TRPA1 Deficiency is Protective in Cuprizone-Induced Demyelination-A New Target Against Oligodendrocyte Apoptosis

被引:53
作者
Saghy, Eva [1 ,2 ]
Sipos, Eva [3 ]
Acs, Peter [3 ]
Bolcskei, Kata [1 ,2 ]
Pohoczky, Krisztina [1 ,2 ]
Kemeny, Agnes [1 ,5 ]
Sandor, Zoltan [1 ,2 ]
Szoke, Eva [1 ,2 ,4 ]
Setalo, Gyorgy, Jr. [5 ,6 ]
Komoly, Samuel [3 ]
Pinter, Erika [1 ,2 ]
机构
[1] Univ Pecs, Fac Med, Dept Pharmacol & Pharmacotherapy, Pecs, Hungary
[2] Univ Pecs, Szentagothai Res Ctr, Mol Pharmacol Res Grp, Pecs, Hungary
[3] Univ Pecs, Fac Med, Dept Neurol, Pecs, Hungary
[4] MTA PTE Chron Pain Res Grp, Pecs, Hungary
[5] Univ Pecs, Fac Med, Dept Med Biol, Pecs, Hungary
[6] Univ Pecs, Szentagothai Res Ctr, Signal Transduct Res Grp, Pecs, Hungary
关键词
TRPA1; oligodendrocyte; demyelination; cuprizone; MAPK; RECEPTOR POTENTIAL A1; ION-CHANNEL TRPA1; MULTIPLE-SCLEROSIS; MOUSE MODEL; NOCICEPTIVE NEURONS; HYDROGEN-PEROXIDE; CNS DEMYELINATION; GENE-EXPRESSION; BREAST-CANCER; WHITE-MATTER;
D O I
10.1002/glia.23051
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:2166 / 2180
页数:15
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