Antioxidant potential of melatonin enhances the response to L-dopa in 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine-parkinsonian mice

Abstract

Background

Parkinson's disease is a neurodegenerative disorder of uncertain pathogenesis characterized by a loss of dopaminergic neurons in substantia nigra pars compacta, and can be modeled by the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The current research was directed to investigate the role of melatonin in preventing the gradual decrease in the response to L-dopa in MPTP-induced parkinsonism in mice.

Methods

Eighty four male Swiss mice were divided into seven groups. Group I is the saline group. The other six groups were injected with MPTP(20 mg/kg/2 h). Group II is the MPTPcontrol group. Group III was treated with L-dopa/carbidopa (100/10 mg/kg, po). Group IV and V were treated with melatonin (5 or 10 mg/kg, po), respectively. Group VI and VII received L-dopa/carbidopa in combination with melatonin in the same above-mentioned doses, respectively.

Results

Results showed that MPTP-treated mice exhibited low striatal dopamine level accompanied by motor impairment and increased oxidative stress. Treatment with L-dopa improved the motor performance of mice. Addition of melatonin to L-dopa therapy improved the motor response to L-dopa and increased striatal dopamine level. This combination reduced lipid peroxidation, ameliorated reduced glutathione and improved antioxidant enzyme activities (p ≤ 0.05).

Conclusions

Overall, our study suggests that the antioxidant potential of melatonin makes it a promising candidate to L-dopa in treating Parkinson's disease.

Introduction

Parkinson's disease (PD) is a progressive neurological disorder characterized by the loss of dopamine in the striatum; which occurs mainly due to the death of the dopaminergic neurons in the substantia nigra pars compacta (SNpc). The concept of oxidative stress and antioxidants may be directly or indirectly involved in the pathogenesis of PD [32] and in animal models [57]. MPTP is a potent and selective nigrostriatal dopaminergic neurotoxicant that can induce parkinsonism when administered to rodents [39], showing evidence of oxidative stress in these models [13, 48].

The currently available pharmacological and non-pharmacological treatments for PD are able to offer only symptomatic relief for patients. Since its introduction in the late 1960s, L-dopa (L-3,4-dihydroxyphenylalanine) has been the cornerstone of the treatment of PD. However, the effectiveness of L-dopa therapy declines on continuous use [7]. Another potential problem with the use of L-dopa in treatment of PD comes from the fact that L-dopa metabolism or autoxidation can give rise to radical species, hydrogen peroxide (H₂O₂), semiquinones, and quinones [17]. The quinones generated are thought to mediate toxicity by covalent binding to nucleophilic groups of biological macromolecules [47]. L-dopa has been shown to induce oxidative stress-mediated apoptosis in cultured neuronal cells [56]. However, there is no evidence from in vivo studies suggesting that L-dopa treatment damages SNpc neurons in PD. Medical therapy that keeps the benefits of L-dopa would be a major advance in the treatment of PD [36]. Recently, it has been postulated that during the preclinical phase of PD the turnover rate of dopamine may increase to compensate the loss of dopamine containing neurons [14]. This increase in the rate of dopamine utilization is likely to accelerate the neurodegenerative process through the generation of quinones, semiquinones and H₂O₂, resulting from the oxidative metabolism of dopamine [17].

Melatonin, a serotonin derivative is a hormone synthesized by neurons in the pineal gland. Studies have demonstrated that melatonin has antioxidant properties by acting as a free radical scavenger [52]. Melatonin has been also associated with the cellular antioxidant defense. It can develop its action at two levels: as a direct antioxidant, due its ability to act as a free radical scavenger, and as an indirect antioxidant, since it is able to induce the expression and/or the activity of the main antioxidant enzymes [54]. It has been shown to cause a considerable dose-dependent reduction in the production of dopaminergic neurodegenerating hydroxyl free radicals [2]. In addition, melatonin is also indirectly effective by enhancing the levels of potential antioxidants such as glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and reduced glutathione (GSH) [19].

Using the hypothesis that oxidative injury underlies the reduction in response to L-dopa, the inclusion of antioxidants with L-dopa treatment may retard the decline in response to L-dopa after long term use. The present study was designed to characterize the effect of melatonin in improving the longevity of L-dopa treatment in the MPTP mouse model of PD.