Curcumin Prevents and Ameliorates Biochemical and Behavioral Toxicities of MPTP in C57BL/6J Mice: Its Potential use in Preventing and Treating Parkinsonism

Parkinson’s disease (PD) is the result of the degeneration of nigrostriatal dopamine neurons and loss of striatal tyrosine hydroxylase and dopamine. The cause is unknown. Studies have shown that fetal exposures to toxins make the nigrostriatal dopamine neurons vulnerable and that later toxic challenges and/or the wear-and-tear of aging cause the already vulnerable neurons to succumb, and producing a model of parkinsonism. Thus, a sensitization stage and a precipitating stage may exist for idiopathic PD. In this study, we used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to produce the proposed sensitization and precipitating stages and determine if curcumin can ameliorate the toxic changes. Note: however that MPTP serves as a protoxin, via it metabolism by monoamine axidase B (MAO-B) to 1-methyl-4-phenylpyridinium (MPP+). MPP+ has affinity for the catecholamine uptake system, is taken up preferentially into dopaminergic neurons with cell bodies in the substantia nigra zona compacta, where it inhibits complex-1 of the electron transport chain. C57BL/6J pregnant mice were treated with low dosage of MPTP during gestation days (GD) 8-12, to cause sub-threshold impairments to the emerging and vulnerable nigrostriatal dopamine neurons in the fetus, thus producing phenotypic sensitization. At 3 months, the offspring of the PBS control and the MPTP group were challenged with PBS or MPTP (10 mg/kg/day) for seven days, to cause further harm and to the produce the precipitating stage. The ameliorating effect of curcumim was tested on both stages, by pretreating with 15 μg/animal during GD 3-12. All animals were studied for motor activities, the levels of TH, and dopamine and its metabolites. The prenatal treatments with curcumin nullify the reduction in birth weight caused by prenatal MPTP, and it blocked the impairments in movement caused by prenatal MPTP, postnatal MPTP and combination of prenatal and postnatal MPTP. Curcumin also restored dopamine to 97.3% from the 47.2% loss caused by prenatal MPTP, and to 68.7% from the 32.8% loss caused by the prenatal and postnatal MPTP treatments. TH expression was also markedly restored. These novel data show the efficacy of curcumin and suggest that the curcumin may be valuable in preventing and ameliorate PD-like changes. Introduction Parkinson’s (PD) disease is an age-related neurodegenerative disease caused by the loss of dopaminergic neurons within the substantianigra (SN). This results in extrapyramidal motor dysfunction, including tremor, rigidity, and bradykinesia [1] and decreased tyrosine hydroxylase (TH) and the production and storage of dopamine (DA) in the striatum [2,3]. At present, DA replacement therapy with levo-dopa, or other drugs with dopaminergic agonists’ properties, can alleviate the symptoms of the disorder. However, although such drugs are effective in the early stages of the disease, longterm therapy has been associated with serious side effects. Oxidative stress and mitochondrial dysfunction are major events that occur during neuronal death that causes PD [4,5]. This has been noted as glutathione (GSH) depletion in dopaminergic cells and mitochondrial dysfunction [6]. Thus, the therapeutic approach of PD treatment could include not only the amelioration of the DA loss, but also the modulation of oxidative stress. Phenolic antioxidants, including flavonoids are an extensive group of naturally-occurring compounds that are widely distributed in plants, and are constituents of various fruits, nuts and leaves [7,8]. Flavonoids are potent antioxidants and free radical scavengers, with efficacy suggested to exceed the antioxidant capacity of vitamins C and E [9-12]. Flavonoids are capable of chelating metal ions and modifying the activity of cellular antioxidants and antioxidant enzymes, such as catalase and GSH [13]. The flavonoids also modulate nitric oxide production, tumor necrosis factor alpha secretion and nuclear factor kβ (NFkβ) dependent gene expression, in vitro, [14] and have anti-inflammatory properties [15-19]. These agents also inhibit the activities of lipoxygenase and cycloxygenase. Moreover, as model antioxidants, they show very little toxicity, even in long-term studies, and they possibly slow down the rate of nigral cell loss in PD [20]. Curcumin (CU) is a well-known food flavor, a naturally-occurring yellow pigment isolated from the rhizomes of the plant found in South Gladson Muthian, Marquitta Smith, Lemuel Dent, Jennifer King, Brenya Griffin, Veronica Mackey and Clivel Charlton* Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, USA *Address for Correspondence Clivel G. Charlton, Department of Neuroscience and Pharmacology, College of Medicine, Meharry Medical College, 1005 DB Todd Blvd. Nashville, TN 37208-3599, USA, Tel: 615 327 6510; Fax: 615 327 6632; E-mail: [email protected] Submission: 05 August, 2015 Accepted: 05 October, 2015 Published: 08 October, 2015 Copyright: © 2015 Muthian G, 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. Research Article Open Access