Synergistic Effect of Donepezil and Neurotropic B Vitamins on Dysregulated Antioxidant, Inflammation and Neurotransmitter Status in Aluminium Chloride-Induced Neurotoxicity in Rats

Abstract

Combination therapy offers a promising advantage because they target multiple pathways involved in the pathogenesis and progression of Alzheimer's disease. This study aimed to investigate the synergistic effect of donepezil and each of vitamin B12, vitamin B6 and vitamin B1 on aluminium chloride (AlCl₃)-induced neurotoxicity in rats. Fifty-four rats were divided into nine groups of six. Group I received distilled water, group II—AlCl₃ (100 mg/kg), group III- AlCl₃ (100 mg/kg) + Donepezil (10 mg/kg), group IV-AlCl₃(100 mg/kg) + Donepezil (10 mg/kg) + Vitamin B12 (5 mg/kg), group V-AlCl₃ (100 mg/kg) + Donepezil (10 mg/kg) + Vitamin B6 (5 mg/kg), group VI-AlCl₃ (100 mg/kg) + Donepezil (10 mg/kg) + Vitamin B1 (5 mg/kg), group VII-AlCl₃ (100 mg/kg) + Vitamin B12 (5 mg/kg), group VIII-AlCl₃ (100 mg/kg) + Vitamin B6 (5 mg/kg), group IX-AlCl₃ (100 mg/kg) + Vitamin B1 (5 mg/kg). Treatment lasted for 40 days. Biochemical analyses of the brain revealed that chronic administration of AlCl₃ significantly increased the level of inflammatory cytokines, caspase 9, malondialdehyde, nitric oxide and acetylcholinesterase (AChE) activity, while causing a significant decrease in superoxide dismutase (SOD) activity, Nrf2, reduced glutathione, dopamine and norepinephrine. Results also showed that AlCl₃ caused cognitive impairment as indicated by a reduction in the percentage alternation index and hypo-activity towards novel object in animals treated with AlCl₃ only. Moreover, results from biochemical evaluations indicated that treatment with donepezil, B vitamins and combination of donepezil and B vitamins attenuated the deficits in dopamine, norepinephrine, Nrf2, SOD and reduced glutathione, while also reducing the elevated levels of malondialdehyde, nitric oxide, AChE, caspase 9 and inflammatory markers. These observations were corroborated by result of histopathological evaluation. The combination of donepezil and vitamin B12, B6 and B1 proved to be more effective than donepezil monotherapy. Donepezil conferred significant protection against AlCl₃–induced neurotoxicity, however, the combination of donepezil and vitamin B12, vitamin B6 and Vitamin B1 significantly performed better in neuroprotective indices than donepezil monotherapy. The combination of donepezil and vitamin B1 was better amongst the three combination therapies in this study.