JaK/STAT Inhibition to Prevent Post-Traumatic Epileptogenesis
Annual rept. 1 July 2012-30 Jun 2013
KENTUCKY UNIV LEXINGTON
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Traumatic Brain Injury TBI is a well-established inducer of temporal lobe epilepsy TLE, a frequently medically intractable and permanent epilepsy syndrome. Unlike many TLE models, which cause global brain injury that do not replicate the human condition, or other TBI models, which do not induce TLE reliably, the controlled cortical impact CCI model of posttraumatic epilepsy in mice results in localized cell loss, synaptic reorganization, and development of TLE. Abnormalities in inhibitory neurotransmission are important aspects of TLE in several animal models. Under this award, the CCI model was established in all three collaborating laboratories. Specific parameters of injury associated with epileptogenesis were determined. It was determined that upregulation of the JaKSTAT3 pathway in the injured hippocampus occurs after CCI, which could be blocked by post-injury administration of a JaKSTAT3 inhibitor. Blocking JaKSTAT3 activity did not prevent loss of GABA cells in the injured hippocampus. Inhibitory postsynaptic currents in the dentate gyrus ipsilateral to the injury were reduced in frequency weeks after the injury, recapitulating findings in other models in which aspects of epileptogenesis were attenuated by STAT3 inhibition. These results critically establish model parameters and control measurements, and provide the basis for remaining proposed experiments.
- Medicine and Medical Research