Transcriptional Repression Therapeutic Target/Epilepsy

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DESCRIPTION (provided by applicant): Status epilepticus and other injurious stimuli to the CNS like traumatic brain injury trigger a variety of responses in hippocampal neurons. We have recently described an acute transcriptional repression of a broad array of neuron-specific genes which occurs in hippocampal neurons of rats following status epilepticus and traumatic brain injury, prior to the subsequent development of epilepsy in these animals. Chief among these repressed genes are neurotransmitter receptors. Downregulation in expression of these genes persists for 7-10 days following injury, and disrupts hippocampal function. This in turn may contribute to the long term development of epilepsy. In this proposal, we shall determine whether blunting this transcriptional repression of neuron-specific genes will block the long-term pathological outcomes of injury, including epilepsy. Histone deacetylase inhibitors have been developed as transcriptional derepressors, and show promise as anti-cancer drugs. The CENTRAL HYPOTHESIS of this proposal is that arresting injury-induced repression of neurotransmitter receptor gene expression through administration of histone deacetylase inhibitors is a viable therapeutic strategy to block the disease process underlying acquired epilepsies. Research directed at testing our central hypothesis will focus on 2 SPECIFIC AIMS: Specific Aim 1. Assess the effects of transcriptional derepressors on neurotransmitter receptor downregulation in hippocampal dentate granule cells following CNS injury. Specific Aim 2. Determine whether transcriptional derepressors will block one of the primary, long term pathological sequelae of CNS injury: epilepsy. Using a combination of electrophysiological, molecular, and whole animal approaches, the present proposal will directly assess the potential of transcriptional derepressors as novel therapeutic agents in the control of epileptogenesis. Since many such agents are currently approved as cancer drugs and frontline anticonvulsants, positive preliminary data from this proposal has the potential to rapidly move into the clinic, as a viable strategy to block or retard the disease process underlying the development of acquired epilepsies. .