Investigating molecular mechanisms in ischemic preconditioning-induced resiliency to severe acute global cerebral ischemia using a mouse model of chronic cerebral hypoperfusion

Investigating molecular mechanisms in ischemic preconditioning-induced resiliency to severe acute global cerebral ischemia using a mouse model of chronic cerebral hypoperfusion | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Investigating molecular mechanisms in ischemic preconditioning-induced resiliency to severe acute global cerebral ischemia using a mouse model of chronic cerebral hypoperfusion Roli Kushwaha, Shashikant Patel, Yuvaraj KS, Pooja Sharma, Arvind Kumar, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5804657/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Mar, 2025 Read the published version in Cellular and Molecular Neurobiology → Version 1 posted 9 You are reading this latest preprint version Abstract Cerebral ischemic preconditioning offers a promising strategy to enhance resilience to severe ischemic insults. Unilateral common carotid artery occlusion (UCCAo) is a valuable model to simulate chronic cerebral hypoperfusion (CCH). This study explored UCCAo induced CCH as a preconditioning stimulus to induce ischemic tolerance against transient global cerebral ischemia (tGCI) induced by bilateral common carotid artery occlusion (BCCAo) in both male and female mice. We evaluated the effects of CCH preconditioning on neuroprotection and recovery through behavioral, histopathological, and molecular analyses. Laser Doppler Imaging (LDI) confirmed significant cerebral hypoperfusion post-UCCAo. Preconditioning reduced mortality rates at day 1 and 7 post surgery as compared to BCCAo, suggesting its neuroprotective potential. Neurodeficit scoring demonstrated significant protection in preconditioned animals with recovery aligning closer to sham controls. Behavioral assays revealed improved motor and cognitive outcomes in preconditioned groups, with sex-specific differences evident in recovery dynamics. Molecular analyses indicated reduced reactive astrocyte (GFAP) and microglial (IBA1) activation in preconditioned animals, reflecting controlled glial responses. Sex-dependent variations in markers of hypoxia (Hif1a), autophagy (Becn1) and neurogenesis (Sox2) highlighted neuroadaptive and cellular influences on ischemic resilience. Preconditioning enhanced synaptic plasticity by upregulating PSD-95, synaptophysin and BDNF levels. Additionally, preconditioning increased VEGF expression in blood serum reflecting vascular remodeling and neuroprotective angiogenesis. This study positions UCCAo induced CCH as a reliable model for exploring ischemic tolerance mechanisms to advance therapeutic strategies for mitigating the effects of ischemic stroke. Neuroprotection Chronic ischemia Astroglial activation Striatum Cognitive impairments Sex differences Full Text Additional Declarations No competing interests reported. Supplementary Files Kushwahaetal.Supplementary.pdf GRAPHICALABSTRACT.tif Cite Share Download PDF Status: Published Journal Publication published 26 Mar, 2025 Read the published version in Cellular and Molecular Neurobiology → Version 1 posted Editorial decision: Revision requested 18 Feb, 2025 Reviews received at journal 18 Feb, 2025 Reviews received at journal 04 Feb, 2025 Reviewers agreed at journal 28 Jan, 2025 Reviewers agreed at journal 20 Jan, 2025 Reviewers invited by journal 18 Jan, 2025 Editor assigned by journal 11 Jan, 2025 Submission checks completed at journal 11 Jan, 2025 First submitted to journal 10 Jan, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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