedman and Heinemann, 2012).

Hence, BBBD plays a critical role in the etiology and pathogenesis of epilepsy. We next turn to describe the timeline of downstream molecular events following BBBD that ultimately lead to epileptogenesis. These molecular events are schematically illustrated in Figure 28–1.

Figure 28–1.. Schematic overview of cell-specific contributions to blood–brain barrier dysfunction-induced epileptogenesis.

Figure 28–1.

Schematic overview of cell-specific contributions to blood–brain barrier dysfunction-induced epileptogenesis. Image credit: BioRender.

BBBD Induces Inflammatory TGFβ Signaling

Following BBBD, serum components extravasate into the brain parenchyma, carrying along signaling molecules that can induce injury response leading to pathological changes. Albumin, the most abundant blood protein, serves as a signaling molecule to trigger an inflammatory response to injury, which sets in motion a cascade of events that represent the earliest stages of epileptogenesis (Fig. 28–1).

Cell-Specific TGFβ Signaling in the Brain

TGFβ signaling is complex and context-dependent (Derynck and Budi, 2019; Diniz et al., 2019). In the canonical TGFβ signaling pathway, the ligand TGFβ binds to constitutively active TGFβII receptors, which in turn phosphorylate the TGFβI receptors also known as activin-like kinase 5 (ALK5) (Wrana et al., 1994). Phosphorylated ALK5 proceeds to phosphorylate intracellular effector proteins SMAD2/3 (SMAD being an acronym from the fusion of Caenorhabditis elegans Sma genes and the Drosophila Mad, Mothers against decapentaplegic) which are translocated to the nucleus, triggering consequent genome-wide transcriptional changes (Cacheaux et al., 2009; Kim et al., 2017).

This canonical TGFβ-SMAD signaling pathway can also be activated by a different ligand, the protein albumin. Activation of the pathway by albumin has been demonstrated in the periphery, in the context of kidney cells (Gekle et al., 2003) and lung endothelial cells (Siddiqui, Siddiqui and Malik, 2004). Co-immunoprecipitation experiments against albumin and TGFβRII in brain lysates confirm direct interaction between albumin and TGFβR (Cacheaux et al., 2009).

Given the pleiotropic nature of TGFβ signaling, it is not surprising that TGFβ can activate numerous cell-type-specific pathways, and even evoke context-dependent effects within a single cell type. In neurons, TGFβ1 activates two distinct TGFβRI signal transduction pathways: the ALK5-SMAD2/3 pathway and the ALK1-SMAD1/5 pathway (König et al., 2005). ALK1 expression is upregulated in neurons in response to injury as a neuroprotective mechanism, mediating activation of the anti-apoptotic NFκ-B pathway. TGFβ signaling has been shown to activate resident microglia, and studies in animal models have confirmed the role of TGFβ signaling in suppressing inflammatory phenotypes in microglia (Brionne et al., 2003; Paglinawan et al., 2003; Makwana et al., 2007; Zöller et al., 2018). Interestingly, exposing microglia to albumin has been shown to result in cell activation and proliferation (Hooper, Taylor and Pocock, 2005) as well as production of inflammatory factors (Hooper et al., 2009; Ralay Ranaivo and Wainwright, 2010). In pericytes, transcriptomic analysis after TGFβ activation demonstrated a complex profile of both pro- and anti-inflammatory modulation, along with reduced phagocytic capability (Rustenhoven et al., 2016, 2017).

Astrocytic Inflammatory TGFβ Signaling in Epileptogenesis

Primary cultured astrocytes and neurons incubated with fluorescently tagged albumin show rapid uptake by astrocytes, but not neurons (Bar-Klein et al., 2014). Furthermore, rat cortical slices directly exposed to fluorescently labeled albumin demonstrated albumin internalization and uptake predominantly localized to astrocytes (Fig. 28–2), and TGFβRI selective inhibition significantly reduced the uptake (Ivens et al., 2007). In cultured primary astrocytes, uptake of albumin was similarly blocked by inhibiting caveolae-mediated endocytosis. Incubation of astrocytes with both caveolae-mediated endocytosis and TGFβRI selective inhibitors prevented most but not all albumin uptake, suggesting that albumin enters astrocytes through pathways involving TGFβR activation and caveolae-mediated endocytosis, but also through additional, thus far undefined, pathways (Bar-Klein et al., 2014). Furthermore, albumin has also been shown to induce astrogliosis through pathways besides TGFβ-SMAD signaling, such as mitogen-activated protein kinase (MAPK) pathways (Ralay Ranaivo and Wainwright, 2010; Ralay Ranaivo, Patel, and Wainwright, 2010; Ralay Ranaivo et al., 2012).

Figure 28–2.. Chronological timeline depicting systemic changes from blood–brain barrier dysfunction to epileptogenesis.

Figure 28–2.

Chronological timeline depicting systemic changes from blood–brain barrier dysfunction to epileptogenesis.

A large body of evidence accumulated over the past decade strongly supports the role of inflammation in epileptogenesis (Vezzani, Balosso, and Ravizza, 2019). Many inflammatory molecules and pathways have been identified in preclinical models and in epilepsy patients, including interleukin-1β (IL-1β), interleukin-6 (IL-6), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), signal transducer and activator of transcription 3 (STAT3), and TGFβ. Albumin serves as a signaling molecule to trigger an inflammatory injury response, whereby astrocytes become reactive and initiate widespread inflammatory signaling, seen by upregulation of genes associated with immune response activation including NF-kB and STAT3 pathway-related genes, cytokines, chemokines, and the complement pathway (Cacheaux et al., 2009; Kim et al., 2017). In primary cultures, TGFβ signaling induced rapid upregulation of the cytokine IL-6 in astrocytes, but not in microglia, via SMAD2/3 (Levy et al., 2015). Electrophysiological recordings in mouse cortico-hippocampal slices showed that cortical excitability increased after IL-6 administration, culminating in epileptiform discharges and spontaneous seizures. Transcriptomic studies further support the pro-inflammatory effects of TGFβ on astrocytes, an effect blocked when albumin was administered with TGFβR inhibitors (Cacheaux et al., 2009). An inflammatory positive feedback loop is created as albumin also induces in astrocytes upregulation of both mRNA and protein levels of the natural ligand of TGFβR, TGFβ1. This positive feedback loop is mediated by ALK5 activation (Bar-Klein et al., 2014). Secreted TGFβ1 is typically stored as a large latent complex in the extracellular matrix (ECM). Albumin exposure also leads to increased expression of astrocytic genes encoding for proteins involved in ECM degradation such as matrix metallopeptidase 9 (MMP9), matrix metallopeptidase 14 (MMP14), and A disintegrin and metalloproteinase with thrombospondin motifs (Adamts1). These proteins, in turn, induce ECM remodeling and trigger the activation of the latent form of TGFβ1 (Yu and Stamenkovic, 2000; Kim et al., 2017), further amplifying the inflammatory response.

BBBD-Induced TGFβ Signaling Diminishes Astrocytic Buffering Capacity and Promotes Epileptogenesis

A range of changes occur in astrocytes in response to exposure to albumin that alter their function, and subsequently alter the function of neurons around them. Astrocytes respond within hours to albumin exposure through a global transcriptional shift, including increased expression of cytokines (Cacheaux et al., 2009; Kim et al., 2017), decreased expression of connexins, and decreased expression of ions and neurotransmitter transporters, ultimately leading to decreased astrocytic gap junction coupling (Braganza et al., 2012; Carmignoto and Haydon, 2012; Seifert and Steinhäuser, 2013) and impaired spatial buffering of potassium ions (K+) and glutamate capacity (David et al., 2009). Furthermore, the phenotypic and functional transformation of the astrocytes mediate an increase in excitatory synaptogenesis (Bar-Klein et al., 2014; Weissberg et al., 2015) and in ECM-remodeling enzymes (Cacheaux et al., 2009; Kim et al., 2017). These changes all promote an increased imbalance of excitation and inhibition and increased neural synchronization that leads to the development of epileptiform activity and paroxysmal slow-wave events over a period of days (Senatorov et al., 2019; Milikovsky et al., 2019) and spontaneous seizures over the following weeks (Bar-Klein et al., 2014; Weissberg et al., 2015) (Fig. 28–2)

BBBD-Induced TGFβ Signaling Diminishes Astrocytic K+ and Glutamate Homeostasis

Glutamate homeostasis and buffering of extracellular K+ are critical factors in maintaining neuronal excitability. Accumulated evidence described next demonstrates that brain exposure to albumin leads to changes in glutamate and K+ homeostasis in astrocytes, changes which are dependent on activation of TGFβR signaling and that are blocked by ALK5 kinase inhibitors. Thus, one potential mechanism in which BBBD and the subsequent TGFβR activation drive epileptogenesis is through the modification of astrocytic properties that lead to increased extracellular K+ and glutamate concentrations.

Astrocytic buffering of glutamate plays a lead role in neuronal hyperexcitability and regulation of seizure activity in animal models (Eid et al., 2008; Heinemann, Kaufer, and Friedman, 2012). In patients with mesial TLE (MTLE) and in BBBD animal models, deficiencies are observed in the astrocytic glutamate metabolizing enzyme, glutamine synthetase (Eid et al., 2008; David et al., 2009). Additionally, in astrocytic glutamate transporters of the solute carrier family (SLC) 1, subfamily A members SLC1A2 and SLC1A3, expression is reduced following BBBD (Chaudhry et al., 1995; Su et al., 2003; David et al., 2009). Such deficiencies in glutamate metabolism and transport by astrocytes may contribute to the increased excitability in the brain that precipitates epileptogenesis and recurrent seizures. Recent work, however, has shown that TGFβ signaling upregulates expression of SLC4A4 in mouse astrocytes (Khakipoor et al., 2017). These observations further illustrate the complexity and context dependence of TGFβ signaling.

TGFβR-mediated albumin uptake into astrocytes was also shown to alter K+ homeostasis. In animal models of BBBD, including focal neocortical BBB disruption, TBI, ischemia, and TLE, downregulation of the astrocytic inwardly rectifying potassium (Kir) 4.1 channels is observed within days (D’Ambrosio et al., 1999; Heinemann et al., 2000). This results in reduced clearance of activity-dependent accumulation of K+ 24 hours following exposure to albumin and leads to NMDA receptor-mediated neuronal hyperexcitability and, ultimately, epileptiform activity (Djukic et al., 2007; Ivens et al., 2007; Heinemann, Kaufer, and Friedman, 2012).

BBD-Induced TGFβ Signaling Modifies Astrocytic Coupling and Water Channels

Another potential link between BBBD-induced changes of astrocytic function and dysregulation of brain excitability is the downregulation of Aquaporin 4 (AQP4), a membrane water channel highly expressed on astrocytic end-feet (Binder et al., 2006; Heinemann, Kaufer, and Friedman, 2012). AQP4-deficient mice show reduced extracellular K+ buffering, increased duration of induced seizures, and lower seizure threshold (Binder et al., 2006; Strohschein et al., 2011). In human patients with MTLE, a decrease in AQP4 density around the perivascular membrane of astrocytes suggests a similar mechanism contributes to impaired extracellular K+ homeostasis in these patients (Eid et al., 2008). Inducing focal BBBD or exposure of the brain tissue to albumin leads to reduced expression of AQP4 in astrocytes (Cacheaux et al., 2009), and AQP4 expression has been shown to be regulated by TGFβ signaling (Nataf, 2020).

Spatial buffering capacity is not just dictated by the individual cells but also by the creation of a network of astrocytes, coupled via gap junctions to form large cellular networks. The degree of connectivity is regulated by expression of connexins, the astrocytic gap junction proteins. Albumin exposure leads to reduced expression of the major connexin proteins (Cacheaux et al., 2009) and decreased astrocytic coupling (Braganza et al., 2012), potentially contributing to the epileptogenic process. Gap junction coupling is also known to contribute to K+ spatial buffering (Strohschein et al., 2011). Injection of albumin into the brain lateral ventricle resulted in decreased gap junction coupling (Braganza et al., 2012), although this may not be mediated by activation of ALK5 TGFβR phosphorylation (Henning, Steinhäuser, and Bedner, 2021).

Astrocytic TGFβ Activation Induces Functional Network Modifications, ECM Remodeling, and Pathological Synaptic Plasticity

BBBD-induced activation of astrocytic TGFβRs is sufficient to induce epileptogenesis in experimental settings (Seiffert et al., 2004; Ivens et al., 2007; Weissberg et al., 2015). The epileptogenic cascade is triggered by widespread inflammatory signaling and proceeds through degradation of the ECM, growth of new excitatory synapses (Weissberg et al., 2015), and reorganization of neural networks to favor excitatory activity and the development of spontaneous seizures (Kim et al., 2016; Swissa et al., 2019).

BBBD-Induced Modulation of GABAergic Neurotransmission

Changes in inhibitory neurotransmission are well documented in epileptogenesis (de Lanerolle et al., 1989; Robbins et al., 1991; Mathern et al., 1995; Marco et al., 1996; Williamson, Patrylo, and Spencer, 1999; Bernard et al., 2000; Loup et al., 2000; Treiman, 2001; Maglóczky and Freund, 2005; Huberfeld et al., 2007; Scharfman and Brooks-Kayal, 2014; Martinello et al., 2018). In the rat neocortex, BBBD in the peri-infarct area is associated with reduced feedback and feedforward inhibition following paired pulse stimulation, and electrographic seizure activity is observed within a week of photothrombotic stroke induction (Lippmann et al., 2017). These findings are preceded by TGFβR and astrocyte activation and downregulation of GABAA receptor subunit genes. Transcriptomic analysis reveals that GABAA receptor subunit genes Gabra4, Gabrd, Gabrg1, and Gabrb2 are also downregulated following induction of BBBD, or cortical exposure to albumin, or TGFβ1 (Cacheaux et al., 2009). This accompanies upregulation in transcripts of tumor necrosis factor (TNF), which is known to promote endocytosis of GABAA receptors and recruitment of AMPA receptors to neuronal membranes (Beattie et al., 2002; Stellwagen et al., 2005; Leonoudakis, Zhao, and Beattie, 2008). It is important to note these observations are made prior to recording of epileptiform activity following TGFβ activation, further illustrating the role of BBBD-induced modulation of GABA neurotransmission as a potential mediator of epileptogenesis.

BBBD-Induced ECM Remodeling Is Mediated by Astrocytic TGFβR Activation

Neurons and astrocytes play a major role in controlling the extracellular environment by secreting ECM components, and, in turn, components of the ECM act as signaling molecules for regulating different aspects of cellular homeostasis (Dityatev and Fellin, 2008). Perineural nets (PNN) are specialized ECM structures found around inhibitory neurons such as parvalbumin-positive GABAergic interneurons (Carstens et al., 2016). PNNs are thought to aid in stabilizing synaptic structures and limiting synaptic plasticity (Sorg et al., 2016). Degradation of PNNs around fast-spiking inhibitory interneurons is observed in rodent models of TLE (Rankin-Gee et al., 2015) and in patients with MTLE (Kim et al., 2016). In the hippocampus of rats treated with pilocarpine-induced SE, PNN degradation is observed within 48 hours following seizure induction and persists for months (McRae and Porter, 2012; Rankin-Gee et al., 2015). Degradation of PNNs is induced by multiple factors including tissue-type plasminogen activator (tPA), ADAMTSs, and MMPs (McRae and Porter, 2012; Kim et al., 2016, 2017).

Albumin extravasation leads to TGFβR-dependent upregulation of enzymes involved in ECM maintenance in astrocytes, including MMP9, tissue inhibitor of metalloproteinases 2 (TIMP2), and ADAMTS1 (Kim et al., 2017). This upregulation results in a permissive environment for synaptic reorganization that may lead to seizure susceptibility. MMP9 inhibition during amygdala kindling in rat models has been shown to prevent PNN degradation, synaptic reorganization, and impede seizure generation (Pollock et al., 2014). An additional consequence of albumin-induced MMP9 upregulation is to promote the positive feedback loop of TGFβR activation by release of latent TGFβ due to ECM degradation, further contributing to the pro-inflammatory cascade that exacerbates seizure generation (Yu and Stamenkovic, 2000; Shi et al., 2011; Kim et al., 2017). ECM remodeling also facilitates excitatory synaptogenesis and axon sprouting, that is, mossy fiber sprouting, associated with the human epileptic brain (Mathern et al., 1996; Marco and DeFelipe, 1997; Perosa et al., 2002; Dityatev, 2010).

BBBD-Induced Excitatory Synaptogenesis Is Mediated by Astrocytic TGFβR Activation

TGFβ1 has been shown to promote dendrite growth and synaptogenesis through SMAD3 phosphorylation in neuronal cultures (Yu et al., 2014). Albumin exposure in cell culture and in vivo models of albumin infusion led to increase in excitatory (and not inhibitory) synapses, dependent on activation of astrocytic ALK5 TGFβR (Weissberg et al., 2015). Interestingly, astrocytes release cytokines such as interleukin-33 (IL-33) that signal microglia to maintain synapse homeostasis (Vainchtein et al., 2018). TGFβ has been reported to regulate the production of IL-33 (Rani et al., 2011), thereby potentially reducing stability and impairing homeostatic synaptic plasticity (Wang et al., 2021).

Additionally, the generation of new excitatory synapses (Weissberg et al., 2015) further increases the potential number of modifiable synapses and contributes to network modifications during epileptogenesis. K+ and glutamate buffering is reduced and neuronal excitability is increased in a frequency-dependent manner, resulting in seizure-like events and spreading depolarization (Ivens et al., 2007). In ex vivo slice preparations, albumin exposure leads to both homo- and heterosynaptic plasticity, reduced long-term depression, and increased long-term potentiation of population spikes, effects that are dependent on TGFβR activation (Salar et al., 2016). Twenty-four hours after albumin infusion into brain lateral ventricles, there is a marked downregulation of Kir 4.1 and rapid reduction in the number of electrically coupled astrocytes. Consequently, ex vivo recordings show that K+ buffering is reduced and neuronal excitability is increased in a frequency-dependent manner, resulting in seizure-like events and spreading depolarization (Seiffert et al., 2004; Bar-Klein et al., 2014). A one-week application of albumin or TGFβ1 infusion through an intracerebroventricular osmotic (ICV) pump results in the appearance of spontaneous seizures from day 4 and on, lasting weeks after exposure and associated with marked reactive gliosis with no apparent neuronal loss (Salar et al., 2016).

Translational Impact—Therapeutic Approaches to BBB Dysfunction in Epilepsy

The prevention of the development of acquired epilepsies is of obvious clinical importance. The latent period of weeks to years of epileptogenesis, before seizures appear, provides a clinical window for treatment to prevent or modify the disease course. However, clinical trials of antiepileptogenic drugs have failed to date. The framework described in this chapter suggests a mechanism that both provides a potential diagnostic biomarker and reveals novel druggable targets. BBBD and the subsequent TGFβ signaling are central to epileptogenesis and thus provide potential targets for such therapeutic approaches. In preclinical studies, application of TGFβR inhibitors blocked multiple albumin-induced epileptogenic processes, including gene expression, astrocytic transformation, inflammatory signaling, synaptogenesis, PNN degradation, increased excitation, and reduced seizure threshold (Senatorov et al., 2019; Ivens et al., 2007; Cacheaux et al., 2009; Bar-Klein et al., 2014; Weissberg et al., 2015; Kim et al., 2017). It is therefore imperative to test the potential of TGFβR inhibitors and other drugs that reverse BBB pathology as antiepileptogenic interventions (detailed below). Indeed, both pharmacological interventions and a selective genetic knockout of TGFβR in astrocytes were shown to raise the seizure threshold under BBBD (Senatorov et al., 2019; Bar-Klein et al., 2014).

Diagnostics: Detecting BBBD as a Biomarker in Epileptogenesis

In defining the key mechanisms of vascular pathology and BBBD that induce postinjury epilepsy, the need arises for a diagnostic tool to detect the earliest stages of pathology to predict disease risk. BBBD as a clinically relevant predictive diagnostic biomarker is a particularly promising approach, as it measures a druggable target. For the development of BBBD-based prognostic biomarkers for the development of epilepsy, a clinically relevant quantifiable BBBD assessment is required. A comprehensive review of current approaches and their shortcomings, as well as a strategic roadmap to the identification, characterization, and validation of biomarkers for epileptogenesis, including BBBD, was recently presented (Simonato et al., 2021) and discussed in detail in other chapters of this book.

Different approaches can be taken to attempt to quantify BBBD in patients: MRI of an exogenously administered tracer that does not cross the intact BBB, detection of CNS-borne molecules in peripheral fluids, and detection of blood-borne molecules in the cerebrospinal fluid (CSF). Imaging-based protocols offer the benefit of creating localized maps of the extent of BBBD, while CSF-based protocols carry obvious limitations due to the invasive nature, and blood, saliva, or urine analysis may offer the benefits of ease and cost-effectiveness, if validated. Several clinically applicable dynamic contrast enhanced MRI (DCE-MRI) approaches for quantifying BBBD in patients were recently presented (Montagne et al., 2015; Veksler et al., 2020), based on intravenous injection of gadolinium-based MRI contrast agents which are unable to cross the intact BBB. Thus, during MRI imaging in healthy individuals, the contrast agent appears only in the vasculature, whereas in patients with BBBD, the contrast agent diffuses into the brain, enabling a quantitative readout of the location and severity of vascular damage. BBBD is then quantified by using analysis algorithms for quantifying the extent and location of signals in the brain (Montagne et al., 2015; Veksler et al., 2020). This approach has documented localized BBBD in cohorts of football players (Marchi et al., 2013; Weissberg et al., 2014; Veksler et al., 2020), patients with epilepsy, Alzheimer disease (AD) (Milikovsky et al., 2019), and bipolar disorder (Calkin et al., 2018; Kamintsky et al., 2019, 2020). The potential of this imaging as an early predictive indicator of disease outcome was investigated in two rat models of induced SE and repeated mild traumatic brain injury. Importantly, DCE-MRI showing BBBD immediately following SE or injury were predictive of subsequent seizure pathology (Parker et al., 2021; Bar-Klein et al., 2014). A multiparametric MRI analysis at 9.4 Tesla, combining dynamic contrast-enhanced, T1 diffusion coefficient, and blood volume fraction MRI acquisition with machine-learning analyses yielded specific imaging identifiers to segregate the epileptogenic from the contralateral seizure-spreading hippocampi in experimental unilateral intra-hippocampal injection of kainic acid (KA) in mice (Boux et al., 2021). Recent reports of a putative biomarker toolkit that will enable a minimally invasive protocol for the assessment of BBBD in blood or saliva is encouraging, though the validation of its utility as a predictive biomarker for epileptogenesis is yet to be tested (Janigro et al., 2020).

BBBD and TGFβR as Targets for Antiepileptogenic Interventions

Insights into the mechanisms behind BBBD-induced epileptogenesis provide an opportunity to explore interventions that target this cascade of events. Direct inhibition of TGFβR signaling shortly after experimental induction of epileptogenesis (via induction of BBBD, SE, or repeated mild TBI) facilitated BBB repair, reduced neuroinflammation, blocked BBBD-induced network reorganization, and prevented the development of epilepsy in rats and mice (Parker et al., 2021; Bar-Klein et al., 2014, 2017; Weissberg et al., 2015). Next, several direct and indirect interventions against BBBD, TGFβR, inflammation, and downstream-related cascades are summarized.

Direct Inhibition of TGFβR Signaling

The data summarized in this chapter so far demonstrate that BBBD and subsequent activation of inflammatory signaling cascades in non-neuronal cells is a potential root cause of epileptogenesis. In rodent models of epileptogenesis, in dogs with naturally occurring epilepsy, and in human patients with TLE, BBBD was directly linked with TGFβ signaling activation, astrogliosis, and neuroinflammation, supporting the hypothesis that BBBD is tightly coupled with TGFβ pro-inflammatory signaling activation in epileptogenesis (Bar-Klein et al., 2014; Hanael et al., 2019).

Together, this body of evidence suggests direct inhibition of TGFβ signaling as a potential target. Several small molecules that are direct inhibitors of ALK5 TGFβR kinase activity have been tested: SJN2511 (Tocris), SB431542 (Sigma Aldrich), and IPW-5371 (Innovation Pathway) (Rabender et al., 2016). Intraperitoneal administration of IPW-5371 has been shown to inhibit albumin-induced TGFβ signaling by reduction of SMAD2 phosphorylation in the mouse hippocampus (Senatorov et al., 2019). IPW-5371 treatment also reduced astrocytic activation, reduced neuronal hyperexcitability, decreased sensitivity to PTZ-induced seizures, and reversed symptoms of age-related cognitive decline in mice (Senatorov et al., 2019). Seven days of ICV infusion of albumin or TGFβ1 resulted in the appearance of spontaneous seizures over the next 14 days in 77% and 100% of rats, respectively. Coinfusion of the ALK5 inhibitor SJN2511 dramatically reduced the percent of epileptic animals; only one rat (12%) displayed a single seizure episode (Weissberg et al., 2015). These results using three different TGFβR inhibitors point to a critical role for TGFβR activation in epileptogenesis that is independent of an individual inhibitor. To further probe the cell-specific role of TGFβR in astrocytes, a mouse knock-down model was generated where the knockout of a floxed TGFβRII gene was achieved using induced expression of the CRE enzyme under control of the astrocytic promoter GLAST. Astrocytic knockdown of TGFβR was shown to block the albumin-induced sensitivity to PTZ-induced seizures (Senatorov et al., 2019).

Indirect Inhibition of TGFβR Signaling

FDA-approved angiotensin II type 1 receptor (AT1) antagonist, Losartan, has TGFβ signaling inhibition properties (el-Agroudy et al., 2003; Guido et al., 2019). As such, it has been used in preclinical studies, effectively blocking the generation of seizures postischemia and after albumin treatment (Bar-Klein et al., 2014). Systemic and ICV administration of Losartan has been shown to significantly retard development of amygdala kindling-induced seizure to a level similar to the anticonvulsant drug levetiracetam (Nozaki et al., 2018). Losartan has also been shown recently to reduce astrocyte activation in the hippocampus and prevent recurrent seizures in pilocarpine-induced models of SE (Hong et al., 2019). In the previous study, Losartan had no effect on the severity of the induced seizure; however, recurrent seizures were significantly reduced along with prevention of SE-induced decrease in tight junction proteins, ZO-1 and occludin, and downregulation of AQP4. Losartan also was shown to inhibit albumin-induced PNN degradation around fast-spiking PV+ inhibitory interneurons (Kim et al., 2017). The exact mechanism of action of losartan as antiepileptogenic is yet to be determined, and given the expression and function of AT1 receptors in astrocytes, one cannot rule out the possibility that Losartan’s effect is mediated by its action on both AT1 and TGFβR signaling.

Other Related Antiepileptogenic Interventions

Inflammation

Inflammation is a major contributor to the pathogenesis of epilepsy, and inflammatory mediators such as IL-1β expression by astrocytes are both induced by seizures and can promote their recurrence (Vezzani et al., 2002; Kim et al., 2012; Vezzani, Balosso, and Ravizza, 2019). Inflammatory signaling and IL-1β overexpression is induced in astrocytes by albumin and requires TGFβR activation. A targeted inhibition of interleukin-1 receptor type 1 (IL-1R1) signaling by naturally occurring IL-1R1 antagonist (IL-1ra) has been shown to reduce seizures in animal models following bicuculline methiodide, kainate, and pilocarpine (Vezzani et al., 2000; Marchi et al., 2009). In patients with inflammation-related intractable epilepsy, anakinra, the promising human recombinant IL-1ra, has been shown to reduce seizures (Jyonouchi and Geng, 2016; Kenney-Jung et al., 2016; DeSena, Do, and Schulert, 2018), including a recent report of significant seizure reduction after regular subcutaneous injection in a patient with febrile infection–related epilepsy syndrome (Lai et al., 2020).

Cyclophilin A-Matrix Metalloproteinase-9

The Cyclophilin A/Matrix Metalloproteinase-9 (MMP9) pathway is another potential target for intervention for BBBD associated pathologies. Apolipoprotein E (APOE) isoform APOE4 is the major genetic risk factor for AD (Yamazaki et al., 2019) and is associated with increased risk for neurodegeneration and other neurological conditions including BBBD in animal models (Montagne, Nikolakopoulou, and Huuskonen, 2021). Recent studies have shown that both the lack of Apoe and expression of APOE4 lead to BBB breakdown via activation of the CypA-NFκB-MMP9 pathway in pericytes (Bell et al., 2012; Montagne, Nikolakopoulou, and Huuskonen, 2021). In cognitively normal human APOE4 carriers, BBBD is also observed, as measured by CSF albumin quotient in association with increased levels of CSF CypA and MMP9 (Halliday et al., 2013). Cyclosporin A (CsA) has been shown to enhance BBB repair following TBI by enhancing expression of tight junction proteins ZO-1 and occludin (Main et al., 2018). The effects of CsA on CypA/MMP9 activation and BBB repair in preclinical studies suggest this may be an important therapeutic approach to treating vascular injury and BBBD-related epileptogenesis.

VEGF/IL-1R1/MMPs

Another potential therapeutic strategy for treatment of BBBD and epileptogenesis is targeting pathways downstream of TGFβ signaling or other non-TGFβ factors secreted by activated astrocytes. Vascular Endothelial Growth Factor (VEGF), IL-1R1, and MMPs have been shown to play critical roles in epileptogenesis, acting downstream of albumin/TGFβ signaling and/or astrocyte activation (Vezzani et al., 2002; Ferrari et al., 2009; Shlosberg et al., 2010; Li et al., 2014; Kim et al., 2017). Expression of VEGF is increased in the brain of patients with TLE, and aberrant VEGF signaling is known to underlie many of the pathologies involved in epileptogenesis, including BBBD and excessive angiogenesis (Castañeda-Cabral et al., 2019; Ogaki, Ikegaya, and Koyama, 2020).

PNN degradation by MMP9 and MMP14 is a critical factor in the pathogenesis of seizures in animal models (Yu and Stamenkovic, 2000; Shi et al., 2011; Kim et al., 2017). Recent reports have also shown that glutamate signaling increases MMP2 and MMP9 activity, triggering BBB leakage in mouse and rat models of SE (Rempe et al., 2018). Marimastat is an MMP inhibitor capable of crossing the BBB and reducing seizure activity in KA-induced SE after acute treatment (Pijet et al., 2020). Although chronic use of Marimestat in clinical trials was associated with musculoskeletal side effects (King et al., 2003), it served as an important proof of concept showing the potential benefits of targeting MMP activity in seizure prevention (Broekaart et al., 2021).

Conclusions

The BBB has long been recognized as crucial for maintenance of the brain’s microenvironment, yet only recently BBBD was identified as driving epileptogenesis via activation of inflammatory signaling cascade in non-neuronal cells. Developments in quantitative imaging of BBB in human patients and mechanism-targeted therapeutic approaches to restore BBB function and inhibit the consequent inflammatory signaling will hopefully allow the development of clinically effective antiepileptogenic therapies and biomarkers for identified patients at risk.

Acknowledgments

This research was supported by NIH grants R01NS066005 and R56NS066005, a Bakar Foundation Fellowship, the Archer Foundation Award, the Borstein Foundation award, the Binational Israel-USA Science Foundation award, and DOD PRMRP Investigator-Initiated Research Award (IIRA).

References

  1. Abbott NJ, Rönnbäck L, Hansson E.  Astrocyte–endothelial interactions at the blood–brain barrier.  Nat Rev Neurosci. Nature Publishing Group; 2006 Jan;7(1):41–53. Available from: https://www​.nature.com/articles/nrn1824 [PubMed: 16371949]
  2. Ando Y, Okada H, Takemura G, Suzuki K, Takada C, Tomita H, Zaikokuji R, Hotta Y, Miyazaki N, Yano H, Muraki I, Kuroda A, Fukuda H, Kawasaki Y, Okamoto H, Kawaguchi T, Watanabe T, Doi T, Yoshida T, Ushikoshi H, Yoshida S, Ogura S.  Brain-specific ultrastructure of capillary endothelial glycocalyx and its possible contribution for blood brain barrier.  Sci Rep. 2018 Nov 30;8(1):17523. Available from: http://dx​.doi.org/10​.1038/s41598-018-35976-2 PMCID: PMC6269538 [PMC free article: PMC6269538] [PubMed: 30504908]
  3. Andreone BJ, Chow BW, Tata A, Lacoste B, Ben-Zvi A, Bullock K, Deik AA, Ginty DD, Clish CB, Gu C.  Blood-brain barrier permeability is regulated by lipid transport-dependent suppression of caveolae-mediated transcytosis.  Neuron. 2017 May 3;94(3):581–594. Available from: http://dx​.doi.org/10​.1016/j.neuron.2017.03.043 PMCID: PMC5474951 [PMC free article: PMC5474951] [PubMed: 28416077]
  4. Armulik A, Genové G, Betsholtz C.  Pericytes: developmental, physiological, and pathological perspectives, problems, and promises.  Dev Cell. 2011 Aug 16;21(2):193–215. Available from: http://dx​.doi.org/10​.1016/j.devcel.2011.07.001 PMID: 21839917 [PubMed: 21839917]
  5. Armulik A, Genové G, Mäe M, Nisancioglu MH, Wallgard E, Niaudet C, He L, Norlin J, Lindblom P, Strittmatter K, Johansson BR, Betsholtz C.  Pericytes regulate the blood-brain barrier.  Nature. 2010 Nov 25;468(7323):557–561. Available from: http://dx​.doi.org/10.1038/nature09522 PMID: 20944627 [PubMed: 20944627]
  6. Ayloo S, Gu C. Transcytosis at the blood-brain barrier. Curr Opin Neurobiol.  2019 Aug;57:32–38. Available from: http://dx​.doi.org/10​.1016/j.conb.2018.12.014 PMCID: PMC6629499 [PMC free article: PMC6629499] [PubMed: 30708291]
  7. Ballabh P, Braun A, Nedergaard M.  The blood–brain barrier: an overview: Structure, regulation, and clinical implications.  Neurobiol Dis. 2004 Jun 1;16(1):1–13. Available from: https://www​.sciencedirect​.com/science/article​/pii/S0969996103002833 [PubMed: 15207256]
  8. Bar-Klein G, Cacheaux LP, Kamintsky L, Prager O, Weissberg I, Schoknecht K, Cheng P, Kim SY, Wood L, Heinemann U, Kaufer D, Friedman A. Losartan prevents acquired epilepsy via TGF-β signaling suppression. Ann Neurol. 2014 Jun;75(6):864–875. Available from: http://dx​.doi.org/10.1002/ana.24147 PMCID: PMC4077937 [PMC free article: PMC4077937] [PubMed: 24659129]
  9. Bar-Klein G, Lublinsky S, Kamintsky L, Noyman I, Veksler R, Dalipaj H, Ov VV, Swissa E, Rosenbach D, Elazary N, Milikovsky DZ, Milk N, Kassirer M, Rosman Y, Serlin Y, Eisenkraft A, Chassidim Y, Parmet Y, Kaufer D, Friedman A.  Imaging blood–brain barrier dysfunction as a biomarker for epileptogenesis.  Brain. Oxford Academic; 2017 Apr 23 ;140(6):1692–1705. Available from: https://academic​.oup​.com/brain/article-abstract​/140/6/1692/3748889 [PubMed: 28444141]
  10. Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK, Von Zastrow M, Beattie MS, Malenka RC.  Control of synaptic strength by glial TNFalpha.  Science. 2002 Mar 22;295(5563):2282–2285. Available from: http://dx​.doi.org/10​.1126/science.1067859 PMID: 11910117 [PubMed: 11910117]
  11. Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, Holtzman DM, Betsholtz C, Armulik A, Sallstrom J, Berk BC, Zlokovic BV.  Apolipoprotein E controls cerebrovascular integrity via cyclophilin A.  Nature. 2012 May 16;485(7399):512–516. Available from: http://dx​.doi.org/10.1038/nature11087 PMCID: PMC4047116 [PMC free article: PMC4047116] [PubMed: 22622580]
  12. Bernard C, Cossart R, Hirsch JC, Esclapez M, Ben-Ari Y.  What is GABAergic inhibition? How is it modified in epilepsy? Epilepsia.  2000;41 Suppl 6:S90–5. Available from: https:​//onlinelibrary​.wiley.com/doi/10.1111/j​.1528-1157.2000.tb01564.x PMID: 10999527 [PubMed: 10999527]
  13. Binder DK, Yao X, Zador Z, Sick TJ, Verkman AS, Manley GT.  Increased seizure duration and slowed potassium kinetics in mice lacking aquaporin-4 water channels.  Glia. 2006 Apr 15;53(6):631–636. Available from: http://dx​.doi.org/10.1002/glia.20318 PMID: 16470808 [PubMed: 16470808]
  14. Boux F, Forbes F, Collomb N, Zub E, Mazière L, de Bock F, Blaquiere M, Stupar V, Depaulis A, Marchi N, Barbier EL.  Neurovascular multiparametric MRI defines epileptogenic and seizure propagation regions in experimental mesiotemporal lobe epilepsy.  Epilepsia. 2021 May;62(5):1244–1255. Available from: http://dx​.doi.org/10.1111/epi.16886 PMID: 33818790 [PubMed: 33818790]
  15. Braganza O, Bedner P, Hüttmann K, von Staden E, Friedman A, Seifert G, Steinhäuser C.  Albumin is taken up by hippocampal NG2 cells and astrocytes and decreases gap junction coupling.  Epilepsia. 2012 Nov;53(11):1898–1906. Available from: http://dx​.doi.org/10​.1111/j.1528-1167.2012.03665.x PMCID: PMC3651829 [PMC free article: PMC3651829] [PubMed: 22967085]
  16. Brionne TC, Tesseur I, Masliah E, Wyss-Coray T.  Loss of TGF-beta 1 leads to increased neuronal cell death and microgliosis in mouse brain.  Neuron. 2003 Dec 18;40(6):1133–1145. Available from: http://dx​.doi.org/10​.1016/s0896-6273(03)00766-9 PMID: 14687548 [PubMed: 14687548]
  17. Broekaart DW, Bertran A, Jia S, Korotkov A, Senkov O, Bongaarts A, Mills JD, Anink JJ, Seco J, Baayen JC, Idema S, Chabrol E, Becker AJ, Wadman WJ, Tarragó T, Gorter JA, Aronica E, Prades R, Dityatev A, van Vliet EA. The matrix metalloproteinase inhibitor IPR-179 has antiseizure and antiepileptogenic effects. J Clin Invest.  2021 Jan 4;131(1). Available from: http://dx​.doi.org/10.1172/JCI138332 PMCID: PMC7773344 [PMC free article: PMC7773344] [PubMed: 33141761]
  18. Cacheaux LP, Ivens S, David Y, Lakhter AJ, Bar-Klein G, Shapira M, Heinemann U, Friedman A, Kaufer D.  Transcriptome profiling reveals TGF-beta signaling involvement in epileptogenesis.  J Neurosci. 2009 Jul 15;29(28):8927–8935. Available from: http://dx​.doi.org/10​.1523/JNEUROSCI.0430-09.2009 PMCID: PMC2875073 [PMC free article: PMC2875073] [PubMed: 19605630]
  19. Calkin C, Kamintsky L, Cairns K, Ruzickova M, Schmidt M, Bowen C, Friedman A.  T127. Blood-brain barrier dysfunction as a biomarker for neuroprogression in bipolar disorder.  Biological Psychiatry.  2018. p. S177. Available from: http://dx​.doi.org/10​.1016/j.biopsych.2018.02.463
  20. Carmignoto G, Haydon PG.  Astrocyte calcium signaling and epilepsy.  Glia. 2012 Aug;60(8):1227–1233. Available from: http://dx​.doi.org/10.1002/glia.22318 PMCID: PMC4532388 [PMC free article: PMC4532388] [PubMed: 22389222]
  21. Carstens KE, Phillips ML, Pozzo-Miller L, Weinberg RJ, Dudek SM.  Perineuronal nets suppress plasticity of excitatory synapses on CA2 pyramidal neurons.  The Journal of Neuroscience.  2016. p. 6312–6320. Available from: http://dx​.doi.org/10​.1523/jneurosci.0245-16.2016 [PMC free article: PMC4899529] [PubMed: 27277807]
  22. Castañeda-Cabral JL, Beas-Zárate C, Rocha-Arrieta LL, Orozco-Suárez SA, Alonso-Vanegas M, Guevara-Guzmán R, Ureña-Guerrero ME. Increased protein expression of VEGF-A, VEGF-B, VEGF-C and their receptors in the temporal neocortex of pharmacoresistant temporal lobe epilepsy patients. J Neuroimmunol.  2019 Mar 15;328:68–72. Available from: http://dx​.doi.org/10​.1016/j.jneuroim.2018.12.007 PMID: 30597392 [PubMed: 30597392]
  23. Chaudhry FA, Lehre KP, van Lookeren Campagne M, Ottersen OP, Danbolt NC, Storm-Mathisen J.  Glutamate transporters in glial plasma membranes: highly differentiated localizations revealed by quantitative ultrastructural immunocytochemistry.  Neuron. 1995 Sep;15(3):711–720. Available from: http://dx​.doi.org/10​.1016/0896-6273(95)90158-2 PMID: 7546749 [PubMed: 7546749]
  24. da Fonseca ACC, Matias D, Garcia C, Amaral R, Geraldo LH, Freitas C, Lima FRS.  The impact of microglial activation on blood-brain barrier in brain diseases.  Front Cell Neurosci. 2014 Nov 3;8:362. Available from: http://dx​.doi.org/10​.3389/fncel.2014.00362 PMCID: PMC4217497 [PMC free article: PMC4217497] [PubMed: 25404894]
  25. Daneman R, Prat A.  The blood-brain barrier.  Cold Spring Harb Perspect Biol. 2015 Jan 5;7(1):a020412. Available from: http://dx​.doi.org/10​.1101/cshperspect.a020412 PMCID: PMC4292164 [PMC free article: PMC4292164] [PubMed: 25561720]
  26. David Y, Cacheaux LP, Ivens S, Lapilover E, Heinemann U, Kaufer D, Friedman A.  Astrocytic dysfunction in epileptogenesis: consequence of altered potassium and glutamate homeostasis?  J Neurosci. 2009 Aug 26;29(34):10588–10599. Available from: http://dx​.doi.org/10​.1523/JNEUROSCI.2323-09.2009 PMCID: PMC2875068 [PMC free article: PMC2875068] [PubMed: 19710312]
  27. De Bock M, Van Haver V, Vandenbroucke RE, Decrock E, Wang N, Leybaert L.  Into rather unexplored terrain-transcellular transport across the blood-brain barrier.  Glia. 2016 Jul;64(7):1097–1123. Available from: https:​//onlinelibrary​.wiley.com/doi/10.1002/glia.22960 [PubMed: 26852907]
  28. de Lanerolle NC, Kim JH, Robbins RJ, Spencer DD.  Hippocampal interneuron loss and plasticity in human temporal lobe epilepsy.  Brain Res. 1989 Aug 28;495(2):387–395. Available from: http://dx​.doi.org/10​.1016/0006-8993(89)90234-5 PMID: 2569920 [PubMed: 2569920]
  29. Derynck R, Budi EH. Specificity, versatility, and control of TGF-β family signaling. Sci Signal. 2019 Feb 26;12(570). Available from: http://dx​.doi.org/10​.1126/scisignal.aav5183 PMCID: PMC6800142 [PMC free article: PMC6800142] [PubMed: 30808818]
  30. DeSena AD, Do T, Schulert GS.  Systemic autoinflammation with intractable epilepsy managed with interleukin-1 blockade.  J Neuroinflammation. 2018 Feb 9;15(1):38. Available from: http://dx​.doi.org/10​.1186/s12974-018-1063-2 PMCID: PMC5807745 [PMC free article: PMC5807745] [PubMed: 29426321]
  31. Diniz LP, Matias I, Siqueira M, Stipursky J, Gomes FCA. Astrocytes and the TGF-β1 pathway in the healthy and diseased brain: a double-edged sword. Mol Neurobiol. 2019 Jul;56(7):4653–4679. Available from: http://dx​.doi.org/10​.1007/s12035-018-1396-y PMID: 30377983 [PubMed: 30377983]
  32. Dityatev A, Fellin T.  Extracellular matrix in plasticity and epileptogenesis.  Neuron Glia Biol. 2008 Aug;4(3):235–247. Available from: http://dx​.doi.org/10​.1017/S1740925X09000118 PMID: 19497143 [PubMed: 19497143]
  33. Dityatev A.  Remodeling of extracellular matrix and epileptogenesis.  Epilepsia.  2010. p. 61–65. Available from: http://dx​.doi.org/10​.1111/j.1528-1167.2010.02612.x [PubMed: 20618403]
  34. Djukic B, Casper KB, Philpot BD, Chin LS, McCarthy KD.  Conditional knock-out of Kir4.1 leads to glial membrane depolarization, inhibition of potassium and glutamate uptake, and enhanced short-term synaptic potentiation.  J Neurosci. 2007 Oct 17;27(42):11354–11365. Available from: http://dx​.doi.org/10​.1523/JNEUROSCI.0723-07.2007 PMCID: PMC6673037 [PMC free article: PMC6673037] [PubMed: 17942730]
  35. D’Ambrosio R, Maris DO, Grady MS, Winn HR, Janigro D. Impaired K+ homeostasis and altered electrophysiological properties of post-traumatic hippocampal glia. Journal of Neuroscience.  Soc Neuroscience; 1999;19(18):8152–8162. Available from: https://www​.jneurosci​.org/content/19/18/8152.short [PMC free article: PMC4066407] [PubMed: 10479715]
  36. Eid T, Williamson A, Lee TSW, Petroff OA, de Lanerolle NC.  Glutamate and astrocytes--key players in human mesial temporal lobe epilepsy?  Epilepsia.  2008;49 Suppl 2:42–52. Available from: http://dx​.doi.org/10​.1111/j.1528-1167.2008.01492.x PMID: 18226171 [PubMed: 18226171]
  37. el-Agroudy AE, Hassan NA, Foda MA, Ismail AM, el-Sawy EA, Mousa O, Ghoneim MA.  Effect of angiotensin II receptor blocker on plasma levels of TGF-beta 1 and interstitial fibrosis in hypertensive kidney transplant patients.  Am J Nephrol. 2003 Sep;23(5):300–306. Available from: http://dx​.doi.org/10.1159/000072820 PMID: 12904684 [PubMed: 12904684]
  38. Ferrari G, Cook BD, Terushkin V, Pintucci G, Mignatti P.  Transforming growth factor-beta 1 (TGF-beta1) induces angiogenesis through vascular endothelial growth factor (VEGF)-mediated apoptosis.  J Cell Physiol. 2009 May;219(2):449–458. Available from: http://dx​.doi.org/10.1002/jcp.21706 PMCID: PMC2749291 [PMC free article: PMC2749291] [PubMed: 19180561]
  39. Friedman A, Heinemann U. Role of blood-brain barrier dysfunction in epileptogenesis. Jasper’s Basic Mechanisms of the Epilepsies. 2012. p.  353–361. Available from: http://dx​.doi.org/10​.1093/med/9780199746545.003.0027
  40. Friedman A, Kaufer D, Heinemann U.  Blood–brain barrier breakdown-inducing astrocytic transformation: Novel targets for the prevention of epilepsy.  Epilepsy Res. 2009 Aug 1;85(2):142–149. Available from: https://www​.sciencedirect​.com/science/article​/pii/S0920121109000758 [PMC free article: PMC3615244] [PubMed: 19362806]
  41. Frigerio F, Frasca A, Weissberg I, Parrella S, Friedman A, Vezzani A, Noé FM.  Long-lasting pro-ictogenic effects induced in vivo by rat brain exposure to serum albumin in the absence of concomitant pathology.  Epilepsia. 2012 Nov;53(11):1887–1897. Available from: https:​//onlinelibrary​.wiley.com/doi/10.1111/j​.1528-1167.2012.03666.x PMCID: PMC3651831 [PMC free article: PMC3651831] [PubMed: 22984896]
  42. Gekle M, Knaus P, Nielsen R, Mildenberger S, Freudinger R, Wohlfarth V, Sauvant C, Christensen EI.  Transforming growth factor-beta1 reduces megalin- and cubilin-mediated endocytosis of albumin in proximal-tubule-derived opossum kidney cells.  J Physiol. Wiley; 2003 Oct;552(2):471–481. Available from: https://doi​.org/10.1113/jphysiol​.2003.048074?locatt​=mode:legacy [PMC free article: PMC2343374] [PubMed: 14561830]
  43. Giannoni P, Claeysen S, Noe F, Marchi N. Peripheral routes to neurodegeneration: passing through the blood–brain barrier. Front Aging Neurosci.  2020;12:3. Available from: https://www​.frontiersin​.org/article/10.3389/fnagi.2020.00003 [PMC free article: PMC7010934] [PubMed: 32116645]
  44. Guido MC, Debbas V, Lopes NM, Ferreira-Filho JCA, Salemi VMC, Pereira LV, Maranhao RC, Laurindo FRM.  P2577Losartan diminishes the expression of TGF-beta and improves cardiomyopathy in mice with Marfan syndrome.  Eur Heart J. Oxford Academic; 2019 Oct 21;40(Supplement_1). Available from: https://academic​.oup​.com/eurheartj/article​/40/Supplement_1/ehz748.0904/5597109
  45. Halliday MR, Pomara N, Sagare AP, Mack WJ, Frangione B, Zlokovic BV.  Relationship between cyclophilin A levels and matrix metalloproteinase 9 activity in cerebrospinal fluid of cognitively normal apolipoprotein E4 carriers and blood-brain barrier breakdown.  JAMA Neurology.  2013. p. 1198. Available from: http://dx​.doi.org/10​.1001/jamaneurol.2013.3841 [PMC free article: PMC4047029] [PubMed: 24030206]
  46. Hanael E, Veksler R, Friedman A, Bar-Klein G, Senatorov VV Jr, Kaufer D, Konstantin L, Elkin M, Chai O, Peery D, Shamir MH.  Blood-brain barrier dysfunction in canine epileptic seizures detected by dynamic contrast-enhanced magnetic resonance imaging.  Epilepsia. 2019 May;60(5):1005–1016. Available from: https:​//onlinelibrary​.wiley.com/doi/10.1111/epi.14739 PMID: 31032909 [PubMed: 31032909]
  47. Hay JR, Johnson VE, Young AMH, Smith DH, Stewart W.  Blood-brain barrier disruption is an early event that may persist for many years after traumatic brain injury in humans.  J Neuropathol Exp Neurol. 2015 Dec;74(12):1147–1157. Available from: http://dx​.doi.org/10​.1097/NEN.0000000000000261 PMID: 26574669 [PMC free article: PMC8744142] [PubMed: 26574669]
  48. Heinemann U, Gabriel S, Jauch R, Schulze K, Kivi A, Eilers A, Kovacs R, Lehmann TN.  Alterations of glial cell function in temporal lobe epilepsy.  Epilepsia.  2000;41 Suppl 6:S185–9. Available from: http://dx​.doi.org/10​.1111/j.1528-1157.2000.tb01579.x PMID: 10999542 [PubMed: 10999542]
  49. Heinemann U, Kaufer D, Friedman A. Blood-brain barrier dysfunction, TGFβ signaling, and astrocyte dysfunction in epilepsy. Glia. 2012 Aug;60(8):1251–1257. Available from: http://dx​.doi.org/10.1002/glia.22311 PMCID: PMC3615248 [PMC free article: PMC3615248] [PubMed: 22378298]
  50. Henning L, Steinhäuser C, Bedner P. Initiation of experimental temporal lobe epilepsy by early astrocyte uncoupling is independent of TGFβR1/ALK5 signaling. Front Neurol. 2021 May 7;12:660591. Available from: https://www​.frontiersin​.org/articles/10.3389/fneur​.2021.660591/full PMCID: PMC8137820 [PMC free article: PMC8137820] [PubMed: 34025561]
  51. Hong S, JianCheng H, JiaWen W, ShuQin Z, GuiLian Z, HaiQin W, Ru Z, Zhen G, HongWei R. Losartan inhibits development of spontaneous recurrent seizures by preventing astrocyte activation and attenuating blood-brain barrier permeability following pilocarpine-induced status epilepticus. Brain Res Bull.  2019 Jul;149:251–259. Available from: http://dx​.doi.org/10​.1016/j.brainresbull.2019.05.002 PMID: 31077774 [PubMed: 31077774]
  52. Hooper C, Pinteaux-Jones F, Fry VAH, Sevastou IG, Baker D, Heales SJ, Pocock JM.  Differential effects of albumin on microglia and macrophages; implications for neurodegeneration following blood-brain barrier damage.  J Neurochem. 2009 May;109(3):694–705. Available from: https:​//onlinelibrary​.wiley.com/doi/10.1111/j​.1471-4159.2009.05953.x PMID: 19187440 [PubMed: 19187440]
  53. Hooper C, Taylor DL, Pocock JM.  Pure albumin is a potent trigger of calcium signalling and proliferation in microglia but not macrophages or astrocytes.  J Neurochem. 2005 Mar;92(6):1363–1376. Available from: http://dx​.doi.org/10​.1111/j.1471-4159.2005.02982.x PMID: 15748155 [PubMed: 15748155]
  54. Huberfeld G, Wittner L, Clemenceau S, Baulac M, Kaila K, Miles R, Rivera C.  Perturbed chloride homeostasis and GABAergic signaling in human temporal lobe epilepsy.  Journal of Neuroscience.  2007. p. 9866–9873. Available from: http://dx​.doi.org/10​.1523/jneurosci.2761-07.2007 [PMC free article: PMC6672644] [PubMed: 17855601]
  55. Ivens S, Kaufer D, Flores LP, Bechmann I, Zumsteg D, Tomkins O, Seiffert E, Heinemann U, Friedman A.  TGF-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis.  Brain. 2007 Feb;130(Pt 2):535–547. Available from: http://dx​.doi.org/10.1093/brain/awl317 PMID: 17121744 [PubMed: 17121744]
  56. Janigro D, Bailey DM, Lehmann S, Badaut J, O’Flynn R, Hirtz C, Marchi N.  Peripheral blood and salivary biomarkers of blood-brain barrier permeability and neuronal damage: clinical and applied concepts.  Front Neurol.  2020;11:577312. Available from: http://dx​.doi.org/10​.3389/fneur.2020.577312 PMCID: PMC7890078 [PMC free article: PMC7890078] [PubMed: 33613412]
  57. Jyonouchi H, Geng L.  Intractable epilepsy (IE) and responses to anakinra, a human recombinant IL-1 receptor agonist (IL-1ra): Case reports.  J Clin Cell Immunol.  2016;7(5). Available from: https://www​.omicsonline​.org/open-access/intractable-epilepsy-ie-and-responses-to-anakinra-a-human-recombinantil1-receptor-agonist-il1ra-case-reports-2155-9899-1000456.php?aid=79799
  58. Kamintsky L, Cairns K, Beyea S, Bowen C, Veksler R, Calkin C, Friedman A.  158. Imaging blood-brain barrier pathology in psychiatric disorders.  Biological Psychiatry.  2019. p. S65–S66. Available from: http://dx​.doi.org/10​.1016/j.biopsych.2019.03.172
  59. Kamintsky L, Cairns KA, Veksler R, Bowen C, Beyea SD, Friedman A, Calkin C.  Blood-brain barrier imaging as a potential biomarker for bipolar disorder progression.  NeuroImage: Clinical.  2020. p. 102049. Available from: http://dx​.doi.org/10​.1016/j.nicl.2019.102049 [PMC free article: PMC7229352] [PubMed: 31718955]
  60. Kassner A, Merali Z.  Assessment of blood–brain barrier disruption in stroke.  Stroke. American Heart Association; 2015 Nov 1;46(11):3310–3315. Available from: https://doi​.org/10.1161/STROKEAHA​.115.008861 [PubMed: 26463696]
  61. Kaur C, Ling EA.  The circumventricular organs.  Histol Histopathol. 2017 Sep;32(9):879–892. Available from: http://dx​.doi.org/10.14670/HH-11-881 PMID: 28177105 [PubMed: 28177105]
  62. Kenney-Jung DL, Vezzani A, Kahoud RJ, LaFrance-Corey RG, Ho ML, Muskardin TW, Wirrell EC, Howe CL, Payne ET.  Febrile infection-related epilepsy syndrome treated with anakinra.  Ann Neurol. 2016 Dec;80(6):939–945. Available from: http://dx​.doi.org/10.1002/ana.24806 PMCID: PMC5225882 [PMC free article: PMC5225882] [PubMed: 27770579]
  63. Khakipoor S, Ophoven C, Schrödl-Häußel M, Feuerstein M, Heimrich B, Deitmer JW, Roussa E. TGF-β signaling directly regulates transcription and functional expression of the electrogenic sodium bicarbonate cotransporter 1, NBCe1 (SLC4A4), via Smad4 in mouse astrocytes. Glia. 2017 Aug;65(8):1361–1375. Available from: https:​//onlinelibrary​.wiley.com/doi/10.1002/glia.23168 [PMC free article: PMC5518200] [PubMed: 28568893]
  64. Kim SY, Buckwalter M, Soreq H, Vezzani A, Kaufer D.  Blood-brain barrier dysfunction-induced inflammatory signaling in brain pathology and epileptogenesis.  Epilepsia. 2012 Nov;53 Suppl 6:37–44. Available from: http://dx​.doi.org/10​.1111/j.1528-1167.2012.03701.x PMCID: PMC3703535 [PMC free article: PMC3703535] [PubMed: 23134494]
  65. Kim SY, Porter BE, Friedman A, Kaufer D.  A potential role for glia-derived extracellular matrix remodeling in postinjury epilepsy.  J Neurosci Res. 2016 Sep;94(9):794–803. Available from: http://dx​.doi.org/10.1002/jnr.23758 PMID: 27265805 [PubMed: 27265805]
  66. Kim SY, Senatorov VV Jr, Morrissey CS, Lippmann K, Vazquez O, Milikovsky DZ, Gu F, Parada I, Prince DA, Becker AJ, Heinemann U, Friedman A, Kaufer D. TGFβ signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults. Sci Rep. 2017 Aug 9;7(1):7711. Available from: http://dx​.doi.org/10​.1038/s41598-017-07394-3 PMCID: PMC5550510 [PMC free article: PMC5550510] [PubMed: 28794441]
  67. King J, Zhao J, Clingan P, Morris D.  Randomised double blind placebo control study of adjuvant treatment with the metalloproteinase inhibitor, Marimastat in patients with inoperable colorectal hepatic metastases: significant survival advantage in patients with musculoskeletal side-effects.  Anticancer Res. 2003 Jan;23(1B):639–645. Available from: https://www​.ncbi.nlm​.nih.gov/pubmed/12680160 PMID: 12680160 [PubMed: 12680160]
  68. Knowland D, Arac A, Sekiguchi KJ, Hsu M, Lutz SE, Perrino J, Steinberg GK, Barres BA, Nimmerjahn A, Agalliu D.  Stepwise recruitment of transcellular and paracellular pathways underlies blood-brain barrier breakdown in stroke.  Neuron. 2014 May 7;82(3):603–617. Available from: http://dx​.doi.org/10​.1016/j.neuron.2014.03.003 PMCID: PMC4016169 [PMC free article: PMC4016169] [PubMed: 24746419]
  69. König HG, Kögel D, Rami A, Prehn JHM.  TGF-{beta}1 activates two distinct type I receptors in neurons: implications for neuronal NF-{kappa}B signaling.  J Cell Biol. 2005 Mar 28;168(7):1077–1086. Available from: http://dx​.doi.org/10.1083/jcb.200407027 PMCID: PMC2171851 [PMC free article: PMC2171851] [PubMed: 15781474]
  70. Krueger M, Härtig W, Reichenbach A, Bechmann I, Michalski D.  Blood-brain barrier breakdown after embolic stroke in rats occurs without ultrastructural evidence for disrupting tight junctions.  PLoS ONE.  2013. p. e56419. Available from: http://dx​.doi.org/10​.1371/journal.pone.0056419 [PMC free article: PMC3582567] [PubMed: 23468865]
  71. Kutuzov N, Flyvbjerg H, Lauritzen M.  Contributions of the glycocalyx, endothelium, and extravascular compartment to the blood-brain barrier.  Proc Natl Acad Sci USA. 2018 Oct 2;115(40):E9429–E9438. Available from: http://dx​.doi.org/10​.1073/pnas.1802155115 PMCID: PMC6176561 [PMC free article: PMC6176561] [PubMed: 30217895]
  72. Lai YC, Muscal E, Wells E, Shukla N, Eschbach K, Hyeong Lee K, Kaliakatsos M, Desai N, Wickström R, Viri M, Freri E, Granata T, Nangia S, Dilena R, Brunklaus A, Wainwright MS, Gorman MP, Stredny CM, Asiri A, Hundallah K, Doja A, Payne E, Wirrell E, Koh S, Carpenter JL, Riviello J.  Anakinra usage in febrile infection related epilepsy syndrome: an international cohort.  Ann Clin Transl Neurol. 2020 Dec;7(12):2467–2474. Available from: http://dx​.doi.org/10.1002/acn3.51229 PMCID: PMC7732241 [PMC free article: PMC7732241] [PubMed: 33506622]
  73. Leonoudakis D, Zhao P, Beattie EC.  Rapid tumor necrosis factor alpha-induced exocytosis of glutamate receptor 2-lacking AMPA receptors to extrasynaptic plasma membrane potentiates excitotoxicity.  J Neurosci. 2008 Feb 27;28(9):2119–2130. Available from: http://dx​.doi.org/10​.1523/JNEUROSCI.5159-07.2008 PMCID: PMC6671833 [PMC free article: PMC6671833] [PubMed: 18305246]
  74. Levy N, Milikovsky DZ, Baranauskas G, Vinogradov E, David Y, Ketzef M, Abutbul S, Weissberg I, Kamintsky L, Fleidervish I, Friedman A, Monsonego A. Differential TGF-β signaling in glial subsets underlies IL-6-mediated epileptogenesis in mice. J Immunol. 2015 Aug 15;195(4):1713–1722. Available from: http://dx​.doi.org/10​.4049/jimmunol.1401446 PMID: 26136430 [PubMed: 26136430]
  75. Li YN, Pan R, Qin XJ, Yang WL, Qi Z, Liu W, Liu KJ.  Ischemic neurons activate astrocytes to disrupt endothelial barrier via increasing VEGF expression.  J Neurochem. 2014 Apr;129(1):120–129. Available from: http://dx​.doi.org/10.1111/jnc.12611 PMCID: PMC3965617 [PMC free article: PMC3965617] [PubMed: 24251624]
  76. Lippmann K, Kamintsky L, Kim SY, Lublinsky S, Prager O, Nichtweiss JF, Salar S, Kaufer D, Heinemann U, Friedman A.  Epileptiform activity and spreading depolarization in the blood-brain barrier-disrupted peri-infarct hippocampus are associated with impaired GABAergic inhibition and synaptic plasticity.  J Cereb Blood Flow Metab. 2017 May;37(5):1803–1819. Available from: http://dx​.doi.org/10​.1177/0271678X16652631 PMCID: PMC5435286 [PMC free article: PMC5435286] [PubMed: 27252228]
  77. Liu JYW, Thom M, Catarino CB, Martinian L, Figarella-Branger D, Bartolomei F, Koepp M, Sisodiya SM.  Neuropathology of the blood–brain barrier and pharmaco-resistance in human epilepsy.  Brain. Oxford Academic; 2012 Jun 28;135(10):3115–3133. Available from: https://academic​.oup​.com/brain/article-abstract​/135/10/3115/295213 [PubMed: 22750659]
  78. Loup F, Wieser HG, Yonekawa Y, Aguzzi A, Fritschy JM.  Selective alterations in GABAA receptor subtypes in human temporal lobe epilepsy.  The Journal of Neuroscience.  2000. p. 5401–5419. Available from: http://dx​.doi.org/10​.1523/jneurosci.20-14-05401.2000 [PMC free article: PMC6772330] [PubMed: 10884325]
  79. Lublinsky S, Major S, Kola V, Horst V, Santos E, Platz J, Sakowitz O, Scheel M, Dohmen C, Graf R, Vatter H, Wolf S, Vajkoczy P, Shelef I, Woitzik J, Martus P, Dreier JP, Friedman A.  Early blood-brain barrier dysfunction predicts neurological outcome following aneurysmal subarachnoid hemorrhage.  EBioMedicine. 2019 May;43:460–472. Available from: http://dx​.doi.org/10​.1016/j.ebiom.2019.04.054 PMCID: PMC6558266 [PMC free article: PMC6558266] [PubMed: 31162113]
  80. Maglóczky Z, Freund TF.  Impaired and repaired inhibitory circuits in the epileptic human hippocampus.  Trends Neurosci. 2005 Jun;28(6):334–340. Available from: http://dx​.doi.org/10​.1016/j.tins.2005.04.002 PMID: 15927690 [PubMed: 15927690]
  81. Main BS, Villapol S, Sloley SS, Barton DJ, Parsadanian M, Agbaegbu C, Stefos K, McCann MS, Washington PM, Rodriguez OC, Burns MP.  Apolipoprotein E4 impairs spontaneous blood brain barrier repair following traumatic brain injury.  Mol Neurodegener. 2018 Apr 4;13(1):17. Available from: http://dx​.doi.org/10​.1186/s13024-018-0249-5 PMCID: PMC5885297 [PMC free article: PMC5885297] [PubMed: 29618365]
  82. Makwana M, Jones LL, Cuthill D, Heuer H, Bohatschek M, Hristova M, Friedrichsen S, Ormsby I, Bueringer D, Koppius A, Bauer K, Doetschman T, Raivich G.  Endogenous transforming growth factor beta 1 suppresses inflammation and promotes survival in adult CNS.  J Neurosci. 2007 Oct 17;27(42):11201–11213. Available from: http://dx​.doi.org/10​.1523/JNEUROSCI.2255-07.2007 PMCID: PMC6673043 [PMC free article: PMC6673043] [PubMed: 17942715]
  83. Marchetti L, Engelhardt B. Immune cell trafficking across the blood-brain barrier in the absence and presence of neuroinflammation. Vasc Biol.  2020 Mar 20;2(1):H1–H18. Available from: http://dx​.doi.org/10.1530/VB-19-0033 PMCID: PMC7439848 [PMC free article: PMC7439848] [PubMed: 32923970]
  84. Marchi N, Angelov L, Masaryk T, Fazio V, Granata T, Hernandez N, Hallene K, Diglaw T, Franic L, Najm I, Janigro D.  Seizure-promoting effect of blood-brain barrier disruption.  Epilepsia. Wiley; 2007 Apr;48(4):732–742. Available from: https:​//onlinelibrary​.wiley.com/doi/10.1111/j​.1528-1167.2007.00988.x PMCID: PMC4135474 [PMC free article: PMC4135474] [PubMed: 17319915]
  85. Marchi N, Bazarian JJ, Puvenna V, Janigro M, Ghosh C, Zhong J, Zhu T, Blackman E, Stewart D, Ellis J, Butler R, Janigro D.  Consequences of repeated blood-brain barrier disruption in football players.  PLoS One. 2013 Mar 6;8(3):e56805. Available from: http://dx​.doi.org/10​.1371/journal.pone.0056805 PMCID: PMC3590196 [PMC free article: PMC3590196] [PubMed: 23483891]
  86. Marchi N, Fan Q, Ghosh C, Fazio V, Bertolini F, Betto G, Batra A, Carlton E, Najm I, Granata T, Janigro D.  Antagonism of peripheral inflammation reduces the severity of status epilepticus.  Neurobiol Dis. 2009 Feb;33(2):171–181. Available from: http://dx​.doi.org/10​.1016/j.nbd.2008.10.002 PMCID: PMC3045783 [PMC free article: PMC3045783] [PubMed: 19010416]
  87. Marco P, DeFelipe J.  Altered synaptic circuitry in the human temporal neocortex removed from epileptic patients.  Exp Brain Res. 1997 Mar;114(1):1–10. Available from: http://dx​.doi.org/10.1007/pl00005608 PMID: 9125446 [PubMed: 9125446]
  88. Marco P, Sola RG, Pulido P, Alijarde MT, Sánchez A, Ramón y Cajal S, DeFelipe J. Inhibitory neurons in the human epileptogenic temporal neocortex. An immunocytochemical study. Brain.  1996 Aug;119(Pt 4):1327–1347. Available from: http://dx​.doi.org/10​.1093/brain/119.4.1327 PMID: 8813295 [PubMed: 8813295]
  89. Martinello K, Sciaccaluga M, Morace R, Mascia A, Arcella A, Esposito V, Fucile S. Loss of constitutive functional γ-aminobutyric acid type A-B receptor crosstalk in layer 5 pyramidal neurons of human epileptic temporal cortex. Epilepsia. 2018 Feb;59(2):449–459. Available from: https:​//onlinelibrary​.wiley.com/doi/10.1111/epi.13991 [PubMed: 29283181]
  90. Mathern GW, Babb TL, Leite JP, Pretorius JK, Yeoman KM, Kuhlman PA.  The pathogenic and progressive features of chronic human hippocampal epilepsy.  Epilepsy Research.  1996. p. 151–161. Available from: http://dx​.doi.org/10​.1016/s0920-1211(96)00052-6 [PubMed: 8985697]
  91. Mathern GW, Babb TL, Pretorius JK, Leite JP. Reactive synaptogenesis and neuron densities for neuropeptide Y, somatostatin, and glutamate decarboxylase immunoreactivity in the epileptogenic human fascia dentata. Journal of Neuroscience. Soc Neuroscience; 1995;15(5):3990–4004. Available from: https://www​.jneurosci​.org/content/15/5/3990.short [PMC free article: PMC6578224] [PubMed: 7751960]
  92. McRae PA, Porter BE.  The perineuronal net component of the extracellular matrix in plasticity and epilepsy.  Neurochem Int. 2012 Dec;61(7):963–972. Available from: http://dx​.doi.org/10​.1016/j.neuint.2012.08.007 PMCID: PMC3930202 [PMC free article: PMC3930202] [PubMed: 22954428]
  93. Milikovsky DZ, Ofer J, Senatorov VV Jr, Friedman AR, Prager O, Sheintuch L, Elazari N, Veksler R, Zelig D, Weissberg I, Bar-Klein G, Swissa E, Hanael E, Ben-Arie G, Schefenbauer O, Kamintsky L, Saar-Ashkenazy R, Shelef I, Shamir MH, Goldberg I, Glik A, Benninger F, Kaufer D, Friedman A. Paroxysmal slow cortical activity in Alzheimer’s disease and epilepsy is associated with blood-brain barrier dysfunction. Sci Transl Med.  2019 Dec 4;11(521). Available from: http://dx​.doi.org/10​.1126/scitranslmed.aaw8954 PMID: 31801888 [PubMed: 31801888]
  94. Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, Toga AW, Jacobs RE, Liu CY, Amezcua L, Harrington MG, Chui HC, Law M, Zlokovic BV.  Blood-brain barrier breakdown in the aging human hippocampus.  Neuron. 2015 Jan 21;85(2):296–302. Available from: http://dx​.doi.org/10​.1016/j.neuron.2014.12.032 PMCID: PMC4350773 [PMC free article: PMC4350773] [PubMed: 25611508]
  95. Montagne A, Nikolakopoulou AM, Huuskonen MT. APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer’s mice via cyclophilin A independently of amyloid-β. Nature Aging.  2021;1(6):506–520. Available from: https://www​.nature.com​/articles/s43587-021-00073-z [PMC free article: PMC8920485] [PubMed: 35291561]
  96. Munji RN, Soung AL, Weiner GA, Sohet F, Semple BD, Trivedi A, Gimlin K, Kotoda M, Korai M, Aydin S, Batugal A, Cabangcala AC, Schupp PG, Oldham MC, Hashimoto T, Noble-Haeusslein LJ, Daneman R.  Profiling the mouse brain endothelial transcriptome in health and disease models reveals a core blood-brain barrier dysfunction module.  Nat Neurosci. 2019 Nov;22(11):1892–1902. Available from: http://dx​.doi.org/10​.1038/s41593-019-0497-x PMCID: PMC6858546 [PMC free article: PMC6858546] [PubMed: 31611708]
  97. Nahirney PC, Reeson P, Brown CE.  Ultrastructural analysis of blood–brain barrier breakdown in the peri-infarct zone in young adult and aged mice.  Journal of Cerebral Blood Flow & Metabolism.  2016. p. 413–425. Available from: http://dx​.doi.org/10​.1177/0271678x15608396 [PMC free article: PMC4759675] [PubMed: 26661190]
  98. Nataf S. The demonstration of an Aqp4/Tgf-beta 1 pathway in murine astrocytes holds implications for both neuromyelitis optica and progressive multiple sclerosis. Int J Mol Sci.  2020 Feb 4;21(3):1035. Available from: http://dx​.doi.org/10.3390/ijms21031035 PMCID: PMC7037715 [PMC free article: PMC7037715] [PubMed: 32033173]
  99. Negi N, Das BK.  CNS: Not an immunoprivilaged site anymore but a virtual secondary lymphoid organ.  Int Rev Immunol. 2018 Jan 2;37(1):57–68. Available from: http://dx​.doi.org/10​.1080/08830185.2017.1357719 PMID: 28961037 [PubMed: 28961037]
  100. Nozaki T, Ura H, Takumi I, Kobayashi S, Maru E, Morita A.  The angiotensin II type I receptor antagonist losartan retards amygdala kindling-induced epileptogenesis.  Brain Res. 2018 Sep 1;1694:121–128. Available from: http://dx​.doi.org/10​.1016/j.brainres.2018.05.027 PMID: 29787768 [PubMed: 29787768]
  101. Obermeier B, Daneman R, Ransohoff RM.  Development, maintenance and disruption of the blood-brain barrier.  Nat Med. 2013 Dec;19(12):1584–1596. Available from: http://dx​.doi.org/10.1038/nm.3407 PMCID: PMC4080800 [PMC free article: PMC4080800] [PubMed: 24309662]
  102. Oby E, Janigro D.  The blood-brain barrier and epilepsy.  Epilepsia. 2006 Nov;47(11):1761–1774. Available from: https:​//onlinelibrary​.wiley.com/doi/10.1111/j​.1528-1167.2006.00817.x PMID: 17116015 [PubMed: 17116015]
  103. Ogaki A, Ikegaya Y, Koyama R. Vascular abnormalities and the role of vascular endothelial growth factor in the epileptic brain. Front Pharmacol.  2020 Feb 4;11:20. Available from: http://dx​.doi.org/10​.3389/fphar.2020.00020 PMCID: PMC7010950 [PMC free article: PMC7010950] [PubMed: 32116699]
  104. Paglinawan R, Malipiero U, Schlapbach R, Frei K, Reith W, Fontana A.  TGFbeta directs gene expression of activated microglia to an anti-inflammatory phenotype strongly focusing on chemokine genes and cell migratory genes.  Glia. 2003 Dec;44(3):219–231. Available from: https:​//onlinelibrary​.wiley.com/doi/10.1002/glia.10286 PMID: 14603463 [PubMed: 14603463]
  105. Parker E, Aboghazleh R, Mumby G, Veksler R, Ofer J, Newton J, et al. Concussion susceptibility is associated with spreading depolarization-induced blood-brain barrier dysfunction and transforming growth factor β signaling. Brain.  2021.
  106. Perosa SR, Porcionatto MA, Cukiert A, Martins JRM, Passeroti CC, Amado D, Matas SLA, Nader HB, Cavalheiro EA, Leite JP, Naffah-Mazzacoratti MG.  Glycosaminoglycan levels and proteoglycan expression are altered in the hippocampus of patients with mesial temporal lobe epilepsy.  Brain Res Bull. 2002 Sep 15;58(5):509–516. Available from: http://dx​.doi.org/10​.1016/s0361-9230(02)00822-5 PMID: 12242104 [PubMed: 12242104]
  107. Pijet B, Konopka A, Rejmak E, Stefaniuk M, Khomiak D, Bulska E, Pikul S, Kaczmarek L.  The matrix metalloproteinase inhibitor marimastat inhibits seizures in a model of kainic acid-induced status epilepticus.  Sci Rep. 2020 Dec 4;10(1):21314. Available from: http://dx​.doi.org/10​.1038/s41598-020-78341-y PMCID: PMC7718901 [PMC free article: PMC7718901] [PubMed: 33277582]
  108. Pollock E, Everest M, Brown A, Poulter MO.  Metalloproteinase inhibition prevents inhibitory synapse reorganization and seizure genesis.  Neurobiology of Disease.  2014;70:21–31. Available from: http://dx​.doi.org/10​.1016/j.nbd.2014.06.003 [PubMed: 24946277]
  109. Profaci CP, Munji RN, Pulido RS, Daneman R.  The blood-brain barrier in health and disease: Important unanswered questions.  J Exp Med. 2020 Apr 6;217(4). Available from: http://dx​.doi.org/10.1084/jem.20190062 PMCID: PMC7144528 [PMC free article: PMC7144528] [PubMed: 32211826]
  110. Raabe A, Schmitz AK, Pernhorst K, Grote A, von der Brelie C, Urbach H, Friedman A, Becker AJ, Elger CE, Niehusmann P.  Cliniconeuropathologic correlations show astroglial albumin storage as a common factor in epileptogenic vascular lesions.  Epilepsia. 2012 Mar;53(3):539–548. Available from: http://dx​.doi.org/10​.1111/j.1528-1167.2012.03405.x PMCID: PMC3669690 [PMC free article: PMC3669690] [PubMed: 22372630]
  111. Rabender C, Mezzaroma E, Mauro AG, Mullangi R, Abbate A, Anscher M, Hart B, Mikkelsen R.  IPW-5371 proves effective as a radiation countermeasure by mitigating radiation-induced late effects.  Radiat Res. 2016 Nov;186(5):478–488. Available from: http://dx​.doi.org/10.1667/RR14403.2 PMCID: PMC5278768 [PMC free article: PMC5278768] [PubMed: 27841740]
  112. Ralay Ranaivo H, Hodge JN, Choi N, Wainwright MS.  Albumin induces upregulation of matrix metalloproteinase-9 in astrocytes via MAPK and reactive oxygen species-dependent pathways.  J Neuroinflammation. 2012 Apr 16;9:68. Available from: http://dx​.doi.org/10.1186/1742-2094-9-68 PMCID: PMC3419618 [PMC free article: PMC3419618] [PubMed: 22507553]
  113. Ralay Ranaivo H, Patel F, Wainwright MS.  Albumin activates the canonical TGF receptor-smad signaling pathway but this is not required for activation of astrocytes.  Exp Neurol. 2010 Dec;226(2):310–319. Available from: http://dx​.doi.org/10​.1016/j.expneurol.2010.09.005 PMID: 20854815 [PubMed: 20854815]
  114. Ralay Ranaivo H, Wainwright MS. Albumin activates astrocytes and microglia through mitogen-activated protein kinase pathways. Brain Res.  2010 Feb 8;1313:222–231. Available from: http://dx​.doi.org/10​.1016/j.brainres.2009.11.063 PMCID: PMC2812578 [PMC free article: PMC2812578] [PubMed: 19961838]
  115. Rani R, Smulian AG, Greaves DR, Hogan SP, Herbert DR. TGF-β limits IL-33 production and promotes the resolution of colitis through regulation of macrophage function. Eur J Immunol. 2011 Jul;41(7):2000–2009. Available from: http://dx​.doi.org/10.1002/eji.201041135 PMCID: PMC3139176 [PMC free article: PMC3139176] [PubMed: 21469118]
  116. Rankin-Gee EK, McRae PA, Baranov E, Rogers S, Wandrey L, Porter BE.  Perineuronal net degradation in epilepsy.  Epilepsia. 2015 Jul;56(7):1124–1133. Available from: http://dx​.doi.org/10.1111/epi.13026 PMID: 26032766 [PubMed: 26032766]
  117. Rempe RG, Hartz AMS, Soldner ELB, Sokola BS, Alluri SR, Abner EL, Kryscio RJ, Pekcec A, Schlichtiger J, Bauer B.  Matrix metalloproteinase-mediated blood-brain barrier dysfunction in epilepsy.  J Neurosci. 2018 May 2;38(18):4301–4315. Available from: http://dx​.doi.org/10​.1523/JNEUROSCI.2751-17.2018 PMCID: PMC5932641 [PMC free article: PMC5932641] [PubMed: 29632167]
  118. Robbins RJ, Brines ML, Kim JH, Adrian T, de Lanerolle N, Welsh S, Spencer DD.  A selective loss of somatostatin in the hippocampus of patients with temporal lobe epilepsy.  Ann Neurol. 1991 Mar;29(3):325–332. Available from: http://dx​.doi.org/10.1002/ana.410290316 PMID: 1675046 [PubMed: 1675046]
  119. Rustenhoven J, Aalderink M, Scotter EL, Oldfield RL, Bergin PS, Mee EW, Graham ES, Faull RLM, Curtis MA, Park TIH, Dragunow M. TGF-beta1 regulates human brain pericyte inflammatory processes involved in neurovasculature function. J Neuroinflammation.  2016 Feb 11;13:37. Available from: http://dx​.doi.org/10​.1186/s12974-016-0503-0 PMCID: PMC4751726 [PMC free article: PMC4751726] [PubMed: 26867675]
  120. Rustenhoven J, Jansson D, Smyth LC, Dragunow M.  Brain pericytes as mediators of neuroinflammation.  Trends Pharmacol Sci. 2017 Mar;38(3):291–304. Available from: http://dx​.doi.org/10​.1016/j.tips.2016.12.001 PMID: 28017362 [PubMed: 28017362]
  121. Salar S, Lapilover E, Müller J, Hollnagel JO, Lippmann K, Friedman A, Heinemann U. Synaptic plasticity in area CA1 of rat hippocampal slices following intraventricular application of albumin. Neurobiol Dis.  2016 Jul;91:155–165. Available from: http://dx​.doi.org/10​.1016/j.nbd.2016.03.008 PMID: 26972679 [PubMed: 26972679]
  122. Salehi A, Zhang JH, Obenaus A.  Response of the cerebral vasculature following traumatic brain injury.  J Cereb Blood Flow Metab. 2017 Jul;37(7):2320–2339. Available from: http://dx​.doi.org/10​.1177/0271678X17701460 PMCID: PMC5531360 [PMC free article: PMC5531360] [PubMed: 28378621]
  123. Saunders NR, Dziegielewska KM, Møllgård K, Habgood MD.  Markers for blood-brain barrier integrity: how appropriate is Evans blue in the twenty-first century and what are the alternatives?  Front Neurosci. 2015 Oct 29;9:385. Available from: http://dx​.doi.org/10​.3389/fnins.2015.00385 PMCID: PMC4624851 [PMC free article: PMC4624851] [PubMed: 26578854]
  124. Scharfman HE, Brooks-Kayal AR.  Is plasticity of GABAergic mechanisms relevant to epileptogenesis?  Adv Exp Med Biol.  2014;813:133–150. Available from: http://dx​.doi.org/10​.1007/978-94-017-8914-1_11 PMCID: PMC4370216 [PMC free article: PMC4370216] [PubMed: 25012373]
  125. Schoknecht K, Prager O, Vazana U, Kamintsky L, Harhausen D, Zille M, Figge L, Chassidim Y, Schellenberger E, Kovács R, Heinemann U, Friedman A.  Monitoring stroke progression: In vivo imaging of cortical perfusion, blood-brain barrier permeability and cellular damage in the rat photothrombosis model.  J Cereb Blood Flow Metab. 2014 Nov 1;34(11):1791–1801. Available from: https://doi​.org/10.1038/jcbfm.2014.147 [PMC free article: PMC4269756] [PubMed: 25160672]
  126. Seifert G, Steinhäuser C.  Neuron–astrocyte signaling and epilepsy.  Exp Neurol. 2013 Jun 1;244:4–10. Available from: https://www​.sciencedirect​.com/science/article​/pii/S0014488611003049 [PubMed: 21925173]
  127. Seiffert E, Dreier JP, Ivens S, Bechmann I, Tomkins O, Heinemann U, Friedman A.  Lasting blood-brain barrier disruption induces epileptic focus in the rat somatosensory cortex.  J Neurosci. 2004 Sep 8;24(36):7829–7836. Available from: http://dx​.doi.org/10​.1523/JNEUROSCI.1751-04.2004 PMCID: PMC6729929 [PMC free article: PMC6729929] [PubMed: 15356194]
  128. Senatorov VV, Friedman AR, Milikovsky DZ, Ofer J, Saar-Ashkenazy R, Charbash A, Jahan N, Chin G, Mihaly E, Lin JM, Ramsay HJ, Moghbel A, Preininger MK, Eddings CR, Harrison HV, Patel R, Shen Y, Ghanim H, Sheng H, Veksler R, Sudmant PH, Becker A, Hart B, Rogawski MA, Dillin A, Friedman A, Kaufer D.  Blood-brain barrier dysfunction in aging induces hyper-activation of TGF-beta signaling and chronic yet reversible neural dysfunction.  Sci. Transl. Med. 2019 May 4;11(521):8283. Available from: http://dx​.doi.org/10.1101/537431 [PubMed: 31801886]
  129. Serlin Y, Ofer J, Ben-Arie G, Veksler R, Ifergane G, Shelef I, Minuk J, Horev A, Friedman A.  Blood-brain barrier leakage: A new biomarker in transient ischemic attacks.  Stroke. 2019 May;50(5):1266–1269. Available from: http://dx​.doi.org/10​.1161/STROKEAHA.119.025247 PMID: 31009340 [PubMed: 31009340]
  130. Shi M, Zhu J, Wang R, Chen X, Mi L, Walz T, Springer TA. Latent TGF-β structure and activation. Nature.  2011;474(7351):343–349. Available from: http://dx​.doi.org/10.1038/nature10152 [PMC free article: PMC4717672] [PubMed: 21677751]
  131. Shlosberg D, Benifla M, Kaufer D, Friedman A.  Blood-brain barrier breakdown as a therapeutic target in traumatic brain injury.  Nat Rev Neurol. 2010 Jul;6(7):393–403. Available from: http://dx​.doi.org/10​.1038/nrneurol.2010.74 PMCID: PMC3625732 [PMC free article: PMC3625732] [PubMed: 20551947]
  132. Siddiqui SS, Siddiqui ZK, Malik AB. Albumin endocytosis in endothelial cells induces TGF-β receptor II signaling. American Journal of Physiology-Lung Cellular and Molecular Physiology. American Physiological Society; 2004 May 1;286(5):L1016–L1026. Available from: https://doi​.org/10.1152/ajplung​.00356.2003 [PubMed: 14729511]
  133. Simonato M, Agoston DV, Brooks-Kayal A, Dulla C, Fureman B, Henshall DC, Pitkänen A, Theodore WH, Twyman RE, Kobeissy FH, Wang KK, Whittemore V, Wilcox KS.  Identification of clinically relevant biomarkers of epileptogenesis—a strategic roadmap.  Nature Reviews Neurology.  2021;17(4):231–242. Available from: http://dx​.doi.org/10​.1038/s41582-021-00461-4 [PubMed: 33594276]
  134. Sokrab TEO, Kalimo H, Johansson BB.  Endogenous serum albumin content in brain after short-lasting epileptic seizures.  Brain Research.  1989;489(2):231–236. Available from: http://dx​.doi.org/10​.1016/0006-8993(89)90855-x [PubMed: 2743155]
  135. Sorg BA, Berretta S, Blacktop JM, Fawcett JW, Kitagawa H, Kwok JCF, Miquel M.  Casting a wide net: role of perineuronal nets in neural plasticity.  The Journal of Neuroscience.  2016;36(45):11459–11468. Available from: http://dx​.doi.org/10​.1523/jneurosci.2351-16.2016 [PMC free article: PMC5125213] [PubMed: 27911749]
  136. Stellwagen D, Beattie EC, Seo JY, Malenka RC.  Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha.  J Neurosci. 2005 Mar 23;25(12):3219–3228. Available from: http://dx​.doi.org/10​.1523/JNEUROSCI.4486-04.2005 PMCID: PMC6725093 [PMC free article: PMC6725093] [PubMed: 15788779]
  137. Strohschein S, Hüttmann K, Gabriel S, Binder DK, Heinemann U, Steinhäuser C.  Impact of aquaporin-4 channels on K+ buffering and gap junction coupling in the hippocampus.  Glia.  2011;59(6):973–980. Available from: https:​//onlinelibrary​.wiley.com/doi/abs/10​.1002/glia.21169?casa_token​=hOou_TfG5mcAAAAA​:M9DU8OXBM9O3QW3wG3HciZwgwIMlGPD1Luuu5hITuSisuTQ396rZz1P2-PR7oWHgtNw-frTZ​_t8ojEKk [PubMed: 21446052]
  138. Su ZZ, Leszczyniecka M, Kang DC, Sarkar D, Chao W, Volsky DJ, Fisher PB.  Insights into glutamate transport regulation in human astrocytes: cloning of the promoter for excitatory amino acid transporter 2 (EAAT2).  Proc Natl Acad Sci USA. 2003 Feb 18;100(4):1955–1960. Available from: http://dx​.doi.org/10​.1073/pnas.0136555100 PMCID: PMC149940 [PMC free article: PMC149940] [PubMed: 12578975]
  139. Sweeney MD, Ayyadurai S, Zlokovic BV.  Pericytes of the neurovascular unit: key functions and signaling pathways.  Nat Neurosci. 2016 May 26;19(6):771–783. Available from: http://dx​.doi.org/10.1038/nn.4288 PMCID: PMC5745011 [PMC free article: PMC5745011] [PubMed: 27227366]
  140. Sweeney MD, Sagare AP, Zlokovic BV.  Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders.  Nat Rev Neurol. 2018 Mar;14(3):133–150. Available from: http://dx​.doi.org/10​.1038/nrneurol.2017.188 PMCID: PMC5829048 [PMC free article: PMC5829048] [PubMed: 29377008]
  141. Swissa E, Serlin Y, Vazana U, Prager O, Friedman A.  Blood–brain barrier dysfunction in status epileptics: Mechanisms and role in epileptogenesis.  Epilepsy Behav. 2019 Dec 1;101:106285. Available from: https://www​.sciencedirect​.com/science/article​/pii/S1525505019303336 [PubMed: 31711869]
  142. Tagge CA, Fisher AM, Minaeva OV, Gaudreau-Balderrama A, Moncaster JA, Zhang XL, Wojnarowicz MW, Casey N, Lu H, Kokiko-Cochran ON, Saman S, Ericsson M, Onos KD, Veksler R, Senatorov VV Jr, Kondo A, Zhou XZ, Miry O, Vose LR, Gopaul KR, Upreti C, Nowinski CJ, Cantu RC, Alvarez VE, Hildebrandt AM, Franz ES, Konrad J, Hamilton JA, Hua N, Tripodis Y, Anderson AT, Howell GR, Kaufer D, Hall GF, Lu KP, Ransohoff RM, Cleveland RO, Kowall NW, Stein TD, Lamb BT, Huber BR, Moss WC, Friedman A, Stanton PK, McKee AC, Goldstein LE.  Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model.  Brain. 2018 Feb 1;141(2):422–458. Available from: http://dx​.doi.org/10.1093/brain/awx350 PMCID: PMC5837414 [PMC free article: PMC5837414] [PubMed: 29360998]
  143. Tietz S, Engelhardt B.  Brain barriers: Crosstalk between complex tight junctions and adherens junctions.  J Cell Biol. 2015 May 25;209(4):493–506. Available from: http://dx​.doi.org/10.1083/jcb.201412147 PMCID: PMC4442813 [PMC free article: PMC4442813] [PubMed: 26008742]
  144. Tomkins O, Shelef I, Kaizerman I, Eliushin A, Afawi Z, Misk A, Gidon M, Cohen A, Zumsteg D, Friedman A.  Blood–brain barrier disruption in post-traumatic epilepsy.  J Neurol Neurosurg Psychiatry. 2008 Jul 1;79(7):774–777. Available from: https://jnnp​.bmj.com/content/79/7/774​.short PMID: 17991703 [PubMed: 17991703]
  145. Treiman DM. GABAergic mechanisms in epilepsy. Epilepsia.  2001;42 Suppl 3:8–12. Available from: http://dx​.doi.org/10​.1046/j.1528-1157.2001.042suppl.3008.x PMID: 11520315 [PubMed: 11520315]
  146. Vainchtein ID, Chin G, Cho FS, Kelley KW, Miller JG, Chien EC, Liddelow SA, Nguyen PT, Nakao-Inoue H, Dorman LC, Akil O, Joshita S, Barres BA, Paz JT, Molofsky AB, Molofsky AV.  Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development.  Science. 2018 Mar 16;359(6381):1269–1273. Available from: http://dx​.doi.org/10​.1126/science.aal3589 PMCID: PMC6070131 [PMC free article: PMC6070131] [PubMed: 29420261]
  147. van Vliet EA, Aronica E, Gorter JA.  Role of blood–brain barrier in temporal lobe epilepsy and pharmacoresistance.  Neuroscience. 2014 Sep 26;277:455–473. Available from: https://www​.sciencedirect​.com/science/article​/pii/S0306452214006034 [PubMed: 25080160]
  148. van Vliet EA, da Costa Araújo S, Redeker S, van Schaik R, Aronica E, Gorter JA.  Blood–brain barrier leakage may lead to progression of temporal lobe epilepsy.  Brain. 2006 Nov 22;130(2):521–534. Available from: https://academic​.oup​.com/brain/article-abstract​/130/2/521/285921 [PubMed: 17124188]
  149. Veksler R, Vazana U, Serlin Y, Prager O, Ofer J, Shemen N, Fisher AM, Minaeva O, Hua N, Saar-Ashkenazy R, Benou I, Riklin-Raviv T, Parker E, Mumby G, Kamintsky L, Beyea S, Bowen CV, Shelef I, O’Keeffe E, Campbell M, Kaufer D, Goldstein LE, Friedman A.  Slow blood-to-brain transport underlies enduring barrier dysfunction in American football players.  Brain. 2020 Jun 1;143(6):1826–1842. Available from: http://dx​.doi.org/10.1093/brain/awaa140 PMCID: PMC7297017 [PMC free article: PMC7297017] [PubMed: 32464655]
  150. Vezzani A, Balosso S, Ravizza T.  Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy.  Nat Rev Neurol. 2019 Aug;15(8):459–472. Available from: http://dx​.doi.org/10​.1038/s41582-019-0217-x PMID: 31263255 [PubMed: 31263255]
  151. Vezzani A, Maroso M, Balosso S, Sanchez MA, Bartfai T.  IL-1 receptor/Toll-like receptor signaling in infection, inflammation, stress and neurodegeneration couples hyperexcitability and seizures.  Brain Behav Immun. 2011 Oct;25(7):1281–1289. Available from: http://dx​.doi.org/10​.1016/j.bbi.2011.03.018 PMID: 21473909 [PubMed: 21473909]
  152. Vezzani A, Moneta D, Conti M, Richichi C, Ravizza T, De Luigi A, De Simoni MG, Sperk G, Andell-Jonsson S, Lundkvist J, Iverfeldt K, Bartfai T.  Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice.  Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11534–11539. Available from: http://dx​.doi.org/10.1073/pnas.190206797 PMCID: PMC17235 [PMC free article: PMC17235] [PubMed: 11016948]
  153. Vezzani A, Moneta D, Richichi C, Aliprandi M, Burrows SJ, Ravizza T, Perego C, De Simoni MG.  Functional role of inflammatory cytokines and antiinflammatory molecules in seizures and epileptogenesis.  Epilepsia.  2002;43 Suppl 5:30–35. Available from: http://dx​.doi.org/10​.1046/j.1528-1157.43.s.5.14.x PMID: 12121291 [PubMed: 12121291]
  154. Villringer K, Sanz Cuesta BE, Ostwaldt AC, Grittner U, Brunecker P, Khalil AA, Schindler K, Eisenblätter O, Audebert H, Fiebach JB.  DCE-MRI blood-brain barrier assessment in acute ischemic stroke.  Neurology. 2017 Jan 31;88(5):433–440. Available from: http://dx​.doi.org/10​.1212/WNL.0000000000003566 PMID: 28031392 [PubMed: 28031392]
  155. Wang Y, Fu WY, Cheung K, Hung KW, Chen C, Geng H, Yung WH, Qu JY, Fu AKY, Ip NY.  Astrocyte-secreted IL-33 mediates homeostatic synaptic plasticity in the adult hippocampus.  Proc Natl Acad Sci USA. 2021 Jan 5;118(1):e2020810118. Available from: http://dx​.doi.org/10​.1073/pnas.2020810118 PMCID: PMC7817131 [PMC free article: PMC7817131] [PubMed: 33443211]
  156. Weissberg I, Veksler R, Kamintsky L, Saar-Ashkenazy R, Milikovsky DZ, Shelef I, Friedman A.  Imaging blood-brain barrier dysfunction in football players.  JAMA Neurol. 2014 Nov;71(11):1453–1455. Available from: http://dx​.doi.org/10​.1001/jamaneurol.2014.2682 PMID: 25383774 [PubMed: 25383774]
  157. Weissberg I, Wood L, Kamintsky L, Vazquez O, Milikovsky DZ, Alexander A, Oppenheim H, Ardizzone C, Becker A, Frigerio F, Vezzani A, Buckwalter MS, Huguenard JR, Friedman A, Kaufer D. Albumin induces excitatory synaptogenesis through astrocytic TGF-β/ALK5 signaling in a model of acquired epilepsy following blood–brain barrier dysfunction. Neurobiol Dis. 2015 Jun 1;78:115–125. Available from: https://www​.sciencedirect​.com/science/article​/pii/S0969996115000972 [PMC free article: PMC4426044] [PubMed: 25836421]
  158. Wilhelm S, Tavares AJ, Dai Q, Ohta S, Audet J, Dvorak HF, Chan WCW.  Analysis of nanoparticle delivery to tumours.  Nature Reviews Materials. 2016 Apr 26;1(5):1–12. Available from: https://www​.nature.com​/articles/natrevmats201614
  159. Williamson A, Patrylo PR, Spencer DD.  Decrease in inhibition in dentate granule cells from patients with medial temporal lobe epilepsy.  Ann Neurol. 1999 Jan;45(1):92–99. Available from: <http://dx​.doi.org/10​.1002/1531-8249(199901)45​:192::aid-art153.0.co;2-n> PMID: 9894882 [PubMed: 9894882]
  160. Wrana JL, Attisano L, Wieser R, Ventura F, Massagué J.  Mechanism of activation of the TGF-beta receptor.  Nature. 1994 Aug 4;370(6488):341–347. Available from: http://dx​.doi.org/10.1038/370341a0 PMID: 8047140 [PubMed: 8047140]
  161. Yamazaki Y, Zhao N, Caulfield TR, Liu CC, Bu G.  Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies.  Nat Rev Neurol. 2019 Sep;15(9):501–518. Available from: http://dx​.doi.org/10​.1038/s41582-019-0228-7 PMCID: PMC7055192 [PMC free article: PMC7055192] [PubMed: 31367008]
  162. Yang AC, Stevens MY, Chen MB, Lee DP, Stähli D, Gate D, Contrepois K, Chen W, Iram T, Zhang L, Vest RT, Chaney A, Lehallier B, Olsson N, du Bois H, Hsieh R, Cropper HC, Berdnik D, Li L, Wang EY, Traber GM, Bertozzi CR, Luo J, Snyder MP, Elias JE, Quake SR, James ML, Wyss-Coray T.  Physiological blood-brain transport is impaired with age by a shift in transcytosis.  Nature. 2020 Jul;583(7816):425–430. Available from: http://dx​.doi.org/10​.1038/s41586-020-2453-z PMCID: PMC8331074 [PMC free article: PMC8331074] [PubMed: 32612231]
  163. Yu CY, Gui W, He HY, Wang XS, Zuo J, Huang L, Zhou N, Wang K, Wang Y. Neuronal and astroglial TGFβ-Smad3 signaling pathways differentially regulate dendrite growth and synaptogenesis. Neuromolecular Med. 2014 Jun;16(2):457–472. Available from: http://dx​.doi.org/10​.1007/s12017-014-8293-y PMID: 24519742 [PubMed: 24519742]
  164. Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-β and promotes tumor invasion and angiogenesis. Genes & Development.  2000;14(2):163–176. Available from: http://dx​.doi.org/10.1101/gad.14.2.163 [PMC free article: PMC316345] [PubMed: 10652271]
  165. Zöller T, Schneider A, Kleimeyer C, Masuda T, Potru PS, Pfeifer D, Blank T, Prinz M, Spittau B. Silencing of TGFβ signalling in microglia results in impaired homeostasis. Nat Commun. 2018 Oct 1;9(1):4011. Available from: http://dx​.doi.org/10​.1038/s41467-018-06224-y PMCID: PMC6167353 [PMC free article: PMC6167353] [PubMed: 30275444]
  166. Zucker DK, Wooten GF, Lothman EW.  Blood-brain barrier changes with kainic acid-induced limbic seizures.  Exp Neurol. 1983 Feb;79(2):422–433. Available from: http://dx​.doi.org/10​.1016/0014-4886(83)90223-6 PMID: 6822273 [PubMed: 6822273]
Copyright Notice

This is an open access publication, available online and distributed under the terms of a Creative Commons Attribution-Non Commercial-No Derivatives 4.0 International licence (CC BY-NC-ND 4.0), a copy of which is available at https://creativecommons.org/licenses/by-nc-nd/4.0/. Subject to this license, all rights are reserved.

Bookshelf ID: NBK609893PMID: 39637183DOI: 10.1093/med/9780197549469.003.0028

Views

  • PubReader
  • Print View
  • Cite this Page
  • PDF version of this title (283M)

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...