Atorvastatin Prevents Early Oxidative Events and Modulates Inflammatory Mediators in the Striatum Following Intranasal 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Administration in Rats
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Atorvastatin is a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor with cholesterol-lowering, anti-inflammatory, and antioxidant properties. Increasing evidence show atorvastatin acts as a protective agent against insults in the central nervous system (CNS). The regular use of statins has been associated with a reduced risk of Parkinson’s disease (PD) development. Here, we evaluated early events involved in the neurotoxicity induced by intranasal (i.n.) infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in rats and the potential of atorvastatin to prevent these early toxic events. Male Wistar rats were pretreated orally with atorvastatin (10 mg/kg/day) or vehicle once a day during seven consecutive days. Twenty-four hours after atorvastatin administration, animals received a single bilateral i.n. infusion of MPTP (1 mg/nostril), and 6 h later, the striatum and the hippocampus were collected to evaluate early oxidative stress parameters and inflammatory cytokines. Atorvastatin prevented MPTP-induced increase in reactive species (RS) generation and in glutathione levels in the striatum. Atorvastatin also prevented the reduction in mitochondrial respiratory chain complex I and II activities evoked by MPTP in the striatum. Atorvastatin per se reduced the levels of the cytokines TNF-α and IL-1β, and surprisingly, it reduced IL-10 and nerve growth factor levels in the striatum. However, the anti-inflammatory IL-10 levels increased in the striatum following atorvastatin plus MPTP treatment. These effects were not observed in the hippocampus. Our findings reinforce and extend the notion of the neuroprotective effects of atorvastatin in a PD model and indicate the modulation of oxidative and inflammatory responses as the mechanisms associated with therapeutic action of atorvastatin in PD.
KeywordsAtorvastatin Parkinson’s disease MPTP Intranasal Oxidative stress Neuroinflammation
3-Hydroxy-3-methylglutaryl coenzyme A
Interleukin 1 beta
Nerve growth factor
Substantia nigra pars compacta
Tumoral necrosis factor alpha
All authors have materially participated in the research and/or article preparation.
This work was supported by grants from Brazilian funding agencies: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Programa de Apoio aos Núcleos de Excelência (PRONEX—Project NENASC), Fundação de Apoio à Pesquisa do Estado de Santa Catarina (FAPESC), FINEP (Financiadora de Estudos e Projetos-IBN-Net no. 01.06.0842-00), and INCT (Instituto Nacional de Ciência e Tecnologia) for the excitotoxicity and neuroprotection. CIT, RDP, ARSS, and AFDB are a recipient of CNPq productivity fellowship.
Compliance with Ethical Standards
All procedures performed in this study were in accordance with the animal protocols of institutional ethics committee (CEUA).
Conflict of Interest
The authors declare that they have no conflicts of interest.
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