The effects of progesterone and its metabolites on TBI

目前，临床上还没有有效的治疗创伤性脑损伤的方法。本研究的长期目标是开发这样一种治疗方法，以增强功能的形态和行为恢复。创伤性脑损伤引发一系列戏剧性的生化事件，导致原发性和继发性神经元丧失和功能障碍。其中许多事件，如血脑屏障的破坏、兴奋性毒性、缺血、氧化应激、神经胶质活化和炎症免疫反应，都会导致脑水肿的增加，这通常会严重致残或致命。越来越多的实验证据表明，在实验动物中，黄体酮及其代谢物在提供神经保护和减少脑外伤后脑水肿方面是安全有效的。这些神经类固醇如何在中枢神经系统中发挥特异性作用以增强功能恢复尚不完全清楚，这一知识上的差距限制了我们进行临床试验的兴趣。本研究的重点是扩展我们对黄体酮及其代谢物如何通过控制引起脑水肿和神经元死亡的事件来增强受损神经系统中神经元修复和功能恢复的认识。我们将使用一个脑损伤模型，在啮齿动物的额叶皮层上制造可控的挫伤。然后，我们将测量孕酮、异孕酮和表异孕酮治疗对TBI后行为恢复、细胞因子表达和氧化应激的影响。提出四个项目：(1)确定孕激素相关代谢物异孕酮和表异孕酮是否具有与黄体酮相似的促进脑外伤后神经保护和行为恢复的作用；(2)检测其代谢物在减少损伤后炎症信号方面是否与黄体酮一样有效；(3)探讨黄体酮相关激素是否调节炎症细胞的时空分布；(4)研究减少这些炎症信号是否会导致氧化应激和神经细胞死亡的减少。

At present, there are no clinically effective treatments for traumatic brain injury (TBI). The long-term objective of this research is to develop such a therapy that will enhance morphological and behavioral recovery of function. TBI triggers a cascade of dramatic, biochemical events leading to primary and secondary neuronal loss and dysfunction. Many of these events, such as disruption of the blood brain barrier, excitotoxicity, ischemia, oxidative stress, glial activation and the inflammatory immune response, contribute to an increase in cerebral edema, which is often severely disabling or fatal to patients. There is growing experimental evidence that, in laboratory animals, progesterone and its metabolites are safe and effective in providing neuroprotection and in reducing cerebral edema after TBI. How these neurosteroids act specifically in the central nervous system to enhance recovery of function is not yet completely understood, and this gap in our knowledge limits interest in proceeding to clinical trials. The focus of the proposed research is to extend our knowledge of how progesterone and its metabolites enhance neuronal repair and recovery of function in the damaged nervous system by controlling the events causing cerebral edema and neuronal death. We will use a model of brain injury that creates controlled contusions of the frontal cortex in rodents. We will then measure the effects of progesterone, allopregnanolone and epiallopregnanolone treatments on behavioral recovery, cytokine expression, and oxidative stress following TBI. Four projects are proposed: (1) determines whether the progesterone-related metabolites, allopregnanolone and epiallopregnanolone, have effects similar to progesterone in promoting neuroprotection and behavioral recovery after TBI; (2) examines whether the metabolites are as effective as progesterone in reducing post-injury inflammatory signals; (3) explores whether these progesterone-related hormones modulate the temporal and spatial distribution of inflammatory cells; (4) investigates whether reducing these inflammatory signals results in the decrease of oxidative stress and neural cell death.