Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut; Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, Connecticut.
Glia. 2014 Jul;62(7):1162-75. doi: 10.1002/glia.22671. Epub 2014 Apr 17.
Astrogliosis is a prominent feature of many, if not all, pathologies of the brain and spinal cord, yet a detailed understanding of the underlying molecular pathways involved in the transformation from quiescent to reactive astrocyte remains elusive. We investigated the contribution of voltage-gated sodium channels to astrogliosis in an in vitro model of mechanical injury to astrocytes. Previous studies have shown that a scratch injury to astrocytes invokes dual mechanisms of migration and proliferation in these cells. Our results demonstrate that wound closure after mechanical injury, involving both migration and proliferation, is attenuated by pharmacological treatment with tetrodotoxin (TTX) and KB-R7943, at a dose that blocks reverse mode of the Na(+) /Ca(2+) exchanger (NCX), and by knockdown of Nav 1.5 mRNA. We also show that astrocytes display a robust [Ca(2+) ]i transient after mechanical injury and demonstrate that this [Ca(2+) ]i response is also attenuated by TTX, KB-R7943, and Nav 1.5 mRNA knockdown. Our results suggest that Nav 1.5 and NCX are potential targets for modulation of astrogliosis after injury via their effect on [Ca(2+) ]i .
星形胶质细胞增生是大脑和脊髓许多（如果不是全部）病变的一个显著特征，但对于静息星形胶质细胞向反应性星形胶质细胞转化所涉及的潜在分子途径，我们仍知之甚少。我们在体外星形胶质细胞机械损伤模型中研究了电压门控钠通道对星形胶质细胞增生的作用。先前的研究表明，星形胶质细胞划痕损伤会引发这两种细胞的迁移和增殖双重机制。我们的结果表明，药物治疗（TTX 和 KB-R7943）和 Nav 1.5 mRNA 敲低可阻断钠钙交换体（NCX）反向模式，可减弱机械损伤后涉及迁移和增殖的伤口闭合。我们还发现星形胶质细胞在机械损伤后显示出强烈的[Ca(2+) ]i 瞬变，并且表明 TTX、KB-R7943 和 Nav 1.5 mRNA 敲低也可减弱该[Ca(2+) ]i 反应。我们的结果表明，Nav 1.5 和 NCX 可能是通过影响[Ca(2+) ]i 来调节损伤后星形胶质细胞增生的潜在靶点。
