Elsevier

Toxicology

Volume 189, Issues 1–2, 15 July 2003, Pages 129-146
Toxicology

Vitamin E therapy in Parkinson's disease

https://doi.org/10.1016/S0300-483X(03)00158-6Get rights and content

Abstract

Though the etiology is not well understood, late-onset Parkinson's disease (PD) appears to result from several key factors including exposure to unknown environmental toxicants, toxic endogenous compounds and genetic alterations. A plethora of scientific evidence suggest that these environmental and endogenous factors cause PD by producing mitochondrial (mito) oxidative stress and damage in the substantia nigra, leading to cell death. Thus assuming a critical role for mito oxidative stress in PD, therapies to treat or prevent PD must target these mito and protect them against oxidative damage. The focus of this article is to briefly review the experimental and clinical evidence for the role of environmental toxicants and mito oxidative stress/damage in PD as well as discuss the potential protective role of mito d-α-tocopherol (T) enrichment and vitamin E therapy in PD. New experimental data are presented that supports the enrichment of mito with T as a critical event in cytoprotection against toxic mito-derived oxidative stress. We propose that chronic, high dose vitamin E dietary supplementation or parenteral vitamin E administration (e.g. vitamin E succinate) may serve as a successful therapeutic strategy for the prevention or treatment of PD (by enriching substantia nigra mito with protective levels of T).

Introduction

Parkinson's disease (PD) is a chronic, late onset, progressive neurodegenerative disease that is characterized by the intraneuronal deposition of alpha synuclein proteins (Lewy bodies) and the irreversible loss (cell death) of dopaminergic neurons in the substantia nigra pars compacta. The etiology of PD is not well understood but appears to result from several factors, including exposure to unknown environmental toxicants (e.g. mitochondrial complex I inhibitors), toxic endogenous compounds (dopamine metabolism), and genetic alterations. An estimated 1% of the United States and European populations over the age of 60 have PD (Maher et al., 2002). Epidemiological evidence clearly implicates environmental factors in non-familial PD, which represents over 90% of all PD cases and onset typically occurs after 50 years of age (Tanner et al., 1999).

Fortunately, excellent experimental model systems are available to study non-familial or late-onset PD. For example the mitochondrial (mito) complex I inhibitors, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and rotenone have been shown to induce a PD-like syndrome in humans, monkeys, and mice (MPTP) and in rats (rotenone) (Ebadi et al., 1996, Betarbet et al., 2000). Using these model systems, researchers have made considerable progress over the past decade in understanding the molecular, biochemical, and pathological processes underlying PD. However, to date, a successful therapeutic strategy for the prevention or treatment of this devastating disease has not been found. The focus of this article is to briefly review the experimental and clinical evidence for the role of environmental toxicants and mito oxidative stress in PD as well as discuss the potential protective role of mito d-α-tocopherol (T) enrichment and vitamin E therapy in PD.

Section snippets

Role of mitochondria and oxidative stress in Parkinson's disease

Based on experimental and clinical data, it is well established that both mito and oxidative stress play critical roles in the pathogenesis of PD (Ebadi et al., 1996, Betarbet et al., 2000). Researchers have shown that both forms of cell death, apoptosis (Hartley et al., 1994, Duan et al., 1999, Gomez et al., 2001) and necrosis (Hartley et al., 1994, Maruyama et al., 2000, Hartmann et al., 2001) appear to be involved in the destruction of dopaminergic neurons in experimental and clinical PD,

Role of environmental toxicants in Parkinson's disease

It is now widely believed that the etiology of late-onset PD has a strong environmental component, with the possibility of coexisting genetic susceptibility (Tanner et al., 1999, Maher et al., 2002, Payami et al., 2002). As briefly outlined below, clinical, epidemiological and experimental studies support the potential role of many different environmental toxicants in the development of PD such as pesticides and herbicides (rotenone, paraquat, heptachlor, dieldrin), metals (manganese, iron,

Use of vitamin E treatment in Parkinson's disease

Once investigators realized that oxidative stress and lipid peroxidation play an important role in the etiology of PD, vitamin E was investigated as a potential treatment for PD, both clinically and in experimental models (Prasad et al., 1999). In terms of antioxidant protection, this is an excellent choice since T is the predominate membrane-bound antioxidant in mammalian cells that scavenges oxygen radicals and protects lipids, nucleic acids and proteins against oxidation (Tappel, 1962,

Recommendation for vitamin E therapy in the prevention and treatment of Parkinson's disease

Experimental and clinical evidence to date has identified mito oxidative stress and damage in the substantia nigra as critical events for the development of PD. Thus, we believe that successful therapeutic strategies for PD must target substantia nigra mitochondria. Clearly, we lack a basic understanding of the environmental events that are responsible for mito oxygen stress in this disease and thus reducing our exposure to such unknown agents is difficult. Instead, we recommend that developing

Acknowledgements

This work was supported by NIH/NIEHS grant # ES05452 and the Gasper and Irene Lazzara Foundation.

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