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HIF-1α Mediates Isoflurane-Induced Vascular Protection in Subarachnoid Hemorrhage.

Milner E, Johnson AW, Nelson JW, Harries MD, Gidday JM, Han BH, Zipfel GJ - Ann Clin Transl Neurol (2015)

Bottom Line: Isoflurane postconditioning provides strong HIF-1α-mediated macro- and microvascular protection in SAH, leading to improved neurological outcome.These results implicate cerebral vessels as a key target for the brain protection afforded by isoflurane postconditioning, and HIF-1α as a critical mediator of this vascular protection.They also identify isoflurane postconditioning as a promising novel therapeutic for SAH.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurological Surgery, Washington University School of Medicine St. Louis, Missouri, 63108 ; Program in Neuroscience, Washington University School of Medicine St. Louis, Missouri, 63108.

ABSTRACT

Objective: Outcome after aneurysmal subarachnoid hemorrhage (SAH) depends critically on delayed cerebral ischemia (DCI) - a process driven primarily by vascular events including cerebral vasospasm, microvessel thrombosis, and microvascular dysfunction. This study sought to determine the impact of postconditioning - the phenomenon whereby endogenous protection against severe injury is enhanced by subsequent exposure to a mild stressor - on SAH-induced DCI.

Methods: Adult male C57BL/6 mice were subjected to sham, SAH, or SAH plus isoflurane postconditioning. Neurological outcome was assessed daily via sensorimotor scoring. Contributors to DCI including cerebral vasospasm, microvessel thrombosis, and microvascular dysfunction were measured 3 days later. Isoflurane-induced changes in hypoxia-inducible factor 1alpha (HIF-1α)-dependent genes were assessed via quantitative polymerase chain reaction. HIF-1α was inhibited pharmacologically via 2-methoxyestradiol (2ME2) or genetically via endothelial cell HIF-1α- mice (EC-HIF-1α-). All experiments were performed in a randomized and blinded fashion.

Results: Isoflurane postconditioning initiated at clinically relevant time points after SAH significantly reduced cerebral vasospasm, microvessel thrombosis, microvascular dysfunction, and neurological deficits in wild-type (WT) mice. Isoflurane modulated HIF-1α-dependent genes - changes that were abolished in 2ME2-treated WT mice and EC-HIF-1α- mice. Isoflurane-induced DCI protection was attenuated in 2ME2-treated WT mice and EC-HIF-1α- mice.

Interpretation: Isoflurane postconditioning provides strong HIF-1α-mediated macro- and microvascular protection in SAH, leading to improved neurological outcome. These results implicate cerebral vessels as a key target for the brain protection afforded by isoflurane postconditioning, and HIF-1α as a critical mediator of this vascular protection. They also identify isoflurane postconditioning as a promising novel therapeutic for SAH.

No MeSH data available.


Related in: MedlinePlus

Postconditioning improves neurological outcome after SAH. Mice underwent sham surgery; subarachnoid hemorrhage (SAH) surgery; or SAH surgery followed by isoflurane postconditioning (2% for 1 h, SAH-postC) starting 15 min, 1 h, 3 h, or 6 h after surgery. Neurobehavioral assessment was performed on post surgery days 0–3 via sensorimotor scoring. N = 6 sham, N = 10 SAH, N = 16 SAH-postC-15′, N = 12 SAH-postC-1 h, N = 14 SAH-postC-3 h, N = 15 SAH-postC-6 h (the same animals as were assessed for vasospasm in Fig.1). Data represent mean ± SEM. *P < 0.05 versus sham, #P < 0.05 versus SAH, by repeated measures ANOVA and Newman–Keuls multiple comparison test.
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fig04: Postconditioning improves neurological outcome after SAH. Mice underwent sham surgery; subarachnoid hemorrhage (SAH) surgery; or SAH surgery followed by isoflurane postconditioning (2% for 1 h, SAH-postC) starting 15 min, 1 h, 3 h, or 6 h after surgery. Neurobehavioral assessment was performed on post surgery days 0–3 via sensorimotor scoring. N = 6 sham, N = 10 SAH, N = 16 SAH-postC-15′, N = 12 SAH-postC-1 h, N = 14 SAH-postC-3 h, N = 15 SAH-postC-6 h (the same animals as were assessed for vasospasm in Fig.1). Data represent mean ± SEM. *P < 0.05 versus sham, #P < 0.05 versus SAH, by repeated measures ANOVA and Newman–Keuls multiple comparison test.

Mentions: To determine whether the breadth of protection afforded by postconditioning extends from the cerebrovasculature to functional outcomes, neurological status was assessed before SAH and daily thereafter via sensorimotor scoring. SAH caused significant neurological deficits, which were markedly attenuated by isoflurane postconditioning beginning at 15 min, 1 h, or 3 h, but not at 6 h, after ictus (Fig.4; P < 0.05, repeated measures ANOVA). The neurovascular protection afforded by isoflurane postconditioning was not related to isoflurane-induced physiological changes, as no significant differences in arterial pH, pCO2, pO2, O2 saturation, hematocrit, and hemoglobin were noted across experimental groups (Table1).


HIF-1α Mediates Isoflurane-Induced Vascular Protection in Subarachnoid Hemorrhage.

Milner E, Johnson AW, Nelson JW, Harries MD, Gidday JM, Han BH, Zipfel GJ - Ann Clin Transl Neurol (2015)

Postconditioning improves neurological outcome after SAH. Mice underwent sham surgery; subarachnoid hemorrhage (SAH) surgery; or SAH surgery followed by isoflurane postconditioning (2% for 1 h, SAH-postC) starting 15 min, 1 h, 3 h, or 6 h after surgery. Neurobehavioral assessment was performed on post surgery days 0–3 via sensorimotor scoring. N = 6 sham, N = 10 SAH, N = 16 SAH-postC-15′, N = 12 SAH-postC-1 h, N = 14 SAH-postC-3 h, N = 15 SAH-postC-6 h (the same animals as were assessed for vasospasm in Fig.1). Data represent mean ± SEM. *P < 0.05 versus sham, #P < 0.05 versus SAH, by repeated measures ANOVA and Newman–Keuls multiple comparison test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4402079&req=5

fig04: Postconditioning improves neurological outcome after SAH. Mice underwent sham surgery; subarachnoid hemorrhage (SAH) surgery; or SAH surgery followed by isoflurane postconditioning (2% for 1 h, SAH-postC) starting 15 min, 1 h, 3 h, or 6 h after surgery. Neurobehavioral assessment was performed on post surgery days 0–3 via sensorimotor scoring. N = 6 sham, N = 10 SAH, N = 16 SAH-postC-15′, N = 12 SAH-postC-1 h, N = 14 SAH-postC-3 h, N = 15 SAH-postC-6 h (the same animals as were assessed for vasospasm in Fig.1). Data represent mean ± SEM. *P < 0.05 versus sham, #P < 0.05 versus SAH, by repeated measures ANOVA and Newman–Keuls multiple comparison test.
Mentions: To determine whether the breadth of protection afforded by postconditioning extends from the cerebrovasculature to functional outcomes, neurological status was assessed before SAH and daily thereafter via sensorimotor scoring. SAH caused significant neurological deficits, which were markedly attenuated by isoflurane postconditioning beginning at 15 min, 1 h, or 3 h, but not at 6 h, after ictus (Fig.4; P < 0.05, repeated measures ANOVA). The neurovascular protection afforded by isoflurane postconditioning was not related to isoflurane-induced physiological changes, as no significant differences in arterial pH, pCO2, pO2, O2 saturation, hematocrit, and hemoglobin were noted across experimental groups (Table1).

Bottom Line: Isoflurane postconditioning provides strong HIF-1α-mediated macro- and microvascular protection in SAH, leading to improved neurological outcome.These results implicate cerebral vessels as a key target for the brain protection afforded by isoflurane postconditioning, and HIF-1α as a critical mediator of this vascular protection.They also identify isoflurane postconditioning as a promising novel therapeutic for SAH.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurological Surgery, Washington University School of Medicine St. Louis, Missouri, 63108 ; Program in Neuroscience, Washington University School of Medicine St. Louis, Missouri, 63108.

ABSTRACT

Objective: Outcome after aneurysmal subarachnoid hemorrhage (SAH) depends critically on delayed cerebral ischemia (DCI) - a process driven primarily by vascular events including cerebral vasospasm, microvessel thrombosis, and microvascular dysfunction. This study sought to determine the impact of postconditioning - the phenomenon whereby endogenous protection against severe injury is enhanced by subsequent exposure to a mild stressor - on SAH-induced DCI.

Methods: Adult male C57BL/6 mice were subjected to sham, SAH, or SAH plus isoflurane postconditioning. Neurological outcome was assessed daily via sensorimotor scoring. Contributors to DCI including cerebral vasospasm, microvessel thrombosis, and microvascular dysfunction were measured 3 days later. Isoflurane-induced changes in hypoxia-inducible factor 1alpha (HIF-1α)-dependent genes were assessed via quantitative polymerase chain reaction. HIF-1α was inhibited pharmacologically via 2-methoxyestradiol (2ME2) or genetically via endothelial cell HIF-1α- mice (EC-HIF-1α-). All experiments were performed in a randomized and blinded fashion.

Results: Isoflurane postconditioning initiated at clinically relevant time points after SAH significantly reduced cerebral vasospasm, microvessel thrombosis, microvascular dysfunction, and neurological deficits in wild-type (WT) mice. Isoflurane modulated HIF-1α-dependent genes - changes that were abolished in 2ME2-treated WT mice and EC-HIF-1α- mice. Isoflurane-induced DCI protection was attenuated in 2ME2-treated WT mice and EC-HIF-1α- mice.

Interpretation: Isoflurane postconditioning provides strong HIF-1α-mediated macro- and microvascular protection in SAH, leading to improved neurological outcome. These results implicate cerebral vessels as a key target for the brain protection afforded by isoflurane postconditioning, and HIF-1α as a critical mediator of this vascular protection. They also identify isoflurane postconditioning as a promising novel therapeutic for SAH.

No MeSH data available.


Related in: MedlinePlus