Thymoquinone prevents neurodegeneration against MPTP in vivo and modulates α-synuclein aggregation in vitro

Abstract

Parkinson's disease (PD) is a common neurodegenerative disease characterized by progressive dopaminergic neurodegeneration with a concomitant increase in oxidative stress and neuroinflammation in the substantia nigra pars compacta (SNc). Recent studies have focused on targeting neuroinflammation and oxidative stress to effectively treat PD. The present study evaluated the neuroprotective effect of thymoquinone (TQ) against 1-methyl-4-phenyl 1,2,3,6 tetrahydropyridine (MPTP)-induced oxidative stress and neuroinflammation in a PD mouse model. TQ (10 mg/kg body weight [b. wt.]) was administered for 1 week prior to MPTP (25 mg/kg b. wt.). MPTP administration caused oxidative stress as evidenced by decreased activities of superoxide dismutase and catalase, a depletion of reduced glutathione, and a concomitant rise in malondialdehyde. It also significantly increased pro-inflammatory cytokines and elevated inflammatory mediators such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in the striatum. Immunohistochemical analysis revealed dopamine neuron loss in the SNc and decreased dopamine transporters in the striatum following MPTP administration; however, these were rescued by TQ treatment. TQ treatment further restored antioxidant enzymes, prevented glutathione depletion, inhibited lipid peroxidation, and attenuated pro-inflammatory cytokines. TQ also decreased the raised levels of inflammatory mediators, such as COX-2 and iNOS. Therefore, TQ is thought to protect against MPTP-induced PD and the observed neuroprotective effects are attributed to its potent antioxidant and anti-inflammatory properties. Moreover, the in vitro analysis found that TQ significantly inhibited α-synuclein aggregation and prevented cell death induced by pre-formed fibrils. Thus, TQ not only scavenges the MPTP-induced toxicity but also prevents α-synuclein-fibril formation and its associated toxicity.

Keywords: MPTP; Neurodegeneration; Neurotoxicity; Parkinson's disease; Thymoquinone; α-synuclein.