外源线粒体减轻谷氨酸诱导神经元损伤的作用及生化机制

Role and biochemical mechanism of exogenous mitochondria in alleviating glutamate-induced neuronal damage

摘要:

脑内过高的兴奋性神经递质谷氨酸与多种神经系统疾病密切相关，包括神经退行性疾病、神经精神疾病、癫痫等。调节谷氨酸浓度并抑制其所致的细胞死亡是减轻神经元兴奋性损伤的必要手段。为了研究线粒体移植能否代谢过量的谷氨酸，降低其神经兴奋性毒性，本研究在实验室前期的工作基础上，通过线粒体移植治疗的方式，利用分离的肝脏线粒体降低谷氨酸水平，同时升高细胞外ATP含量，快速抑制谷氨酸造成的HT22神经元损伤；线粒体持续作用于HT22细胞5 h后，仍然能够降低细胞的氧化应激水平，抑制细胞凋亡，同时提高神经元的代谢功能。在谷氨酸局部注射造成的前额叶皮层损伤的小鼠中，给予外源线粒体可修复神经元损伤，改善动物在旷场实验中的异常症状。本研究揭示了移植的线粒体在细胞外和细胞内均具有一定的药效活性，为神经元兴奋性损伤疾病的治疗提供了新的思路。

Abstract:

The excessive concentration of glutamate in the brain is closely related to various neurological diseases, including neurodegenerative diseases, neuropsychiatric diseases, and epilepsy. It is a necessary approach to alleviate neuronal excitatory injury by regulating the glutamate concentration and inhibiting glutamate-induced cell death. To investigate whether mitochondrial transplantation could metabolize excessive glutamate, thereby reducing its neuronal excitatory injury, on the basis of previous research of our laboratory, this study used isolated liver mitochondria to reduce the glutamate level and increase the extracellular ATP content through the mitochondrial transplantation therapy, thereby rapidly inhibiting HT22 neuronal damage caused by glutamate. After the mitochondria kept acting on HT22 cells for 5 h, they could still reduce cellular oxidative stress levels, inhibit cell apoptosis, and improve the neuronal metabolic function. In the mouse model with prefrontal cortex injury caused by local injection of glutamate, the transplanted mitochondria repaired neuronal damage and alleviated abnormal symptoms in the open field test. In summary, this study reveals that transplanted mitochondria have pharmacological activity both in vitro and in vivo, providing a new idea for the treatment for neuronal excitatory injury-related diseases.