Neuroprotective effects of Modafinil in mouse models of Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is a complex neurodegenerative disease characterized by significant neuronal loss and cognitive impairment. Besides the availability of various drugs for AD, still an effective treatment is required that can reduce the neuronal damage, amyloid beta (Aβ) plaque deposition and alleviate the cognitive deficits associated with the disease. The present study investigates the therapeutic potential of modafinil in aluminium chloride-induced mouse model of AD. Modafinil a wakefulness promoting central nervous system (CNS) stimulant, is associated with cognitive benefits in healthy people. The study consisted of six groups of male BALB/c mice, age 6-8 weeks. The three groups (n = 6 each) were administered AlCl₃ (300mg/kg) in drinking water followed by treatment with donepezil (2 mg/kg) and modafinil (100 mg/kg) through intraperitoneal (i.p) route. The other three groups were given saline, donepezil and modafinil. Donepezil is a second-generation cholinesterase inhibitor, approved for the management of AD, is used as a positive control. Effects of these drug treatments were assessed through behavior analysis for spatial memory using the Y-maze. The spatial memory was significantly improved (p<0.05) in the AlCl₃-treated groups with modafinil (65.55±2.7) and donepezil (74.82±3.9). The presence of Aβ plaques, neuronal morphology, and expression of amyloid precursor protein 770 (APP770) was also assessed. Histopathological examination conducted through Congo red staining revealed the substantial reduction in Aβ plaques in modafinil-treated group as compared to the AlCl₃ and donepezil-treated groups. The neuronal density was also significantly restored (p<0.001) as evident by cell count in hematoxylin and eosin (H&E) staining. The gene expression analysis of APP770 through qPCR showed a remarkable increase in expression in the AlCl₃-treated group (3.7 ± 0.43). Interestingly, it was substantially restored by modafinil (0.32 ± 0.4) and to a lesser extent xviii by donepezil (3.2 ± 0.42). Furthermore, molecular docking studies were performed for drug and protein interactions. The binding potential of modafinil with AD associated proteins i.e., presenilin, synaptic proteins and proteins involved in glycation, inflammation, oxidative stress, and neurogenesis. These preliminary findings suggest potential neuroprotective properties of modafinil; however, further in-depth studies are warranted to elucidate its precise mechanism of action and clinical applicability in AD.