Global cerebral ischemia, as experienced during stroke or cardiac arrest, continues to be a major killer in the US and those who survive the acute attack experience many neurological deficits. Currently, there are no therapies to prevent neurological damage from cardiac arrest or stroke. One of the major obstacles for developing effective treatments is the lack of understanding how and why neurons die when deprived of oxygen. Excitotoxicity, excessive release of glutamate in the CMS, is a pathophysiological event that occurs during ischemia and is thought to be a major culprit in cell death. However, therapies using glutamate receptor antagonists to block excitotoxicity result in many detrimental side effects in humans. Alternatively, increasing the level of inhibitory tone may prevent excitotoxicity. Studies using GABA receptor agonists to block excitotoxicity have yielded inconsistent results, resulting in a loss of interest in GABA activating compounds as therapeutic agents. A possible explanation for these findings was unveiled in more recent studies which show that GABAA receptor protein is decreased following ischemia, possibly decreasing the effectiveness of GABA potentiating drugs. Our lab has been able to reaffirm these findings in Purkinje cells in culture, which receive robust excitatory and inhibitory drive and are particularly susceptible to ischemia. Using electrophysiological recordings to asses the functional activity of GABAA receptors, coupled with molecular biology and histology techniques, I plan to characterize the functional decline in GABAA receptor activity following ischemia and determine the mechanism of neuroprotection granted by the neurosteroid allopregnanolone. ? ? ? ?
| Kelley, Melissa H; Ortiz, Justin; Shimizu, Kaori et al. (2013) Alterations in Purkinje cell GABAA receptor pharmacology following oxygen and glucose deprivation and cerebral ischemia reveal novel contribution of ?1 -subunit-containing receptors. Eur J Neurosci 37:555-63 |
| Kelley, Melissa H; Kuroiwa, Masayuki; Taguchi, Noriko et al. (2011) Sex difference in sensitivity to allopregnanolone neuroprotection in mice correlates with effect on spontaneous inhibitory post synaptic currents. Neuropharmacology 61:724-9 |
