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    Low-Dose Intranasal Metformin Exerts Neuroprotective Effects in a Rat Model of Sporadic Alzheimer's Disease
    (Springer, 2025) Kurtukova, Vladislava; Aktas, Selen; Pupure, Jolanta; Narbute, Karina; Muceniece, Ruta; Pilipenko, Vladimirs
    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.