星形胶质细胞中腺苷与谷氨酸代谢在中枢神经系统氧中毒发生中的作用研究

Hyperbaric oxygen (HBO) has been widely used in submarine escape, diving operations and illness therapies. But prolonged HBO exposure can result in convulsion, which is a severe threat to the life safty of exposed people, and also limit the increase of diving operation efficiency. By now its pathogenesis remains unclear, and the preventative measures are passive. Metabolic functions of Astrocytes for adenosin (Ado) and glutamate play a key role in the excitability propagation of brain. It could also immediately regulate cerebrovascular activities. Whereas the excitability propagation and cerebrovascular activities are all correlated closely with HBO-induced seizure, astrocytes may have pivotal effects to HBO-induced convulsion. In this project, some advanced technologis, such as simultaneously monitoring electroencephalogram (EEG) and cerebral blood flow (CBF) under hyperbaric condition, microdialysis, siRNA, gene knockout, will be employed to probe the effects of HBO on the metabolic functions of astrocytes for Ado and glutamate, and its relationship with HBO-induced convulsion in vivo and in vitro. The research will also involve the effects of HBO on the function of astrocytes to regulate CBF, and the effects of Ado on HBO-induced CBF increase. The project will elucidate the mechanism of HBO-induced convulsion from a new point of view that prolonged HBO exposure will damage the ability of astrocytes in maintaining homeostasis of brain, which is important for finding new targets and preventive measures to HBO-induced convulsion, further to the safety and efficiency of diving operations, and to promoting the therapeutic effects of HBO.

高压氧在潜艇脱险、潜水作业和疾病治疗中有广泛用途，但持续暴露可引发惊厥，严重威胁着暴露人员的安全，制约了潜水作业的效率。目前尚不完全清楚其发病机制，只能采取被动预防措施。星形胶质细胞对腺苷与谷氨酸的代谢在大脑兴奋性传播的调控中有重要作用，它对脑血管活动也有直接的调节作用，而兴奋性传播和脑血管活动都与氧惊厥发作密切相关，因此星形胶质细胞可能对氧惊厥发作有重要影响。本研究采用高压下脑电与脑血流量联合监测，微透析取样，siRNA技术，动物基因敲除等方法，在整体动物，离体细胞等水平，研究高压氧对星形胶质细胞代谢腺苷与谷氨酸功能的影响及其与氧惊厥发生的相关性，高压氧对星形胶质细胞调节脑血流功能的影响，以及腺苷在高压氧引起脑血流改变中的作用。研究从高压氧损伤星形胶质细胞保持大脑内环境稳定这一新角度探讨该病的机制，寻找新的干预靶点，对发展新的预防措施，提高潜水作业安全性和效率，提升高压氧疗效有重要意义。

高压氧在潜水作业和临床疾病治疗中有着广泛的用途。但机体吸入氧分压过高的气体超过一定时程后会出现毒性反应。当氧分压足够高时，毒性反应在较短时间内即可发生，并以中枢神经系统功能紊乱为主要表现，称为中枢神经系统急性氧中毒，最典型的表现是惊厥大发作，称为“氧惊厥”。氧惊厥发作严重威胁着受暴露人员的安全，制约了潜水作业的效率。目前对于氧惊厥发病机制的认识还十分有限，所能采取的预防措施也较为被动，主要是限制吸氧的压力和时程。深入研究氧惊厥的发病机制，找出与其发病直接相关的关键性因素，对于找到更好的预防措施，具有非常重要的现实意义。.研究表明，星形胶质细胞在癫痫的形成和发展过程中具有非常重要的作用，并且它对腺苷与谷氨酸代谢的调节被认为是中枢神经系统中兴奋性产生与传播的重要环节。本项目通过研究高压氧对星形胶质细胞调控腺苷和谷氨酸代谢的影响，探讨这些影响与氧惊厥发作的相关性，以初步明确星形胶质细胞在氧惊厥发作中的作用，并寻找新的干预靶点和措施。.本项目的研究结果表明，星形胶质细胞可以通过调控腺苷而对氧惊厥发作产生重要影响，同时腺苷与氧惊厥发作具有非常密切的联系，提高腺苷含量或激活腺苷A1受体均可有效预防氧惊厥发作。此外，星形胶质细胞可以通过影响谷氨酸—谷氨酰胺循环而调控突触内谷氨酸的含量，从而对氧惊厥发作产生重要影响。.本项目在国内外首次发现并报道了：① 腺苷对氧惊厥具有较好的预防作用；② 星形胶质细胞可以通过调节脑组织中腺苷和谷氨酸含量而对氧惊厥发作产生重要影响；③ 通过提高脑组织中腺苷含量，激活腺苷A1受体，抑制ADK活性，激活GLT-1等途径可以有效预防氧惊厥发作。.本项目的研究成果为氧惊厥的预防研究开辟了新的方向，也为寻找预防氧惊厥的候选药物奠定了基础。