Pathogenic and Therapeutic Perspectives of 17β-Estradiol in the Treatment of Subarachnoid Hemorrhage-induced Vasospasm and Secondary Brain Injury

Chih Lung Lin, Wen Sen Lee, Chin Hsu

研究成果: 雜誌貢獻文章

摘要

Although cerebral vasospasm following subarachnoid hemorrhage (SAH) has been known for more than half of a century, SAH-induced cerebral vasospasm is still a major cause of mortality and neurological morbidity in patients with ruptured intracranial aneurysm. In spite of the intensive research efforts, SAH-induced vasospasm remains incompletely understood from both pathogenic and therapeutic perspectives. At present, effective preventive and therapeutic strategies are available in clinical practice only. Many pathological processes have been proposed for the pathogenesis of delayed cerebral vasospasm following SAH, such as endothelial damage, smooth muscle contraction, change in vascular responsiveness, and inflammatory and/or immunological response of the vascular wall. Gender differences in the outcome of aneurysmal SAH are controversial, and the potential influence of estradiol on SAH-induced vasospasm and secondary brain injury is emerging as an alternative tactic for managing aneurysm in SAH. Treatment with 17β-estradiol (E2) at different physiological levels prevents experimental SAH-induced cerebral vasospasm in rats. The beneficial effect of E2 may, in part, be related to the prevention of augmentation of inducible nitric oxide synthase (iNOS) expression and the preservation of normal endothelial nitric oxide synthase expression following SAH. This mechanism of inhibition of the SAH-induced increase in iNOS levels occurs by increasing the association of the p65/ER complex, which in turn inhibits the binding of p65 to the iNOS DNA. In addition, E2 also acts at the apoptotic signals including tumor necrosis factor-α, caspase-3, and Bcl-2, and increases the levels of adenosine A2A receptor (AR-A2A), ERK, and phospho-Akt in the dentate gyrus to prevent SAH-induced apoptotic death. The antispastic and antiapoptotic effects of E2 are achieved through estrogen receptor-dependent mechanisms. These data support further investigation of using E2 in the treatment of SAH in humans.

原文英語
頁(從 - 到)325-329
頁數5
期刊Journal of Experimental and Clinical Medicine(Taiwan)
4
發行號6
DOIs
出版狀態已發佈 - 十二月 2012

指紋

Subarachnoid Hemorrhage
Brain Injuries
Estradiol
Intracranial Vasospasm
Nitric Oxide Synthase Type II
Therapeutics
Blood Vessels
Adenosine A2A Receptors
Ruptured Aneurysm
Nitric Oxide Synthase Type III
Dentate Gyrus
Intracranial Aneurysm
Pathologic Processes
Muscle Contraction
Caspase 3
Estrogen Receptors
Aneurysm
Smooth Muscle
Tumor Necrosis Factor-alpha
Morbidity

ASJC Scopus subject areas

  • Medicine(all)

引用此文

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title = "Pathogenic and Therapeutic Perspectives of 17β-Estradiol in the Treatment of Subarachnoid Hemorrhage-induced Vasospasm and Secondary Brain Injury",
abstract = "Although cerebral vasospasm following subarachnoid hemorrhage (SAH) has been known for more than half of a century, SAH-induced cerebral vasospasm is still a major cause of mortality and neurological morbidity in patients with ruptured intracranial aneurysm. In spite of the intensive research efforts, SAH-induced vasospasm remains incompletely understood from both pathogenic and therapeutic perspectives. At present, effective preventive and therapeutic strategies are available in clinical practice only. Many pathological processes have been proposed for the pathogenesis of delayed cerebral vasospasm following SAH, such as endothelial damage, smooth muscle contraction, change in vascular responsiveness, and inflammatory and/or immunological response of the vascular wall. Gender differences in the outcome of aneurysmal SAH are controversial, and the potential influence of estradiol on SAH-induced vasospasm and secondary brain injury is emerging as an alternative tactic for managing aneurysm in SAH. Treatment with 17β-estradiol (E2) at different physiological levels prevents experimental SAH-induced cerebral vasospasm in rats. The beneficial effect of E2 may, in part, be related to the prevention of augmentation of inducible nitric oxide synthase (iNOS) expression and the preservation of normal endothelial nitric oxide synthase expression following SAH. This mechanism of inhibition of the SAH-induced increase in iNOS levels occurs by increasing the association of the p65/ER complex, which in turn inhibits the binding of p65 to the iNOS DNA. In addition, E2 also acts at the apoptotic signals including tumor necrosis factor-α, caspase-3, and Bcl-2, and increases the levels of adenosine A2A receptor (AR-A2A), ERK, and phospho-Akt in the dentate gyrus to prevent SAH-induced apoptotic death. The antispastic and antiapoptotic effects of E2 are achieved through estrogen receptor-dependent mechanisms. These data support further investigation of using E2 in the treatment of SAH in humans.",
keywords = "17 beta-estradiol, Brain injury, Subarachnoid hemorrhage, Vasospasm",
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