Ketogenic diet reduces Smac/Diablo and cytochrome c release and attenuates neuronal death in a mouse model of limbic epilepsy.
The ketogenic diet (KD) is effective in the treatment of refractory epilepsy, yet the molecular mechanisms underlying its antiepileptic effects have not been determined. There is increasing evidence that neuronal cell death induced by seizures via mitochondrial pathway and seizures can lead to mitochondrial release of cytochrome c, and we have shown previously that translocation of Smac/DIABLO into the cytosol play a role in the brain damage in a model of limbic seizure. In the present study, we explored the neuroprotective effect of KD in C57BL/6 mice with seizures induced by kainic acid (KA). Status epilepticus triggered by intra-amygdaloid microinjection of KA lead to neuronal death in the selective ipsilateral CA3 subfield of the hippocampus and mitochondrial release of Smac/DIABLO and cytochrome c. We found that KD significantly decreased neuronal death in the ipsilateral CA3 at 24h after KA-induced seizures. Furthermore, KD reduced Smac/DIABLO and cytochrome c release from mitochondria, attenuated activation of casepase-9 and caspase-3 following seizures. These results demonstrate that the neuroprotective effect of KD against brain injury induced by limbic seizures, at least partially, is associated with inhibition of mitochondrial release of Smac/DIABLO and cytochrome c.
Epilepsy Center, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing 100093, China.
Guoming
G
Luan
Yanxin
Y
Zhao
Feng
F
Zhai
Yin
Y
Chen
Tianfu
T
Li
D020155:3-Hydroxybutyric Acid / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism*; D055423:Diet, Ketogenic / Q000379:methods*; D004195:Disease Models, Animal; D004569:Electroencephalography; D004827:Epilepsy / Q000139:chemically induced / Q000178:diet therapy*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D020287:In Situ Nick-End Labeling; D007608:Kainic Acid / Q000633:toxicity; D008032:Limbic System / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C499605:Diablo protein, mouse; D018690:Excitatory Amino Acid Agonists; D024101:Mitochondrial Proteins; D045304:Cytochromes c; D053148:Caspase 3; D053453:Caspase 9; D007608:Kainic Acid; D020155:3-Hydroxybutyric Acid