title: Glutathione depletion, lipid peroxidation and mitochondrial dysfunction are induced by chronic stress in rat brain.
abstract: Damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of neurodegenerative disorders. We have previously demonstrated that chronic stress induced an increase in nitric oxide (NO) production via an expression of inducible NO synthase (iNOS) in brain. Since it has been demonstrated that NO regulates mitochondrial function, we sought to study the susceptibility of the mitochondrial respiratory chain complexes to chronic restrain stress exposure in brain cortex. In adult male rats, stress (immobilization for six hours during 21 days) inhibits the activities of the first complexes of the mitochondrial respiratory chain (inhibition of 69% in complex I-III and of 67% in complex II-III), without affecting complex IV activity, ATP production and oxygen consumption. The mitochondrial marker citrate synthase is not significantly affected by stress after 21 days, indicating that at this time the mitochondrial structure is still intact. Moreover, the administration of the preferred inducible nitric oxide synthase (iNOS) inhibitor aminoguanidine (400 mg/kg i.p. daily from days 7 to 21 of stress) protects against the inhibition of the activity of complexes of the mitochondrial respiratory chain as well as prevents NO(x)(-) accumulation, lipid peroxidation and glutathione depletion induced by stress. These results suggest that a sustained overproduction of NO via iNOS is responsible, at least in part, of the inhibition of mitochondrial respiratory chain caused by stress and that this pathway also accounts for the oxidative stress found in this situation.
authors.affiliation: Dpto. de Farmacología. Facultad de Medicina, Universidad Complutense UCM, Madrid, Spain.
authors.forename: J L
authors.initials: JL
authors.lastname: Madrigal
authors.forename: R
authors.initials: R
authors.lastname: Olivenza
authors.forename: M A
authors.initials: MA
authors.lastname: Moro
authors.forename: I
authors.initials: I
authors.lastname: Lizasoain
authors.forename: P
authors.initials: P
authors.lastname: Lorenzo
authors.forename: J
authors.initials: J
authors.lastname: Rodrigo
authors.forename: J C
authors.initials: JC
authors.lastname: Leza
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism* / Q000503:physiopathology; D002950:Citrate (si)-Synthase / Q000378:metabolism; D042967:Electron Transport Complex I; D042963:Electron Transport Complex II; D014450:Electron Transport Complex III / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D006146:Guanidines / Q000494:pharmacology; D007103:Immobilization; D015227:Lipid Peroxidation / Q000502:physiology*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010088:Oxidoreductases / Q000378:metabolism; D010101:Oxygen Consumption; D051381:Rats; D017208:Rats, Wistar; D013312:Stress, Physiological / Q000378:metabolism* / Q000503:physiopathology; D013385:Succinate Dehydrogenase / Q000378:metabolism
chemical_list: D006146:Guanidines; D009097:Multienzyme Complexes; D009569:Nitric Oxide; D008315:Malondialdehyde; D000255:Adenosine Triphosphate; D010088:Oxidoreductases; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; D009247:NADH, NADPH Oxidoreductases; D003576:Electron Transport Complex IV; D002950:Citrate (si)-Synthase; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III; D005978:Glutathione; C004479:pimagedine