Low-Dose Intranasal Metformin Exerts Neuroprotective Effects in a Rat Model of Sporadic Alzheimer's Disease

Current therapies for sporadic Alzheimer's disease (sAD) provide only symptomatic relief, underscoring the need for treatments targeting its underlying pathophysiological mechanisms. Given the shared features between sAD and type 2 diabetes mellitus-particularly insulin resistance-repurposing antidiabetic agents like metformin has gained interest. Previous studies show that metformin rapidly reaches the brain following intranasal (i/n) administration and remains detectable for at least 2 h at a 3 mg/kg dose, supporting this delivery route for central nervous system targeting. I/n delivery of therapeutic agents bypasses the blood-brain barrier, enhances brain bioavailability, and minimizes peripheral side effects of such agents. In this preclinical study, we investigated whether low-dose i/n metformin (1 and 3 mg/kg) administered for 28 days could halt sAD-type changes. Our results demonstrate that i/n metformin improved cognitive function, including social behavior, in an intracerebroventricular streptozotocin (3 mg/kg)-induced rat model of sAD. Metformin administered i/n also reduced hippocampal microgliosis and apoptosis and enhanced phosphorylation of Akt and adenosine monophosphate-activated protein kinase. Moreover, it decreased hippocampal glycogen synthase kinase-3 beta levels, suggesting modulation of insulin signaling pathways. Notably, these neuroprotective effects were achieved at doses much lower than those used with systemic administration, underscoring the advantages of i/n delivery. Our findings suggest that low-dose i/n metformin is a promising, non-invasive, and disease-modifying therapeutic strategy for sAD, warranting further investigation.