Depletion of reduced glutathione precedes inactivation of mitochondrial enzymes following limbic status epilepticus in the rat hippocampus.
The time course and critical determinants of mitochondrial dysfunction and oxidative stress following limbic status epilepticus (SE) were investigated in hippocampal sub-regions of an electrical stimulation model in rats, at time points 4-44h after status. Mitochondrial and cytosolic enzyme activities were measured spectrophotometrically, and reduced glutathione (GSH) concentrations by HPLC, and compared to results from sham controls. The earliest change in any sub-region was a fall in GSH, appearing as early as 4h in CA3 (-13%, p<0.05), and persisting at all time points. This was followed by a transient fall in complex I activity (CA3, 16h, -13%, p<0.05), and later changes in aconitase (CA1,-18% and CA3, -22% at 44h, p<0.05). The activity of the cytosolic enzyme glyceraldehyde-3-phosphate-dehydrogenase was unaffected at all time points. It is known that GSH levels are dependent both on redox status, and on the availability of the precursor cysteine, in turn dependent on the cysteine/glutamate antiporter, for which extracellular glutamate concentrations are rate limiting. Both mechanisms are likely to contribute indirectly to GSH depletion following seizures. That a relative deficiency in GSH precedes later changes in the activities of complex I and aconitase in vulnerable hippocampal sub-regions, occurring within a clinically relevant therapeutic time window, suggests that strategies to boost GSH levels and/or otherwise reduce oxidative stress following seizures, deserve further study, both in terms of preventing the biochemical consequences of SE and the neuronal dysfunction and clinical consequences.
Sleven
Hannah
H
Epilepsy Group, Centre for Clinical Neurosciences, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
Gibbs
Julie E
JE
Heales
Simon
S
Thom
Maria
M
Cock
Hannah R
HR
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004558:Electric Stimulation; D004569:Electroencephalography; D005978:Glutathione / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology
D005978:Glutathione