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


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 3days 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).


RESULTS
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.


CONCLUSIONS
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.
Department of Nuclear Medicine and Radiology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Tomoko
T
Mutoh
Department of Nuclear Medicine and Radiology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan; Department of Surgical Neurology, Research Institute for Brain and Blood Vessels-AKITA, Akita, Japan. Electronic address: tmutoh@tiara.ocn.ne.jp.
Tatsushi
T
Mutoh
Department of Surgical Neurology, Research Institute for Brain and Blood Vessels-AKITA, Akita, Japan.
Kazumasu
K
Sasaki
Primetech Life Science Laboratory, Tokyo, Japan.
Yukiko
Y
Yamamoto
Primetech Life Science Laboratory, Tokyo, Japan.
Yoshiharu
Y
Tsuru
Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
Hirokazu
H
Tsubone
Department of Surgical Neurology, Research Institute for Brain and Blood Vessels-AKITA, Akita, Japan.
Tatsuya
T
Ishikawa
Department of Nuclear Medicine and Radiology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Yasuyuki
Y
Taki
D000818:Animals; D001930:Brain Injuries / Q000209:etiology / Q000534:rehabilitation*; D004280:Dobutamine / Q000008:administration & dosage; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013345:Subarachnoid Hemorrhage / Q000150:complications*
D004280:Dobutamine; D007530:Isoflurane
Delayed cerebral ischemia; Dobutamine; Isoflurane; Neuroprotection; Postconditioning; Subarachnoid hemorrhage