Neuroprotective potential of Thymoquinone in MPTP Model of Parkinson's Disease

Abstract

Parkinson disease (PD) is the second most common neurodegenerative disorder characterized by loss of dopaminergic neurons in the SNc area. Numerous studies suggest that oxidative stress and inflammation play a critical role in the etiopathogenesis of PD. The current study was undertaken to assess the neuroprotective potential of Thymoquinone (TQ), one of the active components present in black seed or black cumin against MPTP model of PD. Since, PD is a progressive chronic neurodegenerative disorder; we have used sub-chronic protocol for MPTP at the dose of 25mg/Kg/body weight (single injection per day for 5 consecutive days to C57BL/6J adult mice). The administration of MPTP produced significant reduction in antioxidant activities as evidenced by reduced activity of superoxide dismutase (SOD), catalase and depletion of reduced glutathione with a concomitant rise in the lipid peroxidation product, malondialdehyde. We also found that it also significantly enhanced the levels of pro-inflammatory cytokines (IL-1, IL-6 and TNF-alpha) and elevated the inflammatory mediators like cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in the striatum region. Pretreatment of MPTP injected mice with TQ significantly improved the antioxidant enzymes (SOD, Catalase), prevented glutathione depletion and inhibited lipid peroxidation along with attenuation of induction of pro-inflammatory cytokines. Subsequently, TQ also attenuated the increased levels of inflammatory mediators such as COX-2 and iNOS. Additionally, we also found that TQ significantly inhibits alpha-synuclein fibrillation as measured by Thioflavin-S fluorescence assay, and confirmed by Transmission Electron Microscopy and western blot analysis. Based on the observed anti-oxidative and anti-inflammatory effect of TQ, we anticipate that TQ pretreatment will also prevent the dopaminergic neurodegeneration induced by MPTP and will modulate the spreading of alpha-synuclein in the mice. Currently, we are analyzing the dopaminergic neuronal death to assess the neuroprotective effect of TQ in the mice treated with MPTP. We are also examining the modulatory effect of TQ in preventing alpha-synuclein spreading.