Therapeutic Effects of Hydrogen in Animal Models of Parkinson's Disease.pdf

Copyright © 2011 Kyota Fujita et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Since the first description of Parkinson's disease (PD) nearly two centuries ago, a number of studies have revealed the clinical symptoms, pathology, and therapeutic approaches to overcome this intractable neurodegenerative disease. 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) are neurotoxins which produce Parkinsonian pathology. From the animal studies using these neurotoxins, it has become well established that oxidative stress is a primary cause of, and essential for, cellular apoptosis in dopaminergic neurons. Here, we describe the mechanism whereby oxidative stress evokes irreversible cell death, and propose a novel therapeutic strategy for PD using molecular hydrogen. Hydrogen has an ability to reduce oxidative damage and ameliorate the loss of nigrostriatal dopaminergic neuronal pathway in two experimental animal models. Thus, it is strongly suggested that hydrogen might provide a great advantage to prevent or minimize the onset and progression of PD.

The central pathological feature of PD was loss of neurons in substantia nigra pars compacta (SNpc). DA depletion by the loss of dopaminergic neurons in SNpc is a primary symptom of PD [1]. PD is one of the most common neurodegenerative and progressive diseases, along with Alzheimer’s disease (AD) [2, 3]. In these last two decades, many lines of evidence have emerged to suggest that oxidative stress is closely related to the onset and the progression of PD and AD.

Using neurotoxins in experimental animal models, an enormous number of studies have been undertaken to develop neuroprotective drugs against PD. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) was found to be a by-product of the chemical synthesis of a meperidine analog with potent heroin-like effects [4, 5]. MPTP has the ability to induce PD-like pathology and has been used in various species including nonhuman primates, and rodents. Among the neurotoxic mechanism of MPTP, mitochondrial impairment is highly associated with oxidative damage and related neurodegeneration; the detailed mechanism and the linkage between oxidative damage and neurodegeneration are discussed in this review. Although MPTP-induced PD model animals are regarded as the best reproducible model, another neurotoxin, 6-hydroxydopamine (6-OHDA; 2,4,5-trihydroxyphenylethylamine), is also used for toxin-induced animal model of PD [6].

Many trials have focused on the reduction of oxidative stress as a therapeutic strategy because oxidative stress is regarded as one of the major risk factors in the onset of PD as mentioned above. However, there are still no known antioxidant drugs which are clinically used to prevent PD. Here, the neurotoxic mechanism of MPTP which induces Parkinsonian pathology and behavior, and how molecular hydrogen prevents them, is discussed in this review.