Identifying a Therapeutic Window for Intranasal Insulin Administration in a Two-Vessel Rat Model of Forebrain Ischemia and Investigating the Mechanisms of Its Neuroprotective Action

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Abstract Global cerebral ischemia is a significant medical and social challenge that necessitates the development of effective neuroprotectors and treatment strategies. Given that cerebral ischemia has a complex pathogenesis with a prolonged recovery period, the drugs with pleiotropic effects, including intranasal insulin (INI), are of primary interest. INI enters the brain and, through central mechanisms, regulates metabolism while exerting neuroprotective and neuromodulatory effects. Although INI is effective in neurodegenerative diseases, data on its neuroprotective action in cerebral ischemia remain fragmented. The aim of this study was to identify a “therapeutic window” for INI administration and evaluate the mechanisms of its neuroprotective effect in a two-vessel occlusion/hypotension model of forebrain ischemia in rats. INI was administered to rats 2 and 4 h after ischemic exposure at a dose of 0.5 IU/rat/day, and for 7 days onward, once a day, at the same dose. INI proved to be more effective when administered 2 rather than 4 h post exposure, despite subsequent 7-day treatment. When administered 2 h post-ischemically, INI sustained the expression of insulin signaling genes in the hippocampus, normalized cell counts in the CA1 hippocampal region, stimulated gene expression of the anti-apoptotic protein Bcl-2, and reduced the expression of Gfap and Aif1 genes, markers of astrocytes and microglia, thereby suggesting its anti-inflammatory effect. Additionally, INI stimulated thyroid system’s activity, preventing the development of post-ischemic hypothyroidism, which may also contribute to INI-mediated neuroprotection. These effects were either poorly manifested or absent when INI was administered 4 h after cerebral ischemia. Thus, for the first time, we have identified a “therapeutic window” for INI administration in cerebral ischemia and evaluated some mechanisms of its neuroprotective action. The obtained data open new prospects for developing innovative neuroprotection strategies in cerebral ischemia.

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