ACETATE AMELIORATES GLUCOSE DYSREGULATION AND NEUROBEHAVIOURAL DEFICIT IN DEXAMETHASONE PLUS SCOPOLAMINE-TREATED MICE: GUT-HEART-BRAIN CROSSTALK

Abstract

Objective: Cardiometabolic disorders have been shown to be associated with the etiology of neurodegenerative diseases but the mechanisms are elusive. There is increasing evidence that the gut microbiota-derived short-chain fatty acids (SCFAs) plays key role in mediating the beneficial effects of the gut microbiome in maintenance of host health. This study was designed to investigate whether SCFA, acetate, would mitigate dexamethasone plus scopolamine-induced dysmetabolism and cognitive decline. Design and method: Male mice (n = 6/group) received (p.o.) vehicle, dexamethasone with scopolamine (DEX; 0.2 mg/kg + SC; 3.0 mg/kg), DEX+SC with sodium acetate (ACE; 200 mg/kg) and DEX+SC with donepezil hydrochloride (DP; 1.0 mg/kg) for 7 days. Morris water maze was used to examine spatial learning and memory while Y-maze was used to determine working and cognitive memory respectively. Oral glucose tolerance test was carried. Results: Degenerative changes such as weight loss, reduced exploratory/working memory, frontal-dependent motor deficits, cognitive decline, memory dysfunction and anxiety during behavioural assessments were noticed in DEX+SC-treated mice compared to control. Furthermore, DEX+SC treatment led to impaired glucose tolerance, elevated 1-hour postload glucose response and increased triglyceride-glucose index. Likewise oxidative impairment was indicated by depleted plasma, cardiac and brain glutathione reductase, nitric oxide and elevated lipid peroxidation (malondialdehyde). Cholinergic deficits characterized by increased neural acetylcholinestrase (AChE) expression and elevated uric acid, lactate dehydrogenase, lactate the plasma, cardiac and neural tissues of the DEX+SC-treated mice further implied cardiac dysfunction alongside the degenerative changes. Consequently, proteolysis was evident by observed diminshed Nissl profiles in axons and dendrites of neurons which correspond to apoptotic changes observed in H&E staining of prefrontal cortex and hippocampal sections. Conclusions: Interestingly, ACE treatment ameliorated the DEX+SC-induced behavioural deficits and cardiometabolic dysfunctions in mice. The effects of ACE treatment were comparable to the DP in DEX+SC-treated rats. Hence, ACE prevents neural and cardiac oxidative damage, behavioural deficits and glucose deregulation. Furthermore, ACE could be a potential AChE inhibitor. These findings suggest that the gut microbiota-derived SCFA, acetate, would be a cost effective therapeutic target for inhibition of neuro-cardiac degenerative processes and behavioural deficits through the gut-heart-brain crosstalk