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Abstract <p>Global cerebral ischemia is a significant medical and socialchallenge that necessitates the development of effective neuroprotectorsand treatment strategies. Given that cerebral ischemia has a complexpathogenesis with a prolonged recovery period, the drugs with pleiotropiceffects, including intranasal insulin (INI), are of primary interest.INI enters the brain and, through central mechanisms, regulatesmetabolism while exerting neuroprotective and neuromodulatory effects.Although INI is effective in neurodegenerative diseases, data onits neuroprotective action in cerebral ischemia remain fragmented.The aim of this study was to identify a “therapeutic window” forINI administration and evaluate the mechanisms of its neuroprotectiveeffect in a two-vessel occlusion/hypotension model of forebrainischemia in rats. INI was administered to rats 2 and 4 h after ischemicexposure at a dose of 0.5&#xa0;IU/rat/day, and for 7 days onward, oncea day, at the same dose. INI proved to be more effective when administered2 rather than 4 h post exposure, despite subsequent 7-day treatment.When administered 2 h post-ischemically, INI sustained the expressionof insulin signaling genes in the hippocampus, normalized cell countsin the CA1 hippocampal region, stimulated gene expression of the anti-apoptoticprotein Bcl-2, and reduced the expression of <i>Gfap</i> and <i>Aif1</i> genes, markers of astrocytes andmicroglia, thereby suggesting its anti-inflammatory effect. Additionally,INI stimulated thyroid system’s activity, preventing the developmentof post-ischemic hypothyroidism, which may also contribute to INI-mediatedneuroprotection. These effects were either poorly manifested orabsent when INI was administered 4 h after cerebral ischemia. Thus,for the first time, we have identified a “therapeutic window” forINI administration in cerebral ischemia and evaluated some mechanismsof its neuroprotective action. The obtained data open new prospectsfor developing innovative neuroprotection strategies in cerebralischemia.</p>

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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

  • 期刊论文

  • 发表日期：

    2025年5月1日

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  • I. I. Zorina,
  • A. S. Pechalnova,
  • E. E. Chernenko,
  • D. K. Avrova,
  • K. V. Derkach,
  • A. O. Shpakov

摘要

Abstract

Global cerebral ischemia is a significant medical and socialchallenge that necessitates the development of effective neuroprotectorsand treatment strategies. Given that cerebral ischemia has a complexpathogenesis with a prolonged recovery period, the drugs with pleiotropiceffects, including intranasal insulin (INI), are of primary interest.INI enters the brain and, through central mechanisms, regulatesmetabolism while exerting neuroprotective and neuromodulatory effects.Although INI is effective in neurodegenerative diseases, data onits neuroprotective action in cerebral ischemia remain fragmented.The aim of this study was to identify a “therapeutic window” forINI administration and evaluate the mechanisms of its neuroprotectiveeffect in a two-vessel occlusion/hypotension model of forebrainischemia in rats. INI was administered to rats 2 and 4 h after ischemicexposure at a dose of 0.5 IU/rat/day, and for 7 days onward, oncea day, at the same dose. INI proved to be more effective when administered2 rather than 4 h post exposure, despite subsequent 7-day treatment.When administered 2 h post-ischemically, INI sustained the expressionof insulin signaling genes in the hippocampus, normalized cell countsin the CA1 hippocampal region, stimulated gene expression of the anti-apoptoticprotein Bcl-2, and reduced the expression of Gfap and Aif1 genes, markers of astrocytes andmicroglia, thereby suggesting its anti-inflammatory effect. Additionally,INI stimulated thyroid system’s activity, preventing the developmentof post-ischemic hypothyroidism, which may also contribute to INI-mediatedneuroprotection. These effects were either poorly manifested orabsent when INI was administered 4 h after cerebral ischemia. Thus,for the first time, we have identified a “therapeutic window” forINI administration in cerebral ischemia and evaluated some mechanismsof its neuroprotective action. The obtained data open new prospectsfor developing innovative neuroprotection strategies in cerebralischemia.