RESUMO
Accumulating evidences suggest that inflammation-mediated neurons dysfunction participates in the initial and development of Parkinson's disease (PD), whereas mitochondria have been recently recognized as crucial regulators in NLRP3 inflammasome activation. Cordycepin, a major component of cordyceps militaris, has been shown to possess neuroprotective and anti-inflammatory activity. However, the effects of cordycepin in rotenone-induced PD models and the possible mechanisms are still not fully understood. Here, we observed that motor dysfunction and dopaminergic neurons loss induced by rotenone exposure were ameliorated by cordycepin. Cordycepin also reversed Drp1-mediated aberrant mitochondrial fragmentation through increasing AMPK phosphorylation and maintained normal mitochondrial morphology. Additionally, cordycepin effectively increased adenosine 5'-triphosphate (ATP) content, mitochondrial membrane potential (MMP), and reduced mitochondrial ROS levels, as well as inhibited complex 1 activity. More importantly, cordycepin administration inhibited the expression of NLRP3 inflammasome components and the release of pro-inflammatory cytokine in rotenone-induced rats and cultured neuronal PC12 cells. Moreover, we demonstrated that the activation of NLRP3 inflammasome within neurons could be suppressed by the mitochondrial division inhibitor (Mdivi-1). Collectively, the present study provides evidence that cordycepin exerts neuroprotective effects partially through preventing neural NLRP3 inflammasome activation induced by Drp1-dependent mitochondrial fragmentation in rotenone-injected PD models.
Assuntos
Anti-Inflamatórios/uso terapêutico , Desoxiadenosinas/uso terapêutico , Dinaminas/antagonistas & inibidores , Dinâmica Mitocondrial/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Transtornos Parkinsonianos/tratamento farmacológico , Rotenona/toxicidade , Animais , Anti-Inflamatórios/farmacologia , Desoxiadenosinas/farmacologia , Relação Dose-Resposta a Droga , Dinaminas/metabolismo , Inseticidas/toxicidade , Masculino , Dinâmica Mitocondrial/fisiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fármacos Neuroprotetores/farmacologia , Células PC12 , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Cordycepin (Cor), one of the major bioactive components of the traditional Chinese medicine Cordyceps militaris, has been used in clinical practice for several years. However, its neuroprotective effect remains unknown. AIMS: The purpose of the study was to evaluate the neuroprotective effects of Cor using a rotenoneinduced Parkinson's Disease (PD) rat model and to delineate the possible associated molecular mechanisms. METHODS: In vivo, behavioural tests were performed based on the 10-point scale and grid tests. Levels of dopamine and its metabolites in the striatum and the numbers of TH-positive neurons in the Substantia Nigra pars compacta (SNpc) were investigated by high-performance liquid chromatography with electrochemical detection and immunohistochemical staining, respectively. In vitro, cell apoptosis rates and Mitochondrial Membrane Potential (MMP) were analysed by flow cytometry and the mRNA and protein levels of Bax, Bcl-2, Bcl-xL, Cytochrome c (Cyt-c), and caspase-3 were determined by quantitative real-time PCR and western blotting. RESULTS: Showed that Cor significantly improved dyskinesia, increased the numbers of TH-positive neurons in the SNpc, and maintained levels of dopamine and its metabolites in the striatum in rotenone- induced PD rats. We also found that apoptosis was suppressed and the loss of MMP was reversed with Cor treatment. Furthermore, Cor markedly down-regulated the expression of Bax, upregulated Bcl-2 and Bcl-xL, inhibited the activation of caspase-3, and decreased the release of Cyt-c from the mitochondria to the cytoplasm, as compared to those in the rotenone-treated group. CONCLUSION: Therefore, Cor protected dopamine neurons against rotenone-induced apoptosis by improving mitochondrial dysfunction in a PD model, demonstrating its therapeutic potential for this disease.