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前列腺素D2通过DP1受体介导神经元保护作用。

Prostaglandin D2 mediates neuronal protection via the DP1 receptor.

作者信息

Liang Xibin, Wu Liejun, Hand Tracey, Andreasson Katrin

机构信息

Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21205, USA.

出版信息

J Neurochem. 2005 Feb;92(3):477-86. doi: 10.1111/j.1471-4159.2004.02870.x.

Abstract

Cyclo-oxygenases (COXs) catalyze the first committed step in the synthesis of the prostaglandins PGE(2), PGD(2), PGF(2alpha), PGI(2) and thomboxane A(2). Expression and enzymatic activity of COX-2, the inducible isoform of COX, are observed in several neurological diseases and result in significant neuronal injury. The neurotoxic effect of COX-2 is believed to occur through downstream effects of its prostaglandin products. In this study, we examined the function of PGD(2) and its two receptors DP1 and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) (DP2) in neuronal survival. PGD(2) is the most abundant prostaglandin in brain and regulates sleep, temperature and nociception. It signals through two distinct G protein-coupled receptors, DP1 and DP2, that have opposing effects on cyclic AMP (cAMP) production. Physiological concentrations of PGD(2) potently and unexpectedly rescued neurons in paradigms of glutamate toxicity in cultured hippocampal neurons and organotypic slices. This effect was mimicked by the DP1-selective agonist BW245C but not by the PGD(2) metabolite 15d-PGJ(2), suggesting that neuroprotection was mediated by the DP1 receptor. Conversely, activation of the DP2 receptor promoted neuronal loss. The protein kinase A inhibitors H89 and KT5720 reversed the protective effect of PGD(2), indicating that PGD(2)-mediated neuroprotection was dependent on cAMP signaling. These studies indicate that activation of the PGD(2) DP1 receptor protects against excitotoxic injury in a cAMP-dependent manner, consistent with recent studies of PGE(2) receptors that also suggest a neuroprotective effect of prostaglandin receptors. Taken together, these data support an emerging and paradoxical neuroprotective role of prostaglandins in the CNS.

摘要

环氧化酶(COXs)催化前列腺素PGE(2)、PGD(2)、PGF(2α)、PGI(2)和血栓素A(2)合成的第一步关键反应。COX的诱导型同工酶COX-2的表达和酶活性在几种神经疾病中均有观察到,并导致显著的神经元损伤。COX-2的神经毒性作用被认为是通过其前列腺素产物的下游效应发生的。在本研究中,我们检测了PGD(2)及其两种受体DP1和Th2细胞上表达的趋化因子受体同源分子(CRTH2)(DP2)在神经元存活中的功能。PGD(2)是大脑中含量最丰富的前列腺素,可调节睡眠、体温和痛觉。它通过两种不同的G蛋白偶联受体DP1和DP2发出信号,这两种受体对环磷酸腺苷(cAMP)的产生具有相反的作用。生理浓度的PGD(2)在培养的海马神经元和器官型切片的谷氨酸毒性模型中能有效且出人意料地挽救神经元。DP1选择性激动剂BW245C可模拟这种效应,但PGD(2)代谢产物15d-PGJ(2)则不能,这表明神经保护作用是由DP1受体介导的。相反,DP2受体的激活会促进神经元丢失。蛋白激酶A抑制剂H89和KT5720可逆转PGD(2)的保护作用,表明PGD(2)介导的神经保护作用依赖于cAMP信号传导。这些研究表明,PGD(2)DP1受体的激活以cAMP依赖的方式预防兴奋性毒性损伤,这与最近关于PGE(2)受体的研究一致,后者也表明前列腺素受体具有神经保护作用。综上所述,这些数据支持了前列腺素在中枢神经系统中一种新出现的、看似矛盾的神经保护作用。

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