Anesthetic and subanesthetic doses of isoflurane conditioning provides strong protection against delayed cerebral ischemia in a mouse model of subarachnoid hemorrhage

Athiraman, Umeshkumar; Liu, Meizi; Jayaraman, Keshav; Yuan, Jane; Mehla, Jogender; Zipfel, Gregory J.

doi:10.1016/j.brainres.2020.147169

Cited by 12 publications

(21 citation statements)

References 27 publications

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“…This protection was casually linked to endothelial cell-derived HIF-1α [14]. More recently, we have shown that isoflurane conditioning provides strong protection against vasospasminduced DCI and neurological deficits in a mouse model of SAH [15,39] and that this protection is critically dependent on eNOS [15].…”

Section: Discussionmentioning

confidence: 95%

“…With respect to SAH-induced brain injury, SIRT1 has been linked to two of the most important forms of post-ictal secondary brain injury: EBI [34][35][36] and DCI [22]. In the case of anesthetic conditioning, there is a growing body of preclinical and clinical evidence indicating a strong protective effect of inhalational anesthetics against SAH-induced DCI [15,[37][38][39][40]. Milner et al [14] previously noted that isoflurane conditioning provides robust protection against multiple elements of DCI including improved neurologic outcomes in a mouse model of SAH.…”

Section: Discussionmentioning

confidence: 99%

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

Liu

Jayaraman

Giri

et al. 2021

IJMS

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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.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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

Liu

Jayaraman

Giri

et al. 2021

IJMS

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“…In all the above-mentioned studies, concentration of isoflurane employed for the experiments was 2%, which is a supratherapeutic dose and not commonly used for the patients during surgical procedures. Therefore, a subsequent study by Athiraman et al, [ 32 ] comparing three different doses of isoflurane (subanesthetic (0.5%), anesthetic (1%) and a supratherapeutic dose (2%)) in a mouse endovascular perforation SAH model provided interesting observation showing that all three doses of isoflurane afforded significant protection against SAH-induced DCI and no difference in neurovascular protection was appreciated between three doses. No mechanism was explored in this study.…”

Section: Anesthetics/adjuvants In DCI After Sahmentioning

confidence: 99%

“…The most studied inhalational anesthetic in preclinical studies has been isoflurane. Several experimental studies have shown that isoflurane provides significant protection against both EBI and DCI after SAH [ 8 , 9 , 10 , 13 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. To date, however, isoflurane has not been examined in clinical studies of SAH.…”

Section: Summary Of Anesthetics/adjuvants and Neurovascular Protectiomentioning

confidence: 99%

Role of Anesthetics and Their Adjuvants in Neurovascular Protection in Secondary Brain Injury after Aneurysmal Subarachnoid Hemorrhage

Athiraman

Zipfel

2021

IJMS

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Aneurysmal rupture accounts for the majority of subarachnoid hemorrhage and is responsible for most cerebrovascular deaths with high mortality and morbidity. Initial hemorrhage severity and secondary brain injury due to early brain injury and delayed cerebral ischemia are the major determinants of outcomes after aneurysmal subarachnoid hemorrhage. Several therapies have been explored to prevent these secondary brain injury processes after aneurysmal subarachnoid hemorrhage with limited clinical success. Experimental and clinical studies have shown a neuroprotective role of certain anesthetics in cerebrovascular disorders including aneurysmal subarachnoid hemorrhage. The vast majority of aneurysmal subarachnoid hemorrhage patients require general anesthesia for surgical or endovascular repair of their aneurysm. Given the potential impact certain anesthetics have on secondary brain injury after SAH, appropriate selection of anesthetics may prove impactful on overall outcome of these patients. This narrative review focuses on the available evidence of anesthetics and their adjuvants in neurovascular protection in aneurysmal subarachnoid hemorrhage and discusses current impact on clinical care and future investigative directions.

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“…This innovative therapeutic approach, termed conditioning, provides an avenue for exploring comprehensive preventative therapies for DCI [11]. Numerous recent studies, including our own, have demonstrated that isoflurane can offer this form of protection against various DCI-related pathologies [12][13][14][15][16]. The potential for isoflurane conditioning to protect against DCI is noteworthy, given its existing use in the clinical setting.…”

Section: Introductionmentioning

confidence: 99%

Sevoflurane and Desflurane Exposures Following Aneurysmal Subarachnoid Hemorrhage Confer Multifaceted Protection against Delayed Cerebral Ischemia

et al. 2021

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Numerous studies have demonstrated the ability of isoflurane conditioning to provide multifaceted protection against aneurysmal subarachnoid hemorrhage (SAH)-associated delayed cerebral ischemia (DCI); however, preclinical studies have not yet examined whether other commonly used inhalational anesthetics in neurological patients such as sevoflurane or desflurane are also protective against SAH-induced neurovascular deficits. We therefore sought to identify the potential for sevoflurane and desflurane conditioning to protect against DCI in an endovascular perforation mouse model of SAH. Neurological function was assessed daily via neuroscore. Large artery vasospasm and microvessel thrombosis were assessed three days after SAH or sham surgery. Four groups were examined: Sham, SAH + room air, SAH + 2% Sevoflurane, and SAH + 6% Desflurane. For the SAH groups, one hour after surgery, mice received 2% sevoflurane, 6% desflurane, or room air for one hour. We found that conditioning with sevoflurane or desflurane attenuated large artery vasospasm, reduced microvessel thrombosis, and improved neurologic function. Given their frequent clinical use and strong safety profile in patients (including those with SAH), these data strongly support further studies to validate these findings in preclinical and clinical studies and to elucidate the mechanisms by which these agents might be acting.

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Anesthetic and subanesthetic doses of isoflurane conditioning provides strong protection against delayed cerebral ischemia in a mouse model of subarachnoid hemorrhage

Cited by 12 publications

References 27 publications

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

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

Role of Anesthetics and Their Adjuvants in Neurovascular Protection in Secondary Brain Injury after Aneurysmal Subarachnoid Hemorrhage

Sevoflurane and Desflurane Exposures Following Aneurysmal Subarachnoid Hemorrhage Confer Multifaceted Protection against Delayed Cerebral Ischemia

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