Riluzole is a Promising Pharmacological Inhibitor of Bilirubin-Induced Excitotoxicity in the Ventral Cochlear Nucleus
Riluzole is a Promising Pharmacological Inhibitor of Bilirubin-Induced Excitotoxicity in the Ventral Cochlear Nucleus
复制标题
利鲁唑是一种有前途的胆红素诱导的腹侧耳蜗核兴奋性毒性的药理学抑制剂
DOI：
10.1111/cns.12355
复制
发表时间：
2015-03-01
影响因子：
5.5
通讯作者：
Yin, Shan-Kai
中科院分区：
文献类型：
--
作者：
Han, Guo-Ying;Li, Chun-Yan;Yin, Shan-Kai
背景和目的高胆红素血症引起的胆红素脑病是一种严重的神经系统疾病，多发生在新生儿期。到目前为止，还没有有效的药物治疗。谷氨酸介导的兴奋性毒性可能是胆红素脑病的一个重要因素。因此，抑制谷氨酸过度释放的药物可以保护大脑免受胆红素兴奋性毒性的影响。阿曲唑是一种以其抗组胺功能而闻名的处方药。本研究在对胆红素毒性高度敏感的大鼠耳蜗腹侧核（ventral cochlear nucleus，VNC）中观察利鲁唑（riluzole）对胆红素毒性的抑制作用。以Rhod-2-AM为指示剂的钙离子显像用于研究细胞内钙离子。PI/Hoechst staining.Key resultsIn胆红素的情况下，利鲁唑有效地降低自发兴奋性突触后电流（sEPSC）的频率和抑制神经元放电，但不改变sEPSC和谷氨酸激活电流（I-Glu）的振幅。此外，利鲁唑抑制了阿珠单抗诱导的sEPSC和神经元放电频率的增加。阿珠唑可抑制由AMPA和NMDA受体介导的阿珠宾诱导的细胞内钙升高。此外，利鲁唑显着降低了胆红素诱导的细胞death.Conclusions和implicationsThese数据表明，利鲁唑可以保护神经元在腹侧耳蜗核从胆红素诱导的过度兴奋和兴奋毒性通过减少突触前谷氨酸释放。
Background and purposeBilirubin encephalopathy as a result of hyperbilirubinemia is a devastating neurological disorder that occurs mostly in the neonatal period. To date, no effective drug treatment is available. Glutamate-mediated excitotoxicity is likely an important factor causing bilirubin encephalopathy. Thus, drugs suppressing the overrelease of glutamate may protect the brain against bilirubin excitotoxicity. Riluzole is a prescription drug known for its antiglutamatergic function. This study was conducted in the rat's ventral cochlear nucleus, a structure highly sensitive to bilirubin toxicity, to find whether riluzole can be used to inhibit bilirubin toxicity.Experimental approachElectrophysiology changes were detected by perforated patch clamp technique. Calcium imaging using Rhod-2-AM as an indicator was used to study the intracellular calcium. Cell apoptosis and necrosis were measured by PI/Hoechst staining.Key resultsIn the absence of bilirubin, riluzole effectively decreased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and suppressed neuronal firing but did not change the amplitude of sEPSC and glutamate-activated currents (I-Glu). Moreover, riluzole inhibited bilirubin-induced increases in the frequency of sEPSC and neuronal firing. Riluzole could prevent the bilirubin-induced increase in intracellular calcium, mediated by AMPA and NMDA receptors. Furthermore, riluzole significantly reduced bilirubin-induced cell death.Conclusions and implicationsThese data suggest that riluzole can protect neurons in the ventral cochlear nucleus from bilirubin-induced hyperexcitation and excitotoxicity through reducing presynaptic glutamate release.