THYMOQUINONE PREVENTS DOPAMINERGIC NEURONAL LOSS IN ΑLPHA-SYNUCLEIN PFF INDUCED MOUSE MODEL OF PARKINSON’S DISEASE

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders and is characterized by the progressive loss of dopaminergic neurons in the nigrostriatal pathway. Alpha-synuclein (α-syn), a presynaptic protein abundant in nerve terminals, aberrantly aggregates in PD pathology, leading to increased cellular stress, neurotoxicity, and the formation of insoluble inclusions known as Lewy bodies. Numerous studies have explored the antioxidant capacity of naturally occurring compounds to inhibit α-syn aggregation, thereby attenuating progressive neurotoxicity and subsequent neuronal loss. Thymoquinone (TQ), the principal bioactive constituent of Nigella sativa seeds, is considered one of the most promising natural compounds in central nervous system (CNS) drug development. Several studies have reported beneficial effects of TQ in in silico, in vitro, and in vivo PD models, primarily attributed to its antioxidant and anti-inflammatory properties.
This study aimed to elucidate the role of TQ as an inhibitor of α-syn aggregation in a synuclein PFF-induced mouse model of PD. Using a previously established PD mouse model that accelerates synuclein pathology, α-syn preformed fibrils (PFFs) were inoculated into the striatum, inducing α-syn nucleation and propagation to the dopaminergic neuron soma in the substantia nigra pars compacta (SNc). After six weeks, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was administered intraperitoneally at a dose of 10 mg/kg body weight for five consecutive days. TQ administration not only conferred neuroprotection to dopaminergic neuronal soma and terminals but also significantly reduced the development of fibrillar α-syn aggregates in SNc neurons. Furthermore, TQ modulated antioxidant defense and autophagy-related markers, suggesting a multifaceted neuroprotective mechanism.