Transient Receptor Potential Ankyrin-1 (TRPA1) Block Protects against Loss of White Matter Function during Ischaemia in the Mouse Optic Nerve.
Transient Receptor Potential Ankyrin-1 (TRPA1) Block Protects against Loss of White Matter Function during Ischaemia in the Mouse Optic Nerve.
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DOI：
10.3390/ph14090909
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发表时间：
2021-09-09
期刊：
影响因子：
--
通讯作者：
Hamilton NB
中科院分区：
文献类型：
--
作者：
Lajoso W;Flower G;Giacco V;Kaul A;La Mache C;Brăban A;Roxas A;Hamilton NB
少突胶质细胞产生髓鞘，髓鞘为轴突提供绝缘并加速神经元传递。在局部缺血的情况下，髓磷脂受损，导致精神和身体残疾。最近的证据表明，缺血期间的少突胶质细胞损伤可由瞬时受体电位锚蛋白-1（TRPA 1）介导，其激活提高细胞内Ca 2+浓度并损伤致密髓鞘。在这里，我们表明，TRPA 1是组成性活跃的少突胶质细胞和视神经，作为特定的TRPA 1拮抗剂，A-967079，减少基础少突胶质细胞Ca 2+浓度和增加的大小的复合动作电位（CAP）。相反，TRPA 1激动剂以A-967079敏感的方式减少视神经CAP的大小。这些结果表明，神经胶质TRPA 1调节神经元的兴奋性，在白色物质在生理以及病理条件下。重要的是，我们发现TRPA 1的抑制可以防止氧和葡萄糖剥夺（OGD）期间CAP的丢失，并改善恢复。TRPA 1阻断在OGD之前、期间或之后应用时是有效的，这表明TRPA 1介导的损伤在缺血和恢复期间都发生，但重要的是，在缺血性损伤后可以进行治疗性干预。这些结果表明，TRPA 1在大脑中具有重要作用，并且其阻断可有效治疗许多白色疾病。
Oligodendrocytes produce myelin, which provides insulation to axons and speeds up neuronal transmission. In ischaemic conditions, myelin is damaged, resulting in mental and physical disabilities. Recent evidence suggests that oligodendrocyte damage during ischaemia can be mediated by Transient Receptor Potential Ankyrin-1 (TRPA1), whose activation raises intracellular Ca2+ concentrations and damages compact myelin. Here, we show that TRPA1 is constitutively active in oligodendrocytes and the optic nerve, as the specific TRPA1 antagonist, A-967079, decreases basal oligodendrocyte Ca2+ concentrations and increases the size of the compound action potential (CAP). Conversely, TRPA1 agonists reduce the size of the optic nerve CAP in an A-967079-sensitive manner. These results indicate that glial TRPA1 regulates neuronal excitability in the white matter under physiological as well as pathological conditions. Importantly, we find that inhibition of TRPA1 prevents loss of CAPs during oxygen and glucose deprivation (OGD) and improves the recovery. TRPA1 block was effective when applied before, during, or after OGD, indicating that the TRPA1-mediated damage is occurring during both ischaemia and recovery, but importantly, that therapeutic intervention is possible after the ischaemic insult. These results indicate that TRPA1 has an important role in the brain, and that its block may be effective in treating many white matter diseases.
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