The effects of progesterone and its metabolites on TBI

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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.