JaK/STAT Inhibition to Prevent Post-Traumatic Epileptogenesis.

摘要

Traumatic Brain Injury (TBI) is a well-established inducer of temporal lobe epilepsy (TLE), a frequently medically intractable epilepsy syndrome. The controlled cortical impact (CCI) model of posttraumatic epilepsy in mice is a well established animal model of TBI that 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 the two collaborating universities. Specific parameters of injury associated with epileptogenesis were determined. It was determined that upregulation of the JaK/STAT pathway in the injured hippocampus occurs after CCI and was associated with changes in GABA(A) receptor (GABAR) subunit changes, which could be blocked by post-injury administration of a JaK/STAT inhibitor, WP1066. Blocking JaK/STAT3 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. Post-injury administration of a JaK/STAT3 inhibitor did not reduce development of post-traumatic epilepsy, and did not significantly improve memory function, but did enhance the motor recovery. These findings support a role for the JaK/STAT pathway in GABAR regulation and suggest the potential of JAK/STAT inhibitors to enhance recovery after TBI.