The study entitled “Screening and Evaluation of the Neuroprotective Activity of Phytocompounds from Azadirachta indica on the Ceramide Pathway against Cuprizone-Induced Experimental Models of Multiple Sclerosis” investigates the therapeutic potential of Neem bioactives in combating oxidative stress, inflammation, and demyelination associated with multiple sclerosis (MS). MS is a chronic, immune-mediated neurodegenerative disorder characterized by demyelination and neuronal loss in the central nervous system. The research explores the modulation of the ceramide–sphingolipid pathway, a key molecular mechanism implicated in neuroinflammation and apoptosis, through the intervention of Neem phytochemicals such as Nimbolide, Nimbin, and Azadirachtin. An integrated in-silico, in-vitro, and in-vivo methodological framework was adopted. In-silico molecular docking revealed strong binding affinities of Neem compounds toward ceramide pathway enzymes-serine palmitoyl transferase (SPT), ceramide synthase (CERS), and sphingosine-1-phosphate lyase (S1PL)-suggesting their potential to regulate lipid metabolism and inhibit neurodegenerative signaling. In-vitro assays using glial cell models demonstrated that Neem extracts significantly reduced reactive oxygen species (ROS), enhanced antioxidant enzyme activity (SOD, CAT, GPx), and downregulated pro-inflammatory cytokines (TNF-α, IL-6, IL-1β).

Further, in-vivo validation using the cuprizone-induced demyelination mouse model confirmed the neuroprotective action of Neem. Behavioral assessments indicated improvement in locomotor coordination, learning, and memory functions in Neem-treated groups. Biochemical analysis showed restoration of antioxidant defense, reduced lipid peroxidation, and normalization of inflammatory markers. Histopathological evaluations corroborated these findings, showing preserved myelin integrity, reduced vacuolation, and minimal inflammatory infiltration. The overall results establish that Azadirachta indica exerts a multifaceted neuroprotective effect by mitigating oxidative stress and neuroinflammation while enhancing remyelination through modulation of the ceramide pathway. The study underscores the translational potential of Neem as a natural, cost-effective therapeutic alternative for the management of multiple sclerosis and related neurodegenerative disorders, bridging the gap between traditional herbal medicine and contemporary neuropharmacology.