title: TRPA1 deficiency is protective in cuprizone-induced demyelination-A new target against oligodendrocyte apoptosis.
abstract: Multiple sclerosis is a chronic inflammatory, demyelinating degenerative disease of the central nervous system. Current treatments target pathological immune responses to counteract the inflammatory processes. However, these drugs do not restrain the long-term progression of clinical disability. For this reason, new therapeutic approaches and identification of novel target molecules are needed to prevent demyelination or promote repair mechanisms. Transient Receptor Potential Ankyrin 1 (TRPA1) is a nonselective cation channel with relatively high Ca2+permeability. Its pathophysiological role in central nervous system disorders has not been elucidated yet. In the present study, we aimed to assess the distribution of TRPA1 in the mouse brain and reveal its regulatory role in the cuprizone-induced demyelination. This toxin-induced model, characterized by oligodendrocyte apoptosis and subsequent primary demyelination, allows us to investigate the nonimmune aspects of multiple sclerosis. We found that TRPA1 is expressed on astrocytes in the mouse central nervous system. Interestingly, TRPA1 deficiency significantly attenuated cuprizone-induced demyelination by reducing the apoptosis of mature oligodendrocytes. Our data suggest that TRPA1 regulates mitogen-activated protein kinase pathways, as well as transcription factor c-Jun and a proapoptotic Bcl-2 family member (Bak) expression resulting in enhanced oligodendrocyte apoptosis. In conclusion, we propose that TRPA1 receptors enhancing the intracellular Ca2+concentration modulate astrocyte functions, and influence the pro or anti-apoptotic pathways in oligodendrocytes. Inhibition of TRPA1 receptors might successfully diminish the degenerative pathology in multiple sclerosis and could be a promising therapeutic target to limit central nervous system damage in demyelinating diseases. GLIA 2016;64:2166-2180.
authors: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary.|Szentágothai Research Center, Molecular Pharmacology Research Group, University of Pécs, Pécs, Hungary.
authors: Éva
authors: É
authors: Sághy
authors: Department of Neurology, Faculty of Medicine, University of Pécs, Pécs, Hungary.
authors: Éva
authors: É
authors: Sipos
authors: Department of Neurology, Faculty of Medicine, University of Pécs, Pécs, Hungary.
authors: Péter
authors: P
authors: Ács
authors: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary.|Szentágothai Research Center, Molecular Pharmacology Research Group, University of Pécs, Pécs, Hungary.
authors: Kata
authors: K
authors: Bölcskei
authors: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary.|Szentágothai Research Center, Molecular Pharmacology Research Group, University of Pécs, Pécs, Hungary.
authors: Krisztina
authors: K
authors: Pohóczky
authors: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary.|Department of Medical Biology, Faculty of Medicine, University of Pécs, Pécs, Hungary.
authors: Ágnes
authors: Á
authors: Kemény
authors: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary.|Szentágothai Research Center, Molecular Pharmacology Research Group, University of Pécs, Pécs, Hungary.
authors: Zoltán
authors: Z
authors: Sándor
authors: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary.|Szentágothai Research Center, Molecular Pharmacology Research Group, University of Pécs, Pécs, Hungary.|MTA-PTE Chronic Pain Research Group, Pécs, Hungary.
authors: Éva
authors: É
authors: Szőke
authors: Department of Medical Biology, Faculty of Medicine, University of Pécs, Pécs, Hungary.|Signal Transduction Research Group, Szentágothai Research Center, University of Pécs, Pécs, Hungary.
authors: György
authors: G
authors: Sétáló
authors: Department of Neurology, Faculty of Medicine, University of Pécs, Pécs, Hungary.
authors: Sámuel
authors: S
authors: Komoly
authors: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary. erika.pinter@aok.pte.hu.|Szentágothai Research Center, Molecular Pharmacology Research Group, University of Pécs, Pécs, Hungary. erika.pinter@aok.pte.hu.
authors: Erika
authors: E
authors: Pintér
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003471:Cuprizone / Q000633:toxicity*; D003711:Demyelinating Diseases / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005911:Gliosis / Q000139:chemically induced / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008996:Monoamine Oxidase Inhibitors / Q000633:toxicity*; D004676:Myelin Basic Protein / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000074025:TRPA1 Cation Channel / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism
chemical_list: C494773:Bak1 protein, mouse; D008996:Monoamine Oxidase Inhibitors; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D000074025:TRPA1 Cation Channel; C475685:Trpa1 protein, mouse; D050998:bcl-2 Homologous Antagonist-Killer Protein; D016222:Fibroblast Growth Factor 2; D003471:Cuprizone
keywords: MAPK; TRPA1; cuprizone; demyelination; oligodendrocyte