The PI3K/Akt and ERK1/2 signaling pathways mediate the erythropoietin-modulated calcium influx in kainic acid-induced epilepsy
The PI3K/Akt and ERK1/2 signaling pathways mediate the erythropoietin-modulated calcium influx in kainic acid-induced epilepsy
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DOI：
10.1097/wnr.0b013e32835ffe03
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发表时间：
2013-04
期刊：
影响因子：
1.7
通讯作者：
Honghua Zheng;Xiaojing Wang;Zhen Tang;Wei-hong Zheng;Zhengli Li
中科院分区：
文献类型：
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作者：
Honghua Zheng;Xiaojing Wang;Zhen Tang;Wei-hong Zheng;Zhengli Li
促红细胞生成素（EPO）可抑制癫痫的发生，减轻癫痫反复发作时神经元的损伤，但其神经细胞机制尚不清楚。细胞内钙稳态失调是导致癫痫活动进展的关键致病事件，表明EPO可能通过稳定细胞内钙来抑制癫痫发作。本研究观察了EPO对培养大鼠海马神经元电压门控性Ca ~（2+）内流和红藻氨酸（KA）诱导的大鼠群体锋电位（PS）幅度的影响及其机制。KA注射明显增加海马CA 3区EPO和EPO受体的表达以及穿孔通路刺激引起的PS振幅。侧脑室注射外源性大鼠重组EPO可逆转KA诱导的海马CA 3区PS振幅。同样，大鼠重组EPO预处理减弱KA诱导的培养海马神经元电压门控性钙电流（伊卡）的幅度和密度增加。与此相反，瞬时转染大鼠EPO小干扰RNS（siRNA）进一步增强伊卡的振幅和密度在KA的存在下，而乱序控制siRNA没有效果。此外，EPO激活培养的海马神经元中的PI 3 K和ERK 1/2通路，并且PI 3 K/Akt抑制剂LY 294002和ERK 1/2抑制剂U 0126均至少部分阻断外源性EPO对KA诱导的钙电流的抑制作用。这项研究表明，内源性和外源性EPO减少KA敏感的钙内流和伴随的海马神经元的过度兴奋。结果还表明，PI 3 K/Akt和ERK 1/2信号通路介导的EPO调节KA诱导的癫痫钙内流。
Erythropoietin (EPO) suppresses epileptogenesis and limits the neuronal damage associated with recurrent seizures, but the neurocellular mechanism is unclear. Dysregulation of intracellular calcium homeostasis is a key pathogenic event leading to the progression of epileptic activity, suggesting that EPO may suppress seizures by stabilizing intracellular calcium. In this study, we examined the effects of EPO on voltage-gated Ca2+ influx in cultured rat hippocampal neurons and population spike (PS) amplitude in kainic acid (KA)-induced rats and the mechanisms responsible. KA injection markedly increased EPO and EPO receptor expression and the amplitude of PS in the hippocampal CA3 region, evoked by perforant pathway stimulation. Intracerebroventricular injection of exogenous rat recombinant EPO reversed KA-induced PS amplitude in the hippocampal CA3 region. Similarly, rat recombinant EPO pretreatment attenuates the increased voltage-gated calcium current’s (ICa) amplitude and density induced by KA in cultured hippocampal neurons. In contrast, transient transfection of rat EPO small interfering RNS (siRNA) further enhanced ICa amplitude and density in the presence of KA, whereas a scrambled control siRNA had no effect. Further, EPO activates the PI3K and ERK1/2 pathways in cultured hippocampal neurons, and the PI3K/Akt inhibitor LY294002 and ERK1/2 inhibitor U0126 both blocked, at least in part, the suppressive effect of exogenous EPO on KA-induced calcium currents. This study indicates that both endogenous and exogenous EPO decrease KA-sensitive calcium influx and concomitant hyperexcitability in hippocampal neurons. The results also demonstrate that the PI3K/Akt and ERK1/2 signaling pathways mediate the EPO-modulated calcium influx in KA-induced epilepsy.