Mitochondrial dysfunction associated with neuronal death following status epilepticus in rat.
Status epilepticus (SE) in humans and animal models results in significant cerebral damage and an increased risk of subsequent seizures, associated with a characteristic pattern of neuronal loss particularly affecting the hippocampus. Seizure related cell death is considered to be excitotoxic, but studies have been limited, concentrating on terminal events rather than initial mechanisms. We have studied the biochemical events in the first few days following SE. Self-sustaining limbic SE was induced in adult rats using perforant path stimulation, and animals were allowed to recover. Biochemical studies were performed at 16, 44 h and 8 days following SE, using spectrophotometric enzyme assays and HPLC on regional brain homogenates compared with those from sham-operated controls. Haematoxylin and eosin histology was also undertaken at each time point. Brain aconitase and alpha-ketoglutarate dehydrogenase (alphaKDH) activity were both significantly (P<0.05) reduced by approximately 20% in the first 16-44 h following status, but had returned to normal by 8 days. These enzymes are part of the tri-carboxylic acid (Krebbs) cycle in the mitochondrial matrix, and are known to be sensitive to free radical, especially peroxynitrite damage. There was a similar decrease in reduced glutathione levels. Histological studies confirmed evidence of acute neuronal damage up to 44 h, and neuronal loss by 8 days. This is the first in vivo demonstration of this pattern of mitochondrial dysfunction and loss of brain glutathione following SE. The pattern of abnormalities is consistent with reversible mechanisms being involved in excitotoxic cell damage. This, together with the timing of changes, suggests new avenues for therapeutic intervention.
Cock
Hannah R
HR
Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, Queen Square, WC1N 3BG, London, UK. h.cock@ion.ucl.ac.uk
Tong
Xin
X
Hargreaves
Iain P
IP
Heales
Simon J R
SJ
Clark
John B
JB
Patsalos
Phillip N
PN
Thom
Maria
M
Groves
Michael
M
Schapira
Anthony H V
AH
Shorvon
Simon D
SD
Walker
Matthew C
MC
D000818:Animals; D016923:Cell Death / Q000502:physiology; D005978:Glutathione / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000378:metabolism* / Q000473:pathology*
D005978:Glutathione