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.
 
 
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