Abstract
Objective: Ischemic preconditioning (IPC) serves as a protective role in improving ischemic tolerance to subsequent severe stroke. Understanding the mechanisms underlying IPC-induced neuroprotection is essential to reveal potential therapeutic targets of ischemia attack. Here, we tested the hypothesis that moderate level flux of nitrosative stress contributes to IPC-associated neurovascular protection in mice subjected to ischemia-reperfusion injury. Methods: IPC was modeled in WT or eNOS -/- mice with two cycles of 5-min ischemia and 30-min reperfusion. 24h-reperfusion later, mice were subjected to 2h-transient middle cerebral artery occlusion (tMCAO) and neurological deficits, infarct volume, blood-brain barrier (BBB) permeability as well as neurovascular damage-related protein expression were evaluated 24 h later. Peroxynitrite donor SIN-1 preconditioning in brain and knockout of eNOS were further performed to determine the role of nitrosative stress during ischemic preconditioning. Results: IPC treatment ameliorated neurological dysfunction after cerebral ischemia compared to the tMCAO group without IPC, which was accompanied by a reduction of infract volume, evans blue leakage from BBB and MMP9 activation. In contract, inhibition of nitrosative stress by eNOS deficiency blocked the benefits of IPC on neurovascular protection during ischemic stroke. SIN-1 preconditioning at 0.5 mM significantly decreased neurological deficit scores and infarct volume after ischemic stroke. While both of 0.1 mM and 2 mM SIN-1 failed to active cell survival programs against ischemic injury. Conclusion: Nitrosative stress at moderate level is a key mediator of IPC-associated cell survival response and neurovascular protection during ischemic insult, thus implicating a novel therapeutic approach that selectively targeting nitrosative stress to active cell survival response during adaptive phase and ameliorate prolonged ischemic damage during later phase in stroke.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
