Targeting Kv1.3 channels to reduce white matter pathology after traumatic brain injury.
Targeting Kv1.3 channels to reduce white matter pathology after traumatic brain injury.
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DOI：
10.1016/j.expneurol.2016.06.011
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发表时间：
2016-09
影响因子：
5.3
通讯作者：
Phillips LL
中科院分区：
文献类型：
--
作者：
Reeves TM;Trimmer PA;Colley BS;Phillips LL
轴突损伤基本上存在于所有临床显著的创伤性脑损伤（TBI）病例中。虽然迄今为止还没有确定有效的治疗方法，但实验性TBI模型已经显示出使用免疫抑制剂FK 506和环孢菌素-A的有希望的轴突保护，治疗益处归因于钙调磷酸酶抑制或线粒体功能的保护。然而，越来越多的证据表明，这些化合物的神经保护功效也可能涉及直接调节离子通道，特别是Kv1.3。本研究测试了使用氯法齐明（CFZ）阻断Kv1.3通道是否会减轻啮齿动物中TBI诱导的白色病变。损伤后CFZ管理防止抑制复合动作电位（CAP）振幅在成年大鼠胼胝体中线液压冲击TBI后，损伤和治疗效果主要表现在无髓鞘CAP。胼胝体组织提取物中Kv1.3蛋白水平在损伤后显著降低，但CFZ治疗可以防止这种损失。同时，CFZ也减弱了损伤诱导的促炎细胞因子IL 1-β的升高。使用来自P3-5小鼠胼胝体的混合小胶质细胞/星形胶质细胞培养物进一步研究CFZ对胶质功能的影响。培养的胼胝体胶质细胞用脂多糖攻击表现出IL 1-β水平的急剧增加，伴随着小胶质细胞的反应性形态学变化，这两者都被CFZ处理减弱。这些结果支持Kv1.3信号传导在TBI后的白色病理学中的细胞特异性作用，并提出了基于阻断这些通道的治疗方法。这种治疗策略可能对TBI后影响无髓鞘轴突的神经胶质相互作用的正常化特别有效。
Axonal injury is present in essentially all clinically significant cases of traumatic brain injury (TBI). While no effective treatment has been identified to date, experimental TBI models have shown promising axonal protection using immunosuppressants FK506 and Cyclosporine-A, with treatment benefits attributed to calcineurin inhibition or protection of mitochondrial function. However, growing evidence suggests neuroprotective efficacy of these compounds may also involve direct modulation of ion channels, and in particular Kv1.3. The present study tested whether blockade of Kv1.3 channels, using Clofazimine (CFZ), would alleviate TBI-induced white matter pathology in rodents. Postinjury CFZ administration prevented suppression of compound action potential (CAP) amplitude in the corpus callosum of adult rats following midline fluid percussion TBI, with injury and treatment effects primarily expressed in unmyelinated CAPs. Kv1.3 protein levels in callosal tissue extracts were significantly reduced postinjury, but this loss was prevented by CFZ treatment. In parallel, CFZ also attenuated the injury-induced elevation in pro-inflammatory cytokine IL1-β. The effects of CFZ on glial function were further studied using mixed microglia/astrocyte cell cultures derived from P3-5 mouse corpus callosum. Cultures of callosal glia challenged with lipopolysaccharide exhibited a dramatic increase in IL1-β levels, accompanied by reactive morphological changes in microglia, both of which were attenuated by CFZ treatment. These results support a cell specific role for Kv1.3 signaling in white matter pathology after TBI, and suggest a treatment approach based on the blockade of these channels. This therapeutic strategy may be especially efficacious for normalizing neuro-glial interactions affecting unmyelinated axons after TBI.