Living in an oxygenated environment has required the evolution of effective cellular strategies to detect and detoxify metabolites of molecular oxygen known as reactive oxygen species. Here we review evidence that the appropriate and inappropriate production of oxidants, together with the ability of organisms to respond to oxidative stress, is intricately connected to ageing and life span.

Oxidants, oxidative stress and the biology of ageing.

Parkinson's disease: Mechanisms and models

The cause of Parkinson's disease (PD) is unknown, but epidemiological studies suggest an association with pesticides and other environmental toxins, and biochemical studies implicate a systemic defect in mitochondrial complex I. We report that chronic, systemic inhibition of complex I by the lipophilic pesticide, rotenone, causes highly selective nigrostriatal dopaminergic degeneration that is associated behaviorally with hypokinesia and rigidity. Nigral neurons in rotenone-treated rats accumulate fibrillar cytoplasmic inclusions that contain ubiquitin and alpha-synuclein. These results indicate that chronic exposure to a common pesticide can reproduce the anatomical, neurochemical, behavioral and neuropathological features of PD.

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Chronic systemic pesticide exposure reproduces features of Parkinson's disease

Oxidative stress hypothesis in alzheimer's disease

The etiology of neurodegenerative diseases remains enigmatic; however, evidence for defects in energy metabolism, excitotoxicity, and for oxidative damage is increasingly compelling. It is likely that there is a complex interplay between these mechanisms. A defect in energy metabolism may lead to neuronal depolarization, activation of N-methyl-D-aspartate excitatory amino acid receptors, and increases in intracellular calcium, which are buffered by mitochondria. Mitochondria are the major intracellular source of free radicals, and increased mitochondrial calcium concentrations enhance free radical generation. Mitochondrial DNA is particularly susceptible to oxidative stress, and there is evidence of age-dependent damage and deterioration of respiratory enzyme activities with normal aging. This may contribute to the delayed onset and age dependence of neurodegenerative diseases. There is evidence for increased oxidative damage to macromolecules in amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and Alzheimer's disease. Potential therapeutic approaches include glutamate release inhibitors, excitatory amino acid antagonists, strategies to improve mitochondrial function, free radical scavengers, and trophic factors. All of these approaches appear promising in experimental studies and are now being applied to human studies.

Aging, energy, and oxidative stress in neurodegenerative diseases.

Idiopathic Parkinson's disease may have a low-level familial association but does not follow mendelian patterns of inheritance Since inheritance of some components of the electron transport chain is nonmendelian and since inhibition of the electron transport chain with the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine models Parkinson's disease in humans and animals, we evaluated catalytic activities of the electron transport chain in platelet mitochondria purified from patients with idiopathic Parkinson's disease All 10 patients studied had significant reductions of complex I (NADH:ubiquinone oxidoreductase) activity Succinate:cytochrome c oxidoreductase activity was less strikingly reduced We hypothesize that the complex I abnormality may have an etiological role in the pathogenesis of Parkinson's disease and that this defect may be derived via the mitochondrial genome

Abnormalities of the electron transport chain in idiopathic parkinson's disease

Previous work suggested a deficiency in the terminal complex of the mitochondrial electron transport chain, cytochrome c oxidase (COX), in platelet mitochondria of Alzheimer's disease (AD) patients. The present study extends this observation to AD brain mitochondria through assay of electron transport chain activities in mitochondria isolated from autopsied brain samples from AD patients (n = 9) and from controls with and without known neurologic disease (n = 8). AD brain mitochondria demonstrated a generalized depression of activity of all electron transport chain complexes. This depression was most marked in COX activity (p < 0.001). Concentrations of cytochromes b, c1, and aa3 were similar in AD and controls. The electron transport chain is defective in AD brain, and the defect centers about COX.

Electron transport chain defects in Alzheimer's disease brain

We evaluated electron transport chain activity in platelet mitochondria taken from HD patients All 5 patients studied had striking depressions of NADH: ubiquinone oxidoreductase activity (complex I) (536 ± 291 nmol/min/mg; control mean, 1912 ± 564 nmol/min/mg) Other electron transport chain activities were not significantly different from control values HD may be caused by a mutation in 1 of the nuclear coded subunits of NADH: ubiquinone oxidoreductase

Evidence for a defect in NADH ubiquinone oxidoreductase (complex I) in Huntington's disease

Neuroleptic medications are prescribed to millions of patients, but their use is limited by potentially irreversible extrapyramidal side effects. Haloperidol shows striking structural similarities to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which produces parkinsonism apparently through inhibition of NADH:ubiquinone oxidoreductase (complex I) of the mitochondrial electron transport chain. We now report that haloperidol, chlorpromazine, and thiothixene inhibit complex I in vitro in rat brain mitochondria. Clozapine, an atypical antipsychotic reported to have little or no extrapyramidal toxicity, also inhibits complex I, but at a significantly higher concentration. Neuroleptic treated patients have significant depression of platelet complex I activity similar to that seen in idiopathic Parkinson's disease. Complex I inhibition may be associated with the extrapyramidal side effects of these drugs.

Neuroleptic medications inhibit complex I of the electron transport chain.

We evaluated a simplified method for preparation and analysis of platelet cytochrome c oxidase activity in Alzheimer's disease (AD) and control patients. Mean cytochrome c oxidase activity in controls (n = 17) was 0.233 sec-1/mg whereas mean cytochrome c oxidase activity in Alzheimer patients (n = 19) was 0.193 sec-1/mg, p = 0.033. Complex III (ubiquinol:cytochrome c oxidoreductase), complex II (succinic dehydrogenase), and citrate synthase were all assayed as internal controls and were not significantly different in controls and Alzheimer patients. There is a relatively specific loss of platelet cytochrome c oxidase activity in Alzheimer disease patients.

W. D. Parker

Papers

Abnormalities of the electron transport chain in idiopathic parkinson's disease

Electron transport chain defects in Alzheimer's disease brain

Evidence for a defect in NADH ubiquinone oxidoreductase (complex I) in Huntington's disease

Neuroleptic medications inhibit complex I of the electron transport chain.

Reduced platelet cytochrome c oxidase activity in Alzheimer's disease