Preservation of mitochondrial integrity and energy metabolism during experimental status epilepticus leads to neuronal apoptotic cell death in the hippocampus of the rat.
Status epilepticus results in mitochondrial damage or dysfunction and preferential neuronal cell loss in the hippocampus. Since a critical determinant of the eventual cell death fate resides in intracellular ATP concentration, we investigated whether mitochondrial integrity and level of energy metabolism are related with apoptotic cell death in specific hippocampal neuronal populations. A kainic acid (KA)-induced experimental temporal lobe status epilepticus model was used. Qualitative and quantitative analysis of DNA fragmentation, TUNEL immunohistochemistry, double immunofluorescence staining for activated caspase-3, electron microscopy or measurement of ATP level in the bilateral hippocampus was carried out 1, 3 or 7 days after microinjection unilaterally of a low dose of KA (0.5 nmol) into the CA3 hippocampal subfield. Characteristic biochemical (DNA fragmentation), histochemical (TUNEL or activated caspase-3 staining) or ultrastructural (electron microscopy) features of apoptotic cell death were presented bilaterally in the hippocampus 7 days after the elicitation of sustained hippocampal seizure activity by microinjection of KA into the unilateral CA3 subfield. At the same time, CA3 or CA1 subfield on either side manifested a maintained ATP level; alongside relatively intact mitochondria, rough endoplasmic reticulum, Golgi apparatus or cytoplasmic membrane in hippocampal neurons that exhibited ultrastructural features of apoptotic cell death. Our results demonstrated that preserved mitochondrial ultrastructural integrity and maintained energy metabolism during experimental temporal lobe status epilepticus is associated specifically with apoptotic, not necrotic, cell death in hippocampal CA3 or CA1 neurons.
Chuang
Yao-Chung
YC
Department of Neurology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan. ycchuang@adm.cgmh.org.tw
Lin
Jui-Wei
JW
Chen
Shang-Der
SD
Lin
Tsu-Kung
TK
Liou
Chia-Wei
CW
Lu
Cheng-Hsien
CH
Chang
Wen-Neng
WN
D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000502:physiology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D020287:In Situ Nick-End Labeling / Q000379:methods; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008928:Mitochondria / Q000473:pathology* / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors
D018690:Excitatory Amino Acid Agonists; D000255:Adenosine Triphosphate; D053148:Caspase 3; D010751:Phosphopyruvate Hydratase; D007608:Kainic Acid