Progesterone attenuates experimental subarachnoid hemorrhage-induced vasospasm by upregulation of endothelial nitric oxide synthase via Akt signaling pathway.

Chia-Mao Chang,Joon-Khim Loh,Chih-Lung Lin,Yee-Jean Tsai,Chia-Li Chung,Yu-Feng Su,Chih-Zen Chang

doi:10.1155/2014/207616

Abstract

Cerebral vasospasm is the leading cause of mortality and morbidity in patients after aneurysmal subarachnoid hemorrhage (SAH). However, the mechanism and adequate treatment of vasospasm are still elusive. In the present study, we evaluate the effect and possible mechanism of progesterone on SAH-induced vasospasm in a two-hemorrhage rodent model of SAH. Progesterone (8 mg/kg) was subcutaneously injected in ovariectomized female Sprague-Dawley rats one hour after SAH induction. The degree of vasospasm was determined by averaging the cross-sectional areas of basilar artery 7 days after first SAH. Expressions of endothelial nitric oxide synthase (eNOS) and phosphorylated Akt (phospho-Akt) in basilar arteries were evaluated. Prior to perfusion fixation, there were no significant differences among the control and treated groups in physiological parameters recorded. Progesterone treatment significantly (P < 0.01) attenuated SAH-induced vasospasm. The SAH-induced suppression of eNOS protein and phospho-Akt were relieved by progesterone treatment. This result further confirmed that progesterone is effective in preventing SAH-induced vasospasm. The beneficial effect of progesterone might be in part related to upregulation of expression of eNOS via Akt signaling pathway after SAH. Progesterone holds therapeutic promise in the treatment of cerebral vasospasm following SAH.

Highlights

Aneurysmal subarachnoid hemorrhage (SAH) is a serious and fatal disease
The cross-sectional area of basilar arteries was significantly reduced in animals subjected to SAH
Dimmeler et al demonstrated that Akt phosphorylated the Serine 1177 site of eNOS protein and that enhanced eNOS activity; they inhibited the PI3K/Akt pathway and that led to prevention of eNOS activation [28], and Fulton et al had similar findings [29]. These findings showed that Akt plays a crucial role in eNOS activity and this molecular mechanism is important in many ways, including endothelial cell migration and angiogenesis [30], E2induced vasodilation [31], protection in ventilator-associated lung injury [32], and protection in intestinal tissue in the situation of intestinal ischemia by Akt-dependent activation of endothelial nitric oxide synthase and vasodilation [33]

Summary

Introduction

Aneurysmal subarachnoid hemorrhage (SAH) is a serious and fatal disease. The mortality rate is 27% to 44% in SAH patients [1], and 46% of SAH patients survive with serious sequela of cognitive and functional impairment [2]. The main therapy against SAH is securing the cerebral aneurysms and treating the cerebral vasospasm, which develops in 70% of SAH populations between 3 and 14 days after SAH onset [3]. Cerebral vasospasm causes delayed cerebral ischemia and contributes to the major cause of poor outcome and even death in SAH patients [1], but so far there is no definitive treatment against the devastating complication. Growing evidence shows that progesterone, a sex steroid hormone, attenuates brain edema [4] and has beneficial effects on traumatic brain injury [5, 6], stroke [7, 8], experimental autoimmune encephalomyelitis [9, 10], and experimental spinal cord injury [11].

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Conclusion