WIN55,212-2 Attenuates Cognitive Impairments in AlCl3 + d-Galactose-Induced Alzheimer's Disease Rats by Enhancing Neurogenesis and Reversing Oxidative Stress.

Onesimus Mahdi,Samaila Musa Chiroma,Che Norma Mat Taib,Saravanan Jagadeesan,Mohamad Aris Mohd Moklas,Mohamad Taufik Hidayat Baharuldin,Shamala Devi,Nurul Huda Mohd Nor

doi:10.3390/biomedicines9091270

Abstract

Neurotransmission and cognitive dysfunctions have been linked to old age disorders including Alzheimer’s disease (AD). Aluminium is a known neurotoxic metal, whereas d-galactose (d-gal) has been established as a senescence agent. WIN55,212-2 (WIN), is a potent cannabinoid agonist which partially restores neurogenesis in aged rats. The current study aimed to explore the therapeutic potentials of WIN on Aluminium chloride (AlCl3) and d-gal-induced rat models with cognitive dysfunction. Healthy male albino Wistar rats weighing between 200–250 g were injected with d-gal 60 mg/kg intra peritoneally (i.p), while AlCl3 (200 mg/kg) was orally administered once daily for 10 consecutive weeks. Subsequently, from weeks 8–11 rats were co-administered with WIN (0.5, 1 and 2 mg/kg/day) and donepezil 1 mg/kg. The cognitive functions of the rats were assessed with a Morris water maze (MWM). Furthermore, oxidative stress biomarkers; malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) and neurogenesis markers: Nestin and glial fibrillary acidic protein (GFAP) were also evaluated, as well as the histology of the hippocampus. The results revealed that rats exposed to AlCl3 and d-gal alone showed cognitive impairments and marked neuronal loss (p < 0.05) in their hippocampal conus ammonis 1 (CA1). Additionally, a significant decrease in the expressions of GFAP and Nestin was also observed, including increased levels of MDA and decreased levels of SOD and GSH. However, administration of WIN irrespective of the doses given reversed the cognitive impairments and the associated biochemical derangements. As there were increases in the levels SOD, GSH, Nestin and GFAP (p < 0.05), while a significant decrease in the levels of MDA was observed, besides attenuation of the aberrant cytoarchitecture of the rat’s hippocampi. The biochemical profiles of the WIN-treated rats were normal. Thus, these findings offer possible scientific evidence of WIN being an effective candidate in the treatment of AD-related cognitive deficits.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disorder commonly present among the elderly presenting with memory and cognitive dysfunction
The Morris water maze (MWM) test was conducted to assess the therapeutic effect of cannabinoid receptor, WIN on AlCl3 and D -gal-induced cognitive impairments in rats
It elevates the levels of neurogenesis biomarkers, glial fibrillary acidic protein (GFAP)

Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disorder commonly present among the elderly presenting with memory and cognitive dysfunction. Biomedicines 2021, 9, 1270 characteristics of AD are the presence of neurofibrillary tangles (NFTs), senile plaques (SPs) and the loss of cholinergic neurons in the basal forebrain in humans [1]. The disease is progressive by nature, whereby the symptoms continue to rise and the quality of life worsens over years. AD develops via three stages; mild, moderate and severe. AD patients suffer mild memory loss, but as the disease progresses, patients lose their ability to carry out daily activities [4]. AD is thought to be a rising and dire public health concern with enormous social and economic impacts among the elderly [6,7]

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