海马犬尿氨酸代谢失衡在颞叶癫痫中的作用及其机制研究

The effect of kynurenine metabolic dysfunction in central nervous system diseases has recently been recognized as one of the hot topics in life science. Our preliminary study has demonstrated that the metabolic balance between the kynurenine-quinolinic acid pathway and kynurenine-kynurenic acid pathway has been disrupted in the hippocampus of temporal lobe epilepsy (TLE) brain. Based on our previous study, this project proposed a hypothesis that kynurenine-quinolinic acid pathway is over-activated, which produces large amount of toxic metabolites and consequently causes epileptogenesis by increasing the excitability of neurons, on the other hand, the kynurenine-kynurenic acid pathway is inhibited and the neuroprotective metabolite produced by which is therefore diminished. If this hypothesis is proved, we could suppress epileptogenesis by selectively interfering the metabolites and the key enzymes of kynurenine metabolic pathway and therefore prevent and cure epilepsy. In this project, we sought to determine the pathophysiologic effect of kynurenine metabolic dysfunction in TLE and to reveal the cellular and molecular mechanism of how kynurenine metabolic dysfunction regulates epileptogenesis by using the methods of analytical chemistry, pharmacology, molecular biology and electrophysiology in vitro and in vivo. We believe this study would give the perspective in seeking new therapeutic strategy and developing new anti-epileptic drugs.

近年来犬尿氨酸代谢异常在神经系统疾病中的作用已成为生命科学领域的研究热点之一。申请者在前期的预实验中发现颞叶癫痫海马组织中犬尿氨酸沿喹啉酸和犬尿喹啉酸两条分支路径代谢的平衡状态被破坏。本项目在前期的研究基础上提出海马犬尿氨酸沿喹啉酸代谢路径被过度激活，所产生的毒性代谢产物导致神经元兴奋性异常增高引起癫痫发生，并且引起海马结构病理性损伤促进海马异常兴奋性突触环路形成，而犬尿氨酸沿犬尿喹啉酸代谢路径被抑制，生成的具有神经保护作用的代谢产物犬尿喹啉酸减少，其神经保护作用被削弱的新假说。如果该假说得到证实，我们将有望通过选择性干预犬尿氨酸代谢的产物和关键酶使海马犬尿氨酸代谢失衡被有效逆转，达到有效控制癫痫疾病的目的。本项目拟通过分析化学、药理学、分子生物学以及电生理学手段，结合细胞与动物模型，在细胞和分子水平阐明海马犬尿氨酸代谢失衡在颞叶癫痫疾病中的作用和机制，为探寻癫痫药物靶标提供前瞻性的思路。

新近的研究表明犬尿氨酸异常代谢产生的中间代谢产物对中枢神经系统疾病的发生发展产生重要的作用。在本课题研究中，我们发现颞叶癫痫海马组织中犬尿氨酸沿喹啉酸和犬尿喹啉酸两条分支路径代谢的平衡状态被破坏，海马犬尿氨酸沿喹啉酸代谢路径被过度激活，所产生的毒性代谢产物3-羟基犬尿氨酸升高，导致神经元兴奋性异常增高引起癫痫发生，并且引起海马结构病理性损伤促进海马兴奋性增强，而犬尿氨酸沿犬尿喹啉酸代谢路径被抑制，生成的具有神经保护作用的代谢产物犬尿喹啉酸减少，其神经保护作用被削弱。该研究通过分析化学、药理学、分子生物学以及电生理学手段，结合细胞与动物模型，在细胞和分子水平阐明了海马犬尿氨酸代谢失衡在颞叶癫痫疾病中的作用和机制，为寻找癫痫疾病的潜在药物靶点以及探索癫痫疾病全新治疗理念和策略提供前瞻性思路。