Bcl-w protects hippocampus during experimental status epilepticus.
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.
Murphy
Brona
B
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
Dunleavy
Mark
M
Shinoda
Sachiko
S
Schindler
Clara
C
Meller
Robert
R
Bellver-Estelles
Carmen
C
Hatazaki
Seiji
S
Dicker
Patrick
P
Yamamoto
Akitaka
A
Koegel
Ina
I
Chu
Xiangping
X
Wang
Weizhen
W
Xiong
Zhigang
Z
Prehn
Jochen
J
Simon
Roger
R
Henshall
David
D
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D053179:Caspase 7 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation; D004569:Electroencephalography; D004594:Electrophysiology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D007608:Kainic Acid / Q000633:toxicity; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012640:Seizures / Q000378:metabolism / Q000473:pathology; D013226:Status Epilepticus / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; C491073:BCL2L2 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C101155:Bcl2l2 protein, mouse; D008565:Membrane Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D005680:gamma-Aminobutyric Acid; D045304:Cytochromes c; D053179:Caspase 7; D053453:Caspase 9; D007608:Kainic Acid
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