传统观点认为，较高浓度的胆红素方才具有神经兴奋毒性，诱发前庭内侧核（MVN）等为代表的中枢损害。既往临床普遍感受并被我们新近临床研究证实的是，即便轻微胆红素浓度升高，若同时伴有酸中毒则更易发生严重中枢损害，其临床危害巨大但机制不明。酸敏感离子通道（ASICs）广泛分布于中枢神经系统，在酸性环境下被H+激活，介导阳离子内流而增强神经元兴奋性。我们针对新生大鼠MVN神经元的预实验发现，胆红素显著增强ASICs介导的电流强度、诱发神经元过度兴奋和凋亡。为此我们推测，胆红素通过增强ASICs对H+的敏感性，诱导神经元协同兴奋毒性作用。本申报课题将采用分子生物学、电生理、行为学评估等手段，进一步明确：①胆红素对MVN神经元ASICs的调控效应特征；②该调控作用的分子生物学机制；③两者协同毒性的损害特征及拮抗措施。申报课题的完成将有助于解释临床困惑，并提供新生儿高胆红素血症合并酸中毒的针对性治疗方向。

The prevailing view is that bilirubin may induce neuronal excitotoxicity in its high concentration and result in a critical damage of brainstem nucleus, such as medial vestibular nucleus (MVN). Previous clinical observations and our clinical study found that, however, newborns with even a mild increased bilirubin level, once complicated with acidosis, tend to suffer severe brain damage. The underlying mechanism remains unclarified. Acid-sensing ion channels (ASICs) are widely distributed in the central nervous system and activated by H+, which leads to the cation influx and enhancement of neuronal excitability. Our preliminary experiments showed that prolonged exposure bilirubin resulted in a potentiation of currents of ASICs in the MVN neurons, thus dramatically enhancing the neuronal excitability and leading to significant neuron apoptosis. Hereby we propose a hypothesis that bilirubin potentiates the affinity of ASICs to H+ , then induces the critical neural damage by synergistic toxicity. To confirm this hypothesis, we will adopt basic research technology, such as molecular biological, electrophysiological technology and behavior research to investigate the potentiation of ASICs currents, signal pathway and its pathological significance. This project aims to identify: 1) the pharmacological and electrophysiological features of potentiation of ASICs currents in MVN by bilirubin; 2) molecular biological mechanism of modification effects; 3) the characteristics of vestibular neuronal injury and behavior significance induced by the synergistic toxicity of bilirubin and H+. Above all, the project will be helpful to explain clinical confusion and provide some specific treatments to those newborns simultaneous suffering jaundice and acidosis.