Elsevier

Life Sciences

Volume 153, 15 May 2016, Pages 35-40
Life Sciences

Isoflurane postconditioning with cardiac support promotes recovery from early brain injury in mice after severe subarachnoid hemorrhage

https://doi.org/10.1016/j.lfs.2016.04.020Get rights and content

Abstract

Aims

Neurocardiac dysfunction is a life-threatening systemic consequence of subarachnoid hemorrhage (SAH) that contributes to triggering delayed cerebral ischemia (DCI). This study aimed to determine the impact of dobutamine cardiac support during isoflurane postconditioning on post-SAH DCI.

Main methods

Male C57BL/6 mice were subjected to SAH, SAH plus isoflurane postconditioning, or SAH plus isoflurane postconditioning with dobutamine. Severity of SAH was graded from 1 to 4 (mild, 1–2; severe, 3–4) based on T2*-weighted magnetic resonance imaging (MRI). Cardiac output (CO) measured by transthoracic pulsed wave Doppler-echocardiography was titrated at a supra-normal level with intravenous dobutamine infusion. Neurological function was examined daily by neurological score and Rotarod tests. DCI was analyzed 3 days later by determining new infarction on diffusion-weighted MRI. In a separate experiment, mice were pretreated with hypoxia-inducible factor (HIF) inhibitor 2-methoxyestradiol (2ME2).

Key findings

Clinically relevant CO depression was notable in severe SAH grade mice, in which dobutamine CO management combined with isoflurane postconditioning showed earlier and improved functional recovery than postconditioning with single isoflurane inhalation. Incidence of infarction and volumes on day 3 reduced significantly in this subgroup. All of the effects during preconditioning were attenuated by 2ME2 pretreatment.

Significance

Isoflurane postconditioning under dobutamine cardiac support improves recovery from SAH-induced early brain injury, leading to reduced DCI resultant from severe experimental SAH. These results indicate the importance of neuro-cardiac protection, in which HIF may be acting as a critical mediator, as a promising therapeutic approach to SAH.

Introduction

Neurogenic cardiac injury is an early life-threatening systemic consequence of subarachnoid hemorrhage (SAH), which plays an important role in triggering delayed cerebral ischemia (DCI) [1]. DCI is the most common and potentially treatable cause of secondary neurological injury following SAH [2]. The pathogenesis of DCI is primarily vascular (vasospasm, microvascular dysfunction, and microvessel thrombosis) related to post-hemorrhagic early brain injury [3], [4]. In this context, a conditioning-based strategy focusing on endogenous protective cascades that protects the neurovascular unit would represent a robust therapeutic approach to post-SAH DCI. Furthermore, systemic hemodynamic insufficiency associated with acute left ventricular dysfunction following SAH can also contribute to the development of DCI, particularly in severe grade SAH patients [1], [5], [6], [7].

Recent experimental evidence suggests that the major volatile anesthetic isoflurane, when delivered as a postconditioning therapeutic agent, can provide powerful neurovascular protection against SAH, in which vascular endothelium-derived hypoxia-inducible factor (HIF) has been implicated as a critical mediator [8]. However, to the authors' knowledge, little data is available regarding the therapeutic efficacy of cardiac support for HIF-mediated neuroprotection. Therefore, in this proof-of-concept study, we sought to determine the impact of dobutamine-mediated cardiac management during isoflurane postconditioning on post-SAH DCI.

Section snippets

Animals

Male C57BL/6 N mice weighing 21–25 g purchased from Charles River Laboratories Japan (Kanagawa, Japan) were housed in groups of five per cage (28 × 42 × 20 cm). They were maintained at 24 ± 1 °C in an air-conditioned environment with a 12 h light/dark cycle and received a standard rodent diet and water ad libitum. A total of 70 mice were used at 9 weeks of age. All experimental protocols in this study were in compliance with Association for Assessment and Accreditation of Laboratory Animal Care and

Baseline characteristics of the mouse SAH model

Among the 70 total mice, twelve (17%) were scored as grade 1, ten (14%) as grade 2, twenty-six (37%) as grade 3, and twenty-two (31%) as grade 4 for post-SAH evaluation using 3-D T2*WI. MRI-based grading (mild and severe SAH: Control, 30% and 70%; PC, 30% and 70%; PC-DOB 25% and 75%, respectively) and mortality within 3 days of the study period (Control, 25%; PC, 20%; and 20% PC-DOB) were not significantly different among the groups (P > 0.05). No animals died or exhibited MRI DWI-evidence of

Discussion

SAH is characterized by an unique pathophysiology: the occurrence of an initial hit to the brain (“early brain injury”) at the moment of aneurysm rupture/bleeding that leads to intracranial hypertension and/or cerebral ischemia, which is often followed by secondary DCI occurring days after the initial insult via multifactorial mechanisms [22]. Recent experimental data suggest that postconditioning with isoflurane with clinically relevant doses and durations (2% for 1 h, administered 1 h after

Conclusions

Isoflurane postconditioning under dobutamine cardiac support improves recovery from SAH-induced early brain injury, leading to reduced DCI of severe experimental SAH. These results highlight the importance of neuro-cardiac protection, in which HIF may be acting as a critical mediator, as a promising therapeutic approach to SAH.

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgments

This study was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (15K10966), Life Science Foundation of Japan, and Cooperative Research Project Program of Joint Usage/Research Center at the Institute of Development, Aging and Cancer, Tohoku University.

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