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  • Post-Conditioning with Isoflurane Reduces SAH-induced Vasospasm and Microthrombosis via Hypoxia-Inducible Factor 1 and Nitric Oxide Synthase

    Final Number:

    Eric Milner BS; Michael D Harries; Ananth Kesav Vellimana MD; Jeffrey M. Gidday PhD; Byung Hee Han PhD; Gregory J. Zipfel MD

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2013 Annual Meeting

    Introduction: Aneurysmal subarachnoid hemorrhage (SAH) is a devastating disease associated with high rates of mortality (40% at 1 month) and morbidity (only 50% of survivors return to work). Outcome depends critically on delayed cerebral ischemia (DCI), which includes cerebral vasospasm and microthrombosis. Post-conditioning (postC) describes the phenomenon whereby endogenous protection against severe injury is enhanced by exposure to a subsequent mild, stressful stimulus.

    Methods: Adult male C57BL/6 mice were randomized to three groups: mice subjected to sham or endovascular-perforation SAH surgery, and mice subjected to SAH and subsequently post-conditioned with isoflurane (2% for 1 h, starting 1 h after surgery). DCI, defined herein as vasospasm of the ipsilateral middle cerebral artery, and the extent of cortical microthrombosis as assessed by fibrinogen immunohistochemistry, was measured at 3 days. Neurological outcome was assessed daily via sensorimotor scoring. The first experiment used wild-type (WT) mice, and hypoxia-inducible factor 1 (HIF-1)–dependent genes (erythropoietin (EPO), heme oxygenase 1 (HO-1), and inducible nitric oxide synthase (iNOS)) were also assessed via quantitative PCR. The second experiment used mice deficient for endothelial cell HIF-1 (EC-HIF-1-null). The third experiment used WT mice administered the pan-NOS inhibitor L-NAME (20 mg/kg ip once daily).

    Results: Isoflurane post-conditioning markedly reduced SAH-induced DCI in WT mice: vasospasm was completed attenuated and microthrombosis was significantly reduced. Neurological deficits were also significantly attenuated. This postC-induced neurovascular protection was associated with increased mRNA levels of the HIF-1-dependent genes EPO, HO-1, and iNOS (2.0-, 4.1-, and 2.3-fold, respectively) and was lost in EC-HIF-1-null mice. This protection was also lost in WT mice treated with the pan-NOS inhibitor L-NAME.

    Conclusions: Post-conditioning with isoflurane triggers endogenous protective mechanisms against SAH-induced DCI and neurological deficits. This protection depends critically on endothelial HIF-1 and NOS. Future studies should investigate long-term outcomes in experimental SAH, and explore the suitability of post-conditioning strategies in patients.

    Patient Care: No new pharmacologic therapy for delayed cerebral ischemia (DCI) has emerged since nimodipine thirty years ago. Given the devastating nature of aneurysmal subarachnoid hemorrhage (SAH) and the powerful effect of DCI on patient outcomes, new therapies are sorely needed. A strategy employing post-conditioning could improve patient care, either directly via its pleiotropic effects on SAH-induced neurovascular dysfunction, or by identifying molecular targets that could be modulated pharmacologically.

    Learning Objectives: By the conclusion of this session, participants should be able to: 1) identify isoflurane post-conditioning as being capable of augmenting endogenous protective mechanisms against SAH-induced neurovascular dysfunction; and 2) describe the importance of hypoxia-inducible factor 1 and nitric oxide synthase in this protection.

    References: Stroke. 2011 Mar;42(3):776-82. Epub 2011 Feb 11.

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