Anti-inflammatory effects of the anticonvulsant drug levetiracetam on electrophysiological properties of astroglia are mediated via TGFβ1 regulation
Anti-inflammatory effects of the anticonvulsant drug levetiracetam on electrophysiological properties of astroglia are mediated via TGFβ1 regulation
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DOI：
10.1111/j.1476-5381.2010.01038.x
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发表时间：
2011-01-01
影响因子：
7.3
通讯作者：
Prochnow, Nora
中科院分区：
文献类型：
--
作者：
Stienen, Martin N.;Haghikia, Aiden;Prochnow, Nora
背景与目的星形胶质细胞作为免疫活性因子参与炎症反应以及癫痫和癫痫所致脑损伤的发病机制，近年来已被公认。在临床试验和实践中，左乙拉西坦(Lev)已被证明是一种有效的抗癫痫药物(AED)，用于治疗各种形式的癫痫发作，当作为单一或联合治疗时。关于LEV的作用机制(S)，人们知之甚少。到目前为止，证据表明了一种不同于经典AEDs的作用模式。我们已经证明，LEV在体外恢复了星形细胞炎症模型的功能缝隙连接偶联和基本的细胞膜特性。在实验中，我们使用高比例(30%)激活的小胶质细胞共同培养的新生大鼠星形胶质细胞或用促炎症细胞因子IL-1β处理来激发炎症反应。用全细胞膜片钳方法研究了LEV对星形胶质细胞电生理特性的影响(采用全细胞膜片钳方法)，并用ELISA法研究了LEV对星形胶质细胞分泌转化生长因子β1的影响。KEY RESULTSLEV通过改变内向和外向整流电流使受损的星形胶质细胞膜静息电位恢复，并促进炎症和对照共培养细胞中转化生长因子β1的表达。此外，LEV和转化生长因子β1在炎症性共培养中对星形胶质细胞电压门控电流的产生具有相似的促进作用，而转化生长因子β1抗体可阻止LEV的作用。结论和应用数据表明，LEV可能减少星形胶质细胞功能合胞体内癫痫发作事件引起的兴奋的有害扩散，从而稳定神经元-胶质细胞的相互作用。
BACKGROUND AND PURPOSEThe involvement of astrocytes as immune-competent players in inflammation and the pathogenesis of epilepsy and seizure-induced brain damage has recently been recognized. In clinical trials and practice, levetiracetam (LEV) has proven to be an effective antiepileptic drug (AED) in various forms of epileptic seizures, when applied as mono- or added therapy. Little is known about the mechanism(s) of action of LEV. Evidence so far suggests a mode of action different from that of classical AEDs. We have shown that LEV restored functional gap junction coupling and basic membrane properties in an astrocytic inflammatory model in vitro.EXPERIMENTAL APPROACHHere, we used neonatal rat astrocytes co-cultured with high proportions (30%) of activated microglia or treated with the pro-inflammatory cytokine interleukin-1 beta to provoke inflammatory responses. Effects of LEV (50 mu g center dot mL-1) on electrophysiological properties of astrocytes (by whole cell patch clamp) and on secretion of TGF beta 1 (by elisa) were studied in these co-cultures.KEY RESULTSLEV restored impaired astrocyte membrane resting potentials via modification of inward and outward rectifier currents, and promoted TGF beta 1 expression in inflammatory and control co-cultures. Furthermore, LEV and TGF beta 1 exhibited similar facilitating effects on the generation of astrocyte voltage-gated currents in inflammatory co-cultures and the effects of LEV were prevented by antibody to TGF beta 1.CONCLUSIONS AND IMPLICATIONSOur data suggest that LEV is likely to reduce the harmful spread of excitation elicited by seizure events within the astro-glial functional syncytium, with stabilizing consequences for neuronal-glial interactions.