Effects of EP1 receptor on cerebral blood flow in the middle cerebral artery occlusion model of stroke in mice
Effects of EP1 receptor on cerebral blood flow in the middle cerebral artery occlusion model of stroke in mice
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DOI：
10.1002/jnr.21399
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发表时间：
2007-08-15
影响因子：
4.2
通讯作者：
Dore, Sylvain
中科院分区：
文献类型：
--
作者：
Saleem, Sofiyan;Li, Rung-Chi;Dore, Sylvain
脂质介质前列腺素E-2(PGE(2))在多种组织中显示出不同的生物学活性。PGE2受体的四个亚型(EP1-4)参与不同的生理和病理生理状态，但在组织分布、配体结合亲和力和与细胞内信号通路的偶联方面存在差异。为了研究EP1受体的作用，在野生型(WT)和EP1基因敲除(EP1(-/-))小鼠的大脑中动脉阻塞缺血性卒中模型中，研究了生理参数(平均动脉压、pH、血气PaO2和PaCO2以及体温)、脑血流量(CBF)和神经细胞死亡。结扎右侧大脑中动脉60min，用[C-14]安替比林放射自显影测定脑血流量。研究EP1受体在神经元培养中对氧化应激的影响。尽管生理参数没有差异，EP1(-/-)小鼠的CBF显著高于WT小鼠(P<；0.01)，提示该受体在血管张力的生理和病理生理调控中发挥作用。同样，来自EP1(-/-)小鼠的神经元培养细胞对叔丁基氢过氧化氢诱导的氧化应激的抵抗力(90.6+/-5.8%)比来自WT小鼠的神经元(39.6+/-17.2%)更强。EP1受体拮抗剂SC-51089和钙通道阻滞剂维拉帕米均可减轻前列腺素E_2诱导的神经细胞死亡。因此，前列腺素EP1受体在调节脑血流量和神经细胞死亡中起重要作用。这些发现提示，EP1受体的药理调节可能是改善脑血流量和缺血性卒中神经元存活的一种手段。(C)2007年Wiley-Liss，Inc.
The lipid mediator prostaglandin E-2 (PGE(2)) exhibits diverse biologic activity in a variety of tissues. Four PGE2 receptor subtypes (EP1-4) are involved in various physiologic and pathophysiologic conditions, but differ in tissue distribution, ligand-binding affinity, and coupling to intracellular signaling pathways. To characterize the role of the EP1 receptor, physiologic parameters (mean arterial blood pressure, pH, blood gases PaO2 and PaCO2, and body temperature), cerebral blood flow (CBF), and neuronal cell death were studied in a middle cerebral artery occlusion model of ischemic stroke in wild-type (WT) and EP1 knockout (EP1(-/-)) mice. The right middle cerebral artery was occluded for 60 min, and absolute CBF was measured by [C-14] iodoantipyrine autoradiography. The effect of EP1 receptor on oxidative stress in neuronal cultures was investigated. Although no differences were observed in the physiologic parameters, CBF was significantly (P < 0.01) higher in EP1(-/-) mice than in WT mice, suggesting a role for this receptor in physiologic and pathophysiologic control of vascular tone. Similarly, neuronal cultures derived from EP1(-/-)mice were more resistant (90.6 +/- 5.8% viability) to tertbutyl hydroperoxide-induced oxidative stress than neurons from WT mice (39.6 +/- 17.2% viability). The EP1 receptor antagonist SC-51089 and calcium channel blocker verapamil each attenuated the neuronal cell death induced by PGE2. Thus, the prostanoid EP1 receptor plays a significant role in regulating CBF and neuronal cell death. These findings suggest that pharmacologic modulation of the EP1 receptor might be a means to improve CBF and neuronal survival during ischemic stroke. (C) 2007 Wiley-Liss, Inc.