 |
 |
Effects of Antiparkinsonian Drugs on Mitochondrial Function V. Jackson-Lewis, U. Muthane, S. Fahn, and S. Przedborski, New York, NY Objective: To examine the effects of different antiparkinsonian drugs on mitochondrial complex I activity. Background: We have demonstrated that levodopa inhibits complex I activity in rats, which suggests that deficit in complex I activity in Parkinson's disease (PD) can be, at least in part, related to treatment. PD patients are treated with many other medicines; however, the effects of these other agents on complex I is unknown. Methods: Rat brain mitochondria were prepared and incubated with different concentrations of levodopa, bromocriptine, pergolide, trihexyphenidyl, clozapine, and vitamin C and deprenyl. Complex I activity was measured by spectrophotometric assay. Results: Levodopa inhibited complex I activity in a dose-dependent manner. Bromocriptine, pergolide, trihexyphenidyl and clozapine were all without significant effects on mitochondrial function. Vitamin C and deprenyl did not alter complex I activity but did prevent the inhibitory effect of levodopa on complex I activity. Conclusion: Among the different and usual antiparkinsonian agents, only levodopa induced reduction in complex I activity, and both vitamin C and deprenyl are effective in preventing levodopa-induced complex I inhibition. This latter finding provides further support to the use of antioxidants and monoamine oxidase inhibitors in attempts to slow down the progression of PD. Study supported by PDF and NINDS. Authors Kappus H. Diplock AT. Institution Department of Dermatology, Free University of Berlin, Rudolf Virchow Clinic, Germany. Title Tolerance and safety of vitamin E: a toxicological position report. [Review] Source Free Radical Biology & Medicine. 13(1):55-74, 1992. Abstract From numerous publications on the "prophylactic" and "therapeutic" use of vitamin E, it may be concluded that the toxicity of vitamin E is very low. It has been demonstrated in animal experiments that vitamin E has neither mutagenic, teratogenic nor carcinogenic properties. Based on studies in humans, a daily dosage of 100-300 mg vitamin E can be considered harmless from a toxicological point of view. Using double-blind studies involving a large number of subjects, it has been demonstrated that large oral doses of up to 3,200 USP-Units/day led to no consistent adverse effects. From a large body of published data, dosage ranges have been deduced which can be characterized as safe for human subjects even where their use extends over a long period of time. It should, however, be noted that oral intake of high levels of vitamin E can exacerbate the blood coagulation defect of vitamin K deficiency caused by malabsorption or anticoagulant therapy. High levels of vitamin E intake are, therefore, contraindicated in these subjects. [References: 119] Authors Dexter DT. Brooks DJ. Harding AE. Burn DJ. Muller DP. Goss-Sampson MA. Jenner PG. Marsden CD. Institution Biomedical Science Division, King's College, London, UK. Title Nigrostriatal function in vitamin E deficiency: clinical, experimental, and positron emission tomographic studies. Source Annals of Neurology. 35(3):298-303, 1994 Mar. Abstract Four patients with vitamin E deficiency and sensory ataxia were studied using [18F]dopa positron emission tomography. The 2 most disabled patients, who had severe and prolonged vitamin E deficiency due to abetalipoproteinemia, showed reduced [18F]dopa uptake in both putamen and caudate. Putaminal uptake was in a similar range to that seen in Parkinson's disease. Studies of [3H]mazindol binding in the striatum of vitamin E--deficient rats indicated a reduced number of dopamine terminals, which was most severe in ventrolateral striatum. These observations suggest that severe and prolonged vitamin E deficiency results in loss of nigrostriatal nerve terminals, and support the hypothesis that oxidative stress may contribute to the etiology of Parkinson's disease. Authors Ward J. Institution Aged Care Services, Eastern Sydney Area Health Service, Pagewood, New South Wales. Title Free radicals, antioxidants and preventive geriatrics. [Review] Source Australian Family Physician. 23(7):1297-301, 1305, 1994 Jul. Abstract Despite a realisation that antioxidants will not delay ageing in healthy older people, there is increasing scientific interest in the role of free radical oxidants in a number of diseases associated with older age. For most of these diseases there is suggestive theoretical and laboratory evidence but not confirmatory clinical evidence. Free radical damage seems likely to be significant in the pathophysiology of atherosclerosis, ischaemia-reperfusion injury, Parkinson's disease, cataract, some cancers and rheumatoid arthritis. Evidence to suggest a protective effect from antioxidant vitamins exists for ischaemic heart disease, cataract and some cancers. Attempts to influence the outcome of other diseases such as ischaemia-reperfusion injury, Parkinson's disease and rheumatoid arthritis have so far failed to achieve positive results. Research interest in the field is increasing although hampered by methodological difficulties and the limited financial return for drug companies. In the meantime there seems no reason to discourage older people who wish to ingest extra vitamin E and vitamin C. A diet with adequate vegetables and fruits should provide sufficient beta carotene. [References: 30] Authors Youdim MB. Lavie L. Institution Department of Pharmacology, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel. Title Selective MAO-A and B inhibitors, radical scavengers and nitric oxide synthase inhibitors in Parkinson's disease. [Review] Source Life Sciences. 55(25-26):2077-82, 1994. Abstract In the absence of identification of either an endogenously or an exogenously derived dopaminergic neurotoxin, the most valid hypothesis currently envisaged for etiopathology of Parkinson's disease (PD) is selective oxidative stress (OS) in substantia nigra (SN). Although OS is not proven, a significant body of evidence from studies on animal and Parkinsonian brain neurochemistry supports it. This hypothesis is based on excessive formation of reactive oxygen species (O2 and OH.) and demise of systems involved with scavenging or preventing the formation of such radicals from H2O2, generated as a consequence of dopamine oxidation (autoxidation and deamination). Since MAO (monoamine oxidase A and B are the major H2O2 generating enzymes in the SN much attention has been paid to their selective inhibitors as symptomatic and neuroprotective agents in PD. Attention should also be given to radical scavengers (e.g. iron chelators, lipid peroxidative inhibitors and Vitamin E derivatives) as therapeutic neuroprotective agents in PD. This is considered valid since a significant elevation of iron is known to occur selectively in SN zone compacta and within the remaining melanized dopamine neurons of Parkinsonian brains. Although all the mechanism of iron induced oxygen free radical formation is not fully known there is no doubt that it participates with H2O2 (Fenton chemistry) to generate cytotoxic hydroxyl radical (OH.) and induce tissue OS and neurodegeneration in 6-hydroxydopamine model of PD. The dramatic proliferation of reactive amoeboid macrophages and microglia seen in SN of PD brains together with OS is highly compatible with an inflammatory process, similar to what has been observed in Alzheimer's disease and multiple sclerosis brains. This has led us to examine the ability of reactive macrophages to produce oxygen free radicals in response to nitric oxide (NO) production. The latter radical has been implicated in the excitotoxicity of glutaminergic neurons innervating the striatum and SN. Indeed we have now observed that in reactive macrophages NO acts as a signal transducer of O2 production which can synergize with dopamine oxidation. [References: 31] Authors Bischot L. Van den Brink G. Porsius AJ. Institution Department of Pharmacotherapy, Faculty of Pharmacy, Utrecht University, The Netherlands. Title Vitamin E in extrapyramidal disorders. [Review] Source Pharmacy World & Science. 15(4):146-50, 1993 Aug 20. Abstract In this article the effect of vitamin E on two extrapyramidal disorders, tardive dyskinesia and Parkinson's disease, is reviewed. After a brief description of the symptoms, the current hypotheses for the pathogenesis of these diseases are described. A summary of the clinical research that has been done to establish the effectiveness of vitamin E is given. In tardive dyskinesia four clinical trials (double-blind, placebo-controlled) showed improvement in the symptoms with vitamin E in doses of up to 1,600 IU/day. Preliminary studies concerning Parkinson's disease suggested that vitamin E (2,000 IU/day) probably cannot prevent the development of the disease. It was suggested that vitamin E is able to slow the progression of the illness. The results from a large double-blind, placebo-controlled clinical trial, however, did not show any beneficial effect of vitamin E in Parkinson's disease. [References: 35] Authors Abbott RA. Cox M. Markus H. Tomkins A. Institution Centre for International Child Health, Institute of Child Health, London. Title Diet, body size and micronutrient status in Parkinson's disease. Source European Journal of Clinical Nutrition. 46(12):879-84, 1992 Dec. Abstract Nutritional status was assessed in a group of patients with Parkinson's disease. Weight loss since the onset of disease occurred in 52% of the patients and 22% had lost more than 12.8 kg. Although 67% of patients experienced eating difficulties of some kind, dietary intakes of protein and energy were not significantly lower than recommended intakes. Plasma levels of albumin (44.2 g/l vs 45.7 g/l), vitamin A (2.61 vs 2.94 mumol/l), vitamin E (22.0 vs 32.0 mumol/l), iron (15.3 vs 18.3 mumol/l) and zinc (14.2 vs 18.7 mumol/l) were significantly lower (P < 0.05) in the patients than in healthy controls. Levels of ferritin, total iron-binding capacity and copper were similar between groups. The potential significance of low levels of vitamin E and zinc are discussed in relation to oxidative stress in the pathogenesis of this disease. Authors Fahn S. Institution Department of Neurology, Columbia University College of Physicians and Surgeons, New York, New York. Title An open trial of high-dosage antioxidants in early Parkinson's disease. Source American Journal of Clinical Nutrition. 53(1 Suppl):380S-382S, 1991 Jan. Abstract High dosages of tocopherol and ascorbate were administered to patients with early Parkinson's disease as a preliminary open-labeled trial for the eventual controlled double-blind study evaluating antioxidants as a test of the endogenous toxin hypothesis of the etiology of Parkinson's disease. The primary endpoint of the trial was the need to treat patients with levodopa. The time when levodopa became necessary in the treated patients was compared with another group of patients followed elsewhere and not taking antioxidants. The time when levodopa became necessary was extended by 2.5 y in the group taking antioxidants. The results of this pilot study suggest that the progression of Parkinson's disease may be slowed by the administration of these antioxidants. A large multicenter, controlled clinical trial currently underway in North America evaluating tocopherol and deprenyl has the potential to confirm these results. John Cottingham [log in to unmask] OR [log in to unmask]