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. 2023 May 30;12(11):1511.
doi: 10.3390/cells12111511.

Neuropathic-like Nociception and Spinal Cord Neuroinflammation Are Dependent on the TRPA1 Channel in Multiple Sclerosis Models in Mice

Diéssica Padilha Dalenogare  1 , Daniel Souza Monteiro de Araújo  2 , Lorenzo Landini  2 , Mustafa Titiz  2 , Gaetano De Siena  2 , Francesco De Logu  2 , Pierangelo Geppetti  2 , Romina Nassini  2 , Gabriela Trevisan  1
Affiliations

Neuropathic-like Nociception and Spinal Cord Neuroinflammation Are Dependent on the TRPA1 Channel in Multiple Sclerosis Models in Mice

Diéssica Padilha Dalenogare et al. Cells. .

Abstract

Background: Transient receptor potential ankyrin 1 (TRPA1) activation is implicated in neuropathic pain-like symptoms. However, whether TRPA1 is solely implicated in pain-signaling or contributes to neuroinflammation in multiple sclerosis (MS) is unknown. Here, we evaluated the TRPA1 role in neuroinflammation underlying pain-like symptoms using two different models of MS. Methods: Using a myelin antigen, Trpa1+/+ or Trpa1-/- female mice developed relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE) (Quil A as adjuvant) or progressive experimental autoimmune encephalomyelitis (PMS)-EAE (complete Freund's adjuvant). The locomotor performance, clinical scores, mechanical/cold allodynia, and neuroinflammatory MS markers were evaluated. Results: Mechanical and cold allodynia detected in RR-EAE, or PMS-EAE Trpa1+/+ mice, were not observed in Trpa1-/- mice. The increased number of cells labeled for ionized calcium-binding adapter molecule 1 (Iba1) or glial fibrillary acidic protein (GFAP), two neuroinflammatory markers in the spinal cord observed in both RR-EAE or PMS-EAE Trpa1+/+ mice, was reduced in Trpa1-/- mice. By Olig2 marker and luxol fast blue staining, prevention of the demyelinating process in Trpa1-/- induced mice was also detected. Conclusions: Present results indicate that the proalgesic role of TRPA1 in EAE mouse models is primarily mediated by its ability to promote spinal neuroinflammation and further strengthen the channel inhibition to treat neuropathic pain in MS.

Keywords: allodynia; astrocyte; microglia; neuroinflammation; oligodendrocyte; pain.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
TRPA1 genetic deletion prevents the development of mechanical and cold allodynia in relapsing–remitting experimental autoimmune encephalomyelitis (RR–EAE) mouse model. Evaluation of (A) mechanical allodynia, (B) cold allodynia, (C) body weight, and (D) latency to fall in the rotarod test. Data are mean + SEM (n = 6) for (A–D). (B) for baseline valued before RR-EAE induction. * p < 0.05, when compared to Control Trpa1+/+ vs. RR-EAE Trpa1+/+; and # p < 0.05 when compared to PMS-EAE Trpa1+/+ vs. RR-EAE Trpa1−/− [Two-way ANOVA, followed by Bonferroni’s post hoc test].
Figure 2
Figure 2
TRPA1 genetic deletion prevents the development of mechanical and cold allodynia in the progressive experimental autoimmune encephalomyelitis (PMS–EAE) mouse model. Evaluation of (A) mechanical allodynia, (B) cold allodynia, (C) body weight, and (D) latency to fall in the rotarod test. Data are mean + SEM (n = 6) for (A–D). (B) for baseline valued before PMS-EAE induction. * p < 0.05, when compared to Control Trpa1+/+ vs. progressive PMS-EAE Trpa1+/+; and # p < 0.05 when compared to PMS-EAE Trpa1+/+ vs. PMS-EAE Trpa1−/− [Two-way ANOVA, followed by Bonferroni’s post hoc test].
Figure 3
Figure 3
Iba1 (ionized calcium-binding adapter molecule 1) marker level was reduced in the spinal cord of Trpa1−/− mice induced to relapsing–remitting (RR–EAE) or progressive experimental autoimmune encephalomyelitis (PMS–EAE). (A) Representative photomicrographs of spinal cord area for Trpa1+/+ or Trpa1−/− after 35 days of the RR-EAE induction, cumulative data of Iba1+ve cells in (B) total spinal cord, and (C) dorsal horn. (D) Representative photomicrographs of spinal cord area for Trpa1+/+ or Trpa1−/− after 14 days of the PMS-EAE induction, cumulative data of Iba1+ve cells in the (E) total spinal cord, and (F) dorsal horn. Data are mean + SEM (n = 4) for Graphs (A–F). * p < 0.05, when compared to Control Trpa1+/+ vs. RR-EAE or PMS-EAE Trpa1+/+; and # p < 0.05 when compared to RR-EAE or PMS-EAE Trpa1+/+ g vs. PMS-EAE Trpa1−/− [One-way ANOVA, followed by Bonferroni’s post hoc test].
Figure 4
Figure 4
The astrocyte marker (GFAP, glial fibrillary acidic protein) was reduced in the spinal cord of Trpa1−/− mice induced to relapsing–remitting (RR–EAE) or progressive experimental autoimmune encephalomyelitis (PMS–EAE). (A) Representative photomicrographs of spinal cord area for Trpa1+/+ or Trpa1−/− after RR-EAE, (B) cumulative data of GFAP+ve cells in the total spinal cord, and (C) dorsal horn. (D) Representative photomicrographs of spinal cord area for Trpa1+/+ or Trpa1−/− after PMS-EAE, (E) GFAP+ve cells in the spinal cord, and (F) dorsal horn. Data are mean + SEM (n = 4) for Graphs (A–F). * p < 0.05, when compared to Control Trpa1+/+ vs. RR-EAE or PMS-EAE Trpa1+/+; and # p < 0.05 when compared to RR-EAE or PMS-EAE Trpa1+/+ vs. PMS-EAE Trpa1−/− [One-way ANOVA, followed by Bonferroni’s post hoc test].
Figure 5
Figure 5
TRPA1 deletion prevents the demyelinating process, but not clinical signs, after relapsing–remitting (RR–EAE) or progressive experimental autoimmune encephalomyelitis (PMS–EAE) induction. (A) Clinical scores in RR-EAE mice; (B) Clinical scores in PMS-EAE mice; (C) representative photomicrographs of luxol fast blue staining for RR-EAE; (D) representative photomicrographs of luxol fast blue staining for PMS-EAE; (E) Luxol fast blue staining for RR-EAE; and (F) Luxol fast blue staining for PMS-EAE. Data are mean for Graphs (A,B) and + SEM (n = 6) and Graphs (E,F) (n = 4). * p < 0.05, when compared to Control Trpa1+/+ vs. RR-EAE or PMS-EAE Trpa1+/+; and # p < 0.05, ## p < 0.01, when compared to RR-EAE or PMS-EAE Trpa1+/+ vs. PMS-EAE Trpa1−/− [One-way ANOVA, followed by Bonferroni’s post hoc test].
Figure 6
Figure 6
TRPA1 knockout mice showed prevention of demyelinating process after relapsing–remitting (RR–EAE) or progressive experimental autoimmune encephalomyelitis (PMS–EAE) induction. (A) Representative photomicrographs of Olig2 in the spinal cord area for Trpa1+/+ or Trpa1−/− after RR-EAE, cumulative data of Olig2+ cells in (B) total spinal cord, (C) dorsal horn. (D) Representative photomicrographs of the spinal cord for Trpa1+/+ or Trpa1−/− after PMS-EAE, cumulative data of Olig2+ cells in (E) the total spinal cord, and (F) dorsal horn. Data are mean + SEM (n = 4) for Graphs (A–F). * p < 0.05, when compared to Control Trpa1+/+ vs. RR-EAE or PMS-EAE Trpa1+/+; and # p < 0.05 when compared to RR-EAE or PMS-EAE Trpa1+/+ vs. PMS-EAE Trpa1−/− [One-way ANOVA, followed by Bonferroni’s post hoc test].
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