Neurotox-98 Neuroprotection by Progesterones Through Stimulation of Mitochondrial Gene Expression

Neurotoxic agents or trauma can produce direct brain damage or seizures resulting in neuronal cell death. Recent evidence indicates that the gonadal steroid progesterone greatly attenuates the excitotoxicity that leads to neuronal cell loss. However, surprisingly little is known of the mechanism for this effect. The working hypothesis for the proposed studies is that the ovarian hormone, progesterone, either alone or through its metabolites, can protect or intervene against brain injury and that one mechanism of neuroprotection involves upregulation of mitochondrial genes. The specific hypotheses to be tested are 1. Progesterone per se protects against neuronal death caused by status epilepticus in vivo and by NMDA-induced death of cerebellar granule neurons in vitro. 2. Excitotoxic levels of glutamate down-regulate the expression of mitochondrial genes in vitro and in vivo leading to greater vulnerability to injury. 3. Progesterone up-regulates mitochondrial gene expression, hence increasing the resistance of neurons to excitoxicity. Methods to be used include kainate-induced seizures in intact orovariectomized rats, exposure of primary cultures of cerebellar neurons to NMDA, histological assessment of necrotic and apoptotic cell death, measurements of cytochrome oxidase gene expression, and in vitro measurements of mitochondrial electron transport, respiration, Ca2 transport, and cytochrome-c release. The significance of these studies is that they will provide further evidence that progesterone possesses neuroprotective properties relevant to military-related brain injury and that regulation of mitochondrial gene expression is one mechanism by which the vulnerability of neurons to excitotoxicity can be controlled.