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Originally published online as doi:10.2353/ajpath.2007.070269 on August 16, 2007

Published online before print August 16, 2007
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(American Journal of Pathology. 2007;171:1258-1268.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.070269

Bcl-w Protects Hippocampus during Experimental Status Epilepticus

Brona Murphy*, Mark Dunleavy*, Sachiko Shinoda{dagger}{ddagger}, Clara Schindler{dagger}, Robert Meller{dagger}, Carmen Bellver-Estelles*, Seiji Hatazaki*{ddagger}, Patrick Dicker§, Akitaka Yamamoto{dagger}{ddagger}, Ina Koegel*, Xiangping Chu{dagger}, Weizhen Wang{dagger}, Zhigang Xiong{dagger}, Jochen Prehn*, Roger Simon* and David Henshall*

From the Department of Physiology and Medical Physics* and Molecular and Cellular Therapeutics,§ Royal College of Surgeons in Ireland, Dublin, Ireland; the Robert S. Dow Neurobiology Laboratories,{dagger} Legacy Research, Portland, Oregon; and the Department of Neurosurgery,{ddagger} Mie University School of Medicine, Tsu, Mie, Japan

Experimentally evoked seizures can activate the intrinsic mitochondrial cell death pathway, components of which are modulated in the hippocampus of patients with temporal lobe epilepsy. Bcl-2 family proteins are critical regulators of mitochondrial dysfunction, but their significance in this setting remains primarily untested. Presently, we investigated the mitochondrial pathway and role of anti-apoptotic Bcl-2 proteins using a mouse model of seizure-induced neuronal death. Status epilepticus was evoked in mice by intra-amygdala kainic acid, causing cytochrome c release, processing of caspases 9 and 7, and death of ipsilateral hippocampal pyramidal neurons. Seizures caused a rapid decline in hippocampal Bcl-w levels not seen for either Bcl-2 or Bcl-xl. To test whether endogenous Bcl-w was functionally significant for neuronal survival, we investigated hippocampal injury after seizures in Bcl-w-deficient mice. Seizures induced significantly more hippocampal CA3 neuronal loss and DNA fragmentation in Bcl-w-deficient mice compared with wild-type mice. Quantitative electroencephalography analysis also revealed that Bcl-w-deficient mice display a neurophysiological phenotype whereby there was earlier polyspike seizure onset. Finally, we detected higher levels of Bcl-w in hippocampus from temporal lobe epilepsy patients compared with autopsy controls. These data identify Bcl-w as an endogenous neuroprotectant that may have seizure-suppressive functions.






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Copyright © 2007 by the American Society for Investigative Pathology.