Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Apr;28(2):103-120.
doi: 10.1177/1073858420981866. Epub 2020 Dec 21.

Imbalanced Subthreshold Currents Following Sepsis and Chemotherapy: A Shared Mechanism Offering a New Therapeutic Target?

Mark M Rich  1 , Stephen N Housley  2   3 , Paul Nardelli  2 , Randall K Powers  4 , Timothy C Cope  2   3   5
Affiliations

Imbalanced Subthreshold Currents Following Sepsis and Chemotherapy: A Shared Mechanism Offering a New Therapeutic Target?

Mark M Rich et al. Neuroscientist. 2022 Apr.

Abstract

Both sepsis and treatment of cancer with chemotherapy are known to cause neurologic dysfunction. The primary defects seen in both groups of patients are neuropathy and encephalopathy; the underlying mechanisms are poorly understood. Analysis of preclinical models of these disparate conditions reveal similar defects in ion channel function contributing to peripheral neuropathy. The defects in ion channel function extend to the central nervous system where lower motoneurons are affected. In motoneurons the defect involves ion channels responsible for subthreshold currents that convert steady depolarization into repetitive firing. The inability to correctly translate depolarization into steady, repetitive firing has profound effects on motor function, and could be an important contributor to weakness and fatigue experienced by both groups of patients. The possibility that disruption of function, either instead of, or in addition to neurodegeneration, may underlie weakness and fatigue leads to a novel approach to therapy. Activation of serotonin (5HT) receptors in a rat model of sepsis restores the normal balance of subthreshold currents and normal motoneuron firing. If an imbalance of subthreshold currents also occurs in other central nervous system neurons, it could contribute to encephalopathy. We hypothesize that pharmacologically restoring the proper balance of subthreshold currents might provide effective therapy for both neuropathy and encephalopathy in patients recovering from sepsis or treatment with chemotherapy.

Keywords: ICUAW; action potential; chemotherapy; excitability; motoneuron; motor neuron; neuropathy; oxaliplatin; sepsis; subthreshold current.

PubMed Disclaimer

Conflict of interest statement

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Neurological manifestations of sepsis-induced intensive care unit–acquired weakness (ICUAW) and chemotherapy induced neurotoxicity (CIN) with proposed loci of motor dysfunction. Neurological manifestations of CIN and ICUAW are diverse and can be classified by four major dimensions, including cognitive, sensory, autonomic (not shown), and motor/functional. Among the dimensions, motor and functional presentations such as muscle weakness, fatigue, and other behavioral impairments demonstrate the greatest overlap between ICUAW and CIN. Multiple sites of motor dysfunction, for example neuropathy, neuromuscular junction insufficiency, etc. have been proposed to explain both clinical presentations, yet little attention has been paid to the central nervous system component of the motor unit, that is, motoneurons.
Figure 2.
Figure 2.
Disrupted repetitive firing of motoneurons in both sepsis and chronic oxaliplatin-induced neurotoxicity (cOIN). On the left is a cartoon depiction of a single motor unit. Placement of a recording electrode into the motoneuron cell body allows for recordings of the motor unit firing patterns shown on the right. The records show representative instantaneous firing rates (filled black circles: pulses per second [pps]) superimposed on action potentials (colored lines: mV) recorded intracellularly from motoneurons from a control rat (top: gray), a rat 5 weeks after clinically relevant chemotherapy treatment with oxaliplatin (middle: blue) and from a rat 3 days after induction of sepsis by cecal ligation and puncture (bottom: green) in response to matched depolarizing current injection (bottom trace: nA). Note reduced number of action potentials, reduced firing rate and increased variation in firing rate following sepsis and oxaliplatin. For this and all subsequent figures cOIN traces are blue and sepsis traces are green.
Figure 3.
Figure 3.
The functional consequence of impaired rate modulation on motor function. Motor unit recordings of motoneuron action potentials (raster: top) and isometric force generated by the motor unit (the muscle fibers innervated by the individual motoneurons being stimulated, lower trace), from three independent, representative motoneurons (rows) in each experimental group in response to 4, 6, and 8 nA of current injected above rheobase (the minimal current necessary to trigger firing). Firing rates and resultant force were disrupted at all current strengths in chemotherapy and septic motoneurons. The traces at the bottom demonstrate the effect of summing the force generated by the three motor units shown in each group (simulated recruitment of three motor units) across each injected current strength. Summing multiple motor units (in this simulated recruitment analysis) does improve resultant muscle force yet fails to restore the smooth, predictable motor unit output observed in control. Note that increasing motoneuron depolarization provides little to no improvement in motor unit force output, indicating that rate-modulation cannot compensate for the defect in force production.
Figure 4.
Figure 4.
Subthreshold membrane potential oscillations with unaltered action potentials in motoneurons following both sepsis and chemotherapy. Representative intracellular records of membrane potential for control (top: gray), chemotherapy (middle: blue), and septic (bottom: green) motoneurons in response to matched depolarizing current injection. Subthreshold oscillations in membrane potential following sepsis and oxaliplatin are highlighted in left inset with expanded axes. The oscillations precede the generation of action potentials and are absent in control. Right inset shows temporally expanded view of single action potentials (spikes) during repetitive firing. Measured properties included (Vrest: resting membrane potential [mV]; Vthr: voltage threshold for action potential generation [mV]; Vamp: action potential amplitude [mV]; AHPamp: after hyperpolarization amplitude [mV]) and derived (dV/dt: first derivative of action potential voltage [mV/ms]). None of these action potential characteristics were significantly different between septic, oxaliplatin treated, and control motoneurons.
Figure 5.
Figure 5.
Stable repetitive firing depends on the proper balance of Na persistent inward current (NaP) and subthreshold potassium current (Ksthr). Each record (A-F) shows representative instantaneous firing rates (filled black circles: pulses per second [pps], top trace), and action potentials (lines: mV, middle trace) and current injection (nA, lower trace) during a 5-second in vivo intracellular recording from a rat spinal cord motoneuron. (a) A record from a healthy motoneuron. (b) Lowering the persistent inward current NaP/Ksthr ratio in the motoneuron shown in A reproduces impaired repetitive firing observed for septic and chemotherapy motoneurons. Note that with dynamic clamp, current injection is varied, rather than continuous (insets in b, d, and f). (c) A record from a motoneuron in a rat that had been septic for 2 days. The motoneuron fires erratically and cannot sustain repetitive firing throughout the 5-second current injection. (d) Increasing the NaP/Ksthr ratio via dynamic clamp in the motoneuron shown in C normalized repetitive firing. (e) A further record from the same motoneuron 20 minutes after pharmacologic treatment to increase the NaP/Ksthr ratio (3 mg/kg lorcaserin). Motoneuron firing is normalized. (f) Firing of the same motoneuron after lowering the NaP/Ksthr ratio with dynamic clamp, which reversed the effect of lorcaserin. When dynamic clamp is turned off, the effect of lorcaserin treatment is again evident, as firing is rapid and steady throughout the current injection (data not shown). Arrows indicate the path from original motoneuron recording (a and c) through pharmacologic and dynamic clamp tests of impaired repetitive firing’s dependency on NaP/Ksthr ratio.
Figure 6.
Figure 6.
Model of biophysical determinants of impaired motoneuron repetitive firing. Two-dimensional conductance space is constructed from parameters utilized in dynamic clamp experimental study of motoneurons from control and septic rats. Individual neurons are indicated by small outlined, color-coded circles projected onto the conductance space. Two-dimensional ellipsoids enclosing 95% of experimental group data were computed with least-squares elliptical fitting. The magnitude and direction of dynamic clamp manipulations (perturbations) of Na persistent inward current (NaP) and subthreshold potassium current (Ksthr) are indicated along the horizontal and vertical axes respectively. The origin was defined as the mean dynamic clamp manipulation (nS) to NaP (94.2 nS) and Ksthr (−44.7 nS) to restore normal repetitive firing of septic motoneurons (gray neurons). A linear transformation of these two values was applied to all neurons. This provided a simple reorientation of the parameter space, centering normal firing at the origin and allowed easy comparisons with restored firing while preserving the interneuron comparisons. There is a relatively narrow operating range around the origin affording stable repetitive firing (total range of 180 nS for NaP and 120 nS for Ksthr). The plot is subdivided into four quadrants with varying ratios of NaP/Ksthr: <1 (top-left), ~1 (top-right), >1 (bottom right), and ~1 (bottom left). An additional diagonal dotted line is drawn from bottom left to top right indicating the iso-NaP/Ksthr where the balance of currents is normal. Wild type motoneurons in which the ratio of NaP/Ksthr was reduced to mimic sepsis (green) are clustered along a line orthogonal to the iso-NaP/Ksthr and exclusively located in the low NaP/Ksthr quadrant. After pharmacologic restoration of repetitive firing in septic motoneuron, the same dynamic clamp parameters are required to reinduce unstable firing (blue). Note that nearly all of the blue two-dimensional ellipsoid’s area is enclosed in the green ellipsoid, indicating the dependency of unstable repetitive firing on low NaP/Ksthr. Arrows indicate the phase transitions between the three experimental tests indicating ability to induce, correct and reintroduce corrupt repetitive firing. Note that all nS comparisons indicate relative changes induced by dynamic clamp and are not representative of absolute conductances required of healthy motoneurons.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Aaronson NK, Mattioli V, Minton O, Weis J, Johansen C, Dalton SO, and others. 2014. Beyond treatment—psychosocial and behavioural issues in cancer survivorship research and practice. Eur J Cancer Suppl 12:54–64. - PMC - PubMed
    1. Alcindor T, Beauger N. 2011. Oxaliplatin: a review in the era of molecularly targeted therapy. Curr Oncol 18:18. - PMC - PubMed
    1. Alverdy JC, Keskey R, Thewissen R. 2020. Can the cecal ligation and puncture model be repurposed to better inform therapy in human sepsis? Infect Immun 88. - PMC - PubMed
    1. André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, and others. 2004. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer N Engl J Med 350:2343–51. - PubMed
    1. André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, and others. 2009. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 27:3109–16. - PubMed

Publication types