Zheng Honghua, Wang Xiaojing, Tang Zhengang, Zheng Weihong, Li Zhengli
Department of Basic Medicine, Medical College, Affiliated Zhongshan Hospital, Xiamen University, Xiamen, Fujian Province, China.
Neuroreport. 2013 Apr 17;24(6):335-41. doi: 10.1097/WNR.0b013e32835ffe03.
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 Ca(2+) 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 (I(Ca)) amplitude and density induced by KA in cultured hippocampal neurons. In contrast, transient transfection of rat EPO small interfering RNS (siRNA) further enhanced I(Ca) 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.
促红细胞生成素（EPO）可抑制癫痫发生，并限制与反复癫痫发作相关的神经元损伤，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，这表明EPO可能通过稳定细胞内钙来抑制癫痫发作。在本研究中，我们研究了EPO对培养的大鼠海马神经元电压门控性Ca（2+）内流以及对海藻酸（KA）诱导的大鼠群体峰电位（PS）幅度的影响及其作用机制。注射KA可显著增加EPO和EPO受体的表达，以及由穿通通路刺激诱发的海马CA3区PS的幅度。脑室内注射外源性大鼠重组EPO可逆转KA诱导的海马CA3区PS幅度。同样，大鼠重组EPO预处理可减弱KA诱导的培养海马神经元电压门控钙电流（I（Ca））幅度和密度的增加。相反，在存在KA的情况下，瞬时转染大鼠EPO小干扰RNA（siRNA）可进一步增强I（Ca）幅度和密度，而乱序对照siRNA则无作用。此外，EPO可激活培养海马神经元中的PI3K和ERK1/2信号通路，PI3K/Akt抑制剂LY294002和ERK1/2抑制剂U0126均至少部分阻断了外源性EPO对KA诱导的钙电流的抑制作用。本研究表明，内源性和外源性EPO均可减少KA敏感的钙内流以及海马神经元随之出现的过度兴奋性。结果还表明，PI3K/Akt和ERK1/2信号通路介导了EPO在KA诱导的癫痫中对钙内流的调节作用。
