Metformin, an antidiabetic drug, reduces neurodegeneration in rat hippocampus by disrupting adenosine receptor signalling
Adenosine signalling has been implicated in the pathophysiology of CNS disorders, such as stroke, epilepsy and Parkinson’s disease (PD). Recent reports suggest that prolonged activation of adenosine A1 and A2A receptors during stroke increases hippocampal neurodegeneration. Epidemiological studies suggested that the anti-diabetic drug metformin could promote neuroprotection in stroke patients, but the precise mechanism of this neuroprotective property remains unclear, and current literature was often conflicting. Based on pilot studies carried out initially in ex vivo rat hippocampal brain slices, we investigated our hypothesis that metformin binds to adenosine receptors to mediate neuroprotection. Using in vivo administration of adenosine A1 receptor agonist N(6)cyclopentyladenosine (CPA), with or without the A1R antagonist dipropylcyclopentylxanthine (DPCPX), and elevation of endogenous adenosine in our ex-vivo hypoxia-reperfusion model, we aimed to characterize the effects of metformin co-treatments on the electrophysiological, biochemical, and morphological changes in rat hippocampus and correlated these with behavioral outcomes. Results indicated that metformin treatments prevented synaptic depression induced by CPA administration or hypoxia treatments. Moreover, metformin reduced adenosine A1 receptor-mediated hippocampal neurodegeneration and behavioral deficits. Finally, radioligand binding studies revealed a potential binding affinity of metformin to A1Rs from hippocampal membranes. In conclusion, the clinically approved metformin was effective in preventing A1R-mediated hippocampal neuronal damage, synaptic depression and accompanying behavioral abnormalities. Metformin, with partial binding affinity to at least the A1R, exhibits neuroprotective properties by acting to antagonize the effects of endogenous adenosine during ischemic conditions. This study provides support that chronic A1R stimulation promotes neurodegeneration and behavioral deficits that can be partially inhibited by the clinically approved and putative A1R antagonist metformin.
Adenosine, Metformin, Stroke, Neuroprotection, Hippocampus
Master of Science (M.Sc.)