D. T. Dexter

Basal Lipid Peroxidation in Substantia Nigra Is Increased in Parkinson's Disease

Abstract: Polyunsaturated fatty acid (PUFA) levels (an index of the amount of substrate available for lipid peroxidation) were measured in several brain regions from patients who died with Parkinsons disease and age‐matched control human postmortem brains. PUFA levels were reduced in parkinsonian substantia nigra compared to other brain regions and to control tissue. However, basal malondialdehyde (MDA; an intermediate in the lipid peroxidation process) levels were increased in parkinsonian nigra compared with other parkinsonian brain regions and control tissue. Expressing basal MDA levels in terms of PUFA content, the difference between parkinsonian and control substantia nigra was even more pronounced. Stimulating MDA production by incubating tissue with FeSO4 plus ascorbic acid, FeSO4 plus H2O2, or air alone produced lower MDA levels in the parkinsonian substantia nigra, probably reflecting the lower PUFA content. These results may indicate that an increased level of lipid peroxidation continues to occur in the parkinsonian nigra up to the time of death, perhaps because of continued exposure to excess free radicals derived from some endogenous or exogenous neurotoxic species.

Mitochondrial complex I deficiency in Parkinson's disease.

The structure and function of mitochondrial respiratory-chain enzyme proteins were studied postmortem in the substantia nigra of nine patients with Parkinsons disease and nine matched controls. Total protein and mitochondrial mass were similar in the two groups. NADH-ubiquinone reductase (Complex I) and NADH cytochrome c reductase activities were significantly reduced, whereas succinate cytochrome c reductase activity was normal. These results indicated a specific defect of Complex I activity in the substantia nigra of patients with Parkinsons disease. This biochemical defect is the same as that produced in animal models of parkinsonism by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and adds further support to the proposition that Parkinsons disease may be due to an environmental toxin with action(s) similar to those of MPTP.

Increased Nigral Iron Content and Alterations in Other Metal Ions Occurring in Brain in Parkinson's Disease

Abstract: Levels of iron, copper, zinc, manganese, and lead were measured by inductively coupled plasma spectroscopy in parkinsonian and age‐matched control brain tissue. There was 31‐35% increase in the total iron content of the parkinsonian substantia nigra when compared to control tissue. In contrast, in the globus pallidus total iron levels were decreased by 29% in Parkinsons disease. There was no change in the total iron levels in any other region of the parkinsonian brain. Total copper levels were reduced by 34–45% in the substantia nigra in Parkinsons disease; no difference was found in the other brain areas examined. Zinc levels were increased in substantia nigra in Parkinsons disease by 50–54%, and the zinc content of the caudate nucleus and lateral putamen was also raised by 18–35%. Levels of manganese and lead were unchanged in all areas of the parkinsonian brain studied when compared to control brains, except for a small decrease (20%) in manganese content of the medial putamen. Increased levels of total iron in the substantia nigra may cause the excessive formation of toxic oxygen radicals, leading to dopamine cell death.

Anatomic and Disease Specificity of NADH CoQ1 Reductase (Complex I) Deficiency in Parkinson's Disease

Abstract: 1‐Methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) is thought to produce parkinsonism in humans and other primates through its inhibition of complex I. The recent discovery of mitochondrial complex I deficiency in the substantia nigra of patients with Parkinsons disease has provided a remarkable link between the idiopathic disease and the action of the neurotoxin MPTP. This article shows that complex I deficiency in Parkinsons disease is anatomically specific for the substantia nigra, and is not present in another neurodegenerative disorder involving the substantia nigra. Evidence is also provided to show that there is no correlation between l‐3,4‐dihydroxyphenylalanine therapy and complex I deficiency. These results suggest that complex I deficiency may be the underlying cause of dopaminergic cell death in Parkinsons disease.

A Selective Increase in Particulate Superoxide Dismutase Activity in Parkinsonian Substantia Nigra

The total activity of superoxide dismutase (SOD) and cytosolic and particulate activity of SOD in human substantia nigra and cerebellum were measured by a spectrophotometric method based on the ability of SOD to inhibit the autoxidation of adrenaline. The cystosolic and particulate isoenzymes of SOD were differentiated by the inclusion of potassium cyanide which selectively inhibits cytosolic copper/zinc‐dependent SOD activity. In autopsied human brains, there was no difference in total SOD) activity, or the activity of SOD in cytosol in substantia nigra jof patients dying with Parkinsons disease compared to age‐matched controls. However, the activity of the particulate form of SOD was higher in the parkinsonian substantia nigra compared to control tissue. In the cerebellum there was no difference in the total, cytosolic, or particulate activity of SOD between parkinsonian patients and age‐matched controls. Increased activity of SOD in particulate fraction may be a protective response to elevated levels of toxic free radicals in the parkinsonian substantia nigra. Alternatively, increased SOD activity may induce cell death through the accumulation of hydrogen peroxide.

Intense oxidative DNA damage promoted by L-dopa and its metabolites. Implications for neurodegenerative disease.

Oxidative DNA damage can cause mutation and cell death. We show that l‐DOPA, dopamine and 3‐O‐methyl‐DOPA cause extensive oxidative DNA damage in the presence of H2O2 and traces of copper ions. 8‐Hydroxyguanine is the major product. Iron ions were much less effective and manganese ions did not catalyse DNA damage. We propose that copper ion release, in the presence of l‐DOPA and its metabolites, may be an important mechanism of neurotoxicity, e.g. in Parkinsons disease and amyotrophic lateral sclerosis.

Decreased ferritin levels in brain in Parkinson's disease

Abstract: Ferritin levels were measured in postmortem brain tissue from patients dying with Parkinsons disease [treated with L‐3,4‐dihydroxyphenylalanine (L‐DOPA)] and from control patients. Ferritin levels were decreased in the substantia nigra, caudate‐putamen, globus pallidus, cerebral cortex, and cerebellum when compared with age‐matched control tissues. However, in CSF from L‐DOPA‐treated patients and in serum from L‐DOPA‐treated and untreated parkinsonian patients, ferritin levels were normal. Previous studies have suggested an increased total iron content in substantia nigra of parkinsonian brain. The failure of substantia nigra ferritin formation to be stimulated by increased iron levels suggests some defect in iron handling in this critical brain region in Parkinsons disease. The reason for decreased ferritin levels throughout the parkinsonian brain is not clear but does not seem to reflect a general system deficit in ferritin.

Characterization of the potential antioxidant and pro-oxidant actions of some neuroleptic drugs

It has been suggested in the literature that neuroleptic drugs may be able to exert antioxidant and/or pro-oxidant actions in vivo. The feasibility of this was tested by measuring the ability of chlorpromazine, prochlorperazine, metoclopramide, methotrimeprazine and haloperidol to scavenge biologically relevant oxygen-derived species in vitro. None of the drugs reacted with superoxide radical at a significant rate. Chlorpromazine, prochlorperazine, metoclopramide and methotrimeprazine were very powerful scavengers of hydroxyl radicals, reacting at almost a diffusion-controlled rate. Chlorpromazine showed some ability to inhibit iron ion-dependent hydroxyl radical formation. Chlorpromazine, methotrimeprazine, promethazine and prochlorperazine were powerful inhibitors of iron ion-dependent liposomal lipid peroxidation, scavengers of organic peroxyl radicals and inhibitors of haem protein/hydrogen peroxide-dependent peroxidation of arachidonic acid. Chlorpromazine, prochlorperazine, metoclopramide, methotrimeprazine and haloperidol were powerful scavengers of hypochlorous acid. Haloperidol showed no ability to inhibit lipid peroxidation or to scavenge peroxyl radicals, and reproducibly increased lipid peroxidation catalysed by haem proteins, in both the presence and absence of hydrogen peroxide. The relevance of these in vitro observations to events in vivo is discussed.

The influence of brain acetaldehyde on oxidative status, dopamine metabolism and visual discrimination task

The toxic effect of acetaldehyde on brain oxidative capacity and dopamine metabolism has been investigated in rat brains after a single intraperitoneal injection of acetaldehyde (5 mmol/kg) and the results compared with those from chronically ethanol fed rats. Acetaldehyde was present in rat brain 120 hr after a single dose of acetaldehyde, confirming that it is able to cross the blood-brain barrier. Brain catalase increased significantly after acetaldehyde or chronic ethanol administration although there were no other significant changes in the total brain activity of superoxide dismutase, glutathione peroxidase or glutathione reductase. Dopamine turnover was increased in both experimental groups. The acute dose of acetaldehyde reduced the ability of the rats to relearn a computer visual discrimination task.

Brain iron in the ferrocene-loaded rat: Its chelation and influence on dopamine metabolism

After administration of the ferrocene derivative 3,5,5-trimethyl hexanoyl ferrocene to rats for 4 weeks various brain regions including substantia nigra, cerebellum and cerebral cortex showed up to 50% increase in iron content. Subsequent administration of one of the hydroxypyridones CP20, CP24 and CP94, or the siderophore desferrioxamine caused a significant decrease in the iron content of these various brain regions. Each of the hydroxypyridones and the siderophore influenced dopamine metabolism by causing significant variations in both homovanillic acid and dopamine turnover.