Role of SIRT1 in Isoflurane Conditioning-Induced Neurovascular Protection against Delayed Cerebral Ischemia Secondary to Subarachnoid Hemorrhage

Meizi Liu,Gregory J Zipfel,Keshav Jayaraman,Umeshkumar Athiraman,Tusar Giri

doi:10.3390/ijms22084291

Meizi Liu, Gregory J Zipfel + Show 3 more

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https://doi.org/10.3390/ijms22084291

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Abstract

We recently reported that isoflurane conditioning provided multifaceted protection against subarachnoid hemorrhage (SAH)-induced delayed cerebral ischemia (DCI), and this protection was through the upregulation of endothelial nitric oxide synthase (eNOS). SIRT1, an NAD-dependent deacetylase, was shown to be one of the critical regulators of eNOS. The aim of our current study is to examine the role of SIRT1 in isoflurane conditioning-induced neurovascular protection against SAH-induced DCI. Mice were divided into four groups: sham, SAH, or SAH with isoflurane conditioning (with and without EX-527). Experimental SAH via endovascular perforation was performed. Anesthetic conditioning was performed with isoflurane 2% for 1 h, 1 h after SAH. EX-527, a selective SIRT1 inhibitor, 10 mg/kg was injected intraperitoneally immediately after SAH in the EX-527 group. SIRT1 mRNA expression and activity levels were measured. Vasospasm, microvessel thrombosis, and neurological outcome were assessed. SIRT1 mRNA expression was downregulated, and no difference in SIRT1 activity was noted after isoflurane exposure. Isoflurane conditioning with and without EX-527 attenuated vasospasm, microvessel thrombosis and improved neurological outcomes. Our data validate our previous findings that isoflurane conditioning provides strong protection against both the macro and micro vascular deficits induced by SAH, but this protection is likely not mediated through the SIRT1 pathway.

Highlights

Aneurysmal subarachnoid hemorrhage (SAH) is a severe form of stroke with extremely high morbidity and mortality [1], much of which stems from a secondary brain injury process called delayed cerebral ischemia (DCI) [2]
SIRT1 mRNA expression and activity were measured at different time points after
SIRT1 mRNA expression and activity were measured at different time points after decreased SIRT1 mRNA expression until 12 h (p < 0.05), and a nonsignificant decrease in single time exposure to 2% isoflurane for one hour

Summary

Introduction

Aneurysmal subarachnoid hemorrhage (SAH) is a severe form of stroke with extremely high morbidity and mortality [1], much of which stems from a secondary brain injury process called delayed cerebral ischemia (DCI) [2]. DCI was solely attributed to vasospasm, which is characterized by large artery narrowing 4–12 d after. In recent years, several additional processes affecting the microcirculation have been causally linked to DCI, including autoregulatory dysfunction [4,5]. DCI, which is likely due to targeting individual elements of what has proven to be a multifactorial process. Future therapies should be designed to target both large artery vasospasm and microcirculatory deficits to be effective. To address this issue, we and others have applied a therapeutic strategy—conditioning—that leverages endogenous molecular mechanisms to exert a powerful and remarkably pleiotropic protective effect against DCI after SAH. Neurons were felt to be the principal target of this response (neuronal conditioning) [8], but multiple lines of evidence show that glia (glial conditioning) [9]

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