CRTH2, a prostaglandin D2 receptor, mediates depression-related behavior in mice
CRTH2, a prostaglandin D2 receptor, mediates depression-related behavior in mice
复制标题
DOI：
10.1016/j.bbr.2015.02.013
复制
发表时间：
2015-05-01
影响因子：
2.7
通讯作者：
Hashimoto, Hitoshi
中科院分区：
文献类型：
--
作者：
Onaka, Yusuke;Shintani, Norihito;Hashimoto, Hitoshi
抑郁症是一种复杂的神经精神疾病，其分子病因尚不清楚。炎性细胞因子和分子中间体（包括三兰定）被认为参与抑郁症;然而，三兰定及其各自的受体在抑郁症中的作用在很大程度上是未知的。利用遗传学和药理学方法，我们在这里表明，在辅助性T细胞2型（CRTH 2），前列腺素D2（PGD 2）的第二个受体表达的趋化受体同源分子，介导抑郁症相关的行为在小鼠中。CRTH 2缺陷（CRTH 2（-/-））小鼠在慢性皮质酮治疗诱导的抑郁症中表现出抗抑郁药样活性。与该观察结果一致，通过临床可用药物雷马曲班对CRTH 2的药理学抑制也挽救了良好建立的模型中的异常社会互动和抑郁相关行为，包括慢性皮质酮、脂多糖和肿瘤诱导的病理相关抑郁模型。重要的是，通过皮质酮治疗的慢性应激增加了大脑中PGD 2产生酶（如环氧合酶-2和lipocalin型PGD 2合酶）的mRNA水平。此外，CRTH 2（-/-）小鼠海马去甲肾上腺素能系统的活性增加，但多巴胺能或血清素能系统的活性没有增加。结合未处理的CRTH 2（-/-）小鼠在强迫游泳试验中显示出抗抑郁样活性的观察结果，这些结果提供了证据，证明中枢CRTH 2介导的信号传导与抑郁相关行为密切相关。(C)2015 Elsevier B. V.版权所有。
Depression is a complex neuropsychiatric disorder with an unclear molecular etiology. Inflammatory cytokines and molecular intermediates (including prostaglandins) are suggested to be involved in depression; however, the roles of prostaglandins and their respective receptors are largely unknown in depression. Using genetic and pharmacological approaches, we show here that chemoattractant receptorhomologous molecule expressed on T helper type 2 cells (CRTH2), a second receptor for prostaglandin D2 (PGD2), mediates depression-related behavior in mice. CRTH2-deficient (CRTH2(-/-)) mice showed antidepressant-like activity in a chronic corticosterone treatment-induced depression. Consistent with this observation, the pharmacological inhibition of CRTH2 via the clinically available drug ramatroban also rescued abnormal social interaction and depression-related behavior in well-established models, including chronic corticosterone-, lipopolysaccharide-, and tumor-induced pathologically relevant depression models. Importantly, chronic stress via corticosterone treatment increased mRNA levels in PGD2-producing enzymes, such as cyclooxygenase-2 and lipocalin-type PGD2 synthase, in the brain. Furthermore, the activity of the hippocampal noradrenergic system but not the dopaminergic or serotonergic systems was increased in CRTH2(-/-) mice. Together with the observation that untreated CRTH2(-/-) mice showed antidepressant-like activity in the forced swim test, these results provide evidence that central CRTH2-mediated signaling is critically involved in depression-related behavior. (C) 2015 Elsevier B.V. All rights reserved.