Timapiprant, a prostaglandin D2 receptor antagonist, ameliorates pathology in a rat Alzheimer's model.
Timapiprant, a prostaglandin D2 receptor antagonist, ameliorates pathology in a rat Alzheimer's model.
复制标题
DOI：
10.26508/lsa.202201555
复制
发表时间：
2022-09-27
影响因子：
4.4
通讯作者：
中科院分区：
文献类型：
--
作者：
前列腺素D2是一种主要的脑内前列腺素，我们报道了作为PGD2受体DP2拮抗剂的激动剂可以减少阿尔茨海默病转基因大鼠的病理和认知缺陷。我们研究了前列腺素D2通路在阿尔茨海默病中的相关性，因为前列腺素D2是大脑中的一种主要前列腺素。因此，鉴于前列腺素E2途径在阿尔茨海默病中的已知影响，它对阿尔茨海默病的贡献值得关注。我们使用TgF344-AD转基因大鼠模型，因为它表现出年龄依赖和进行性阿尔茨海默病的病理。TgF344-AD和野生型仔鼠海马区前列腺素D2水平显著高于前列腺素E2。前列腺素D2通过DP1和DP2受体传递信号。与野生型大鼠相比，TgF344-AD组小胶质细胞DP1受体较丰富，神经元DP2受体较少。在参与前列腺素D2和前列腺素E2途径的33个基因中，脑内主要的前列腺素D2合成酶(Lipocalin型PGDS)的表达最高。我们用timapiprant治疗一组大鼠(野生型和TgF344-AD雄性)，timapiprant是一种有效的高选择性DP2拮抗剂，正在开发中，用于治疗过敏性炎症。Timapiprant显著减轻了TgF344-AD男性的阿尔茨海默病病理和认知缺陷。因此，选择性DP2拮抗剂具有治疗阿尔茨海默病的潜力。
PGD2 is a major brain prostaglandin and we report that timapiprant that is an antagonist for the PGD2 receptor DP2 reduces pathology and cognitive deficits in a transgenic rat model of Alzheimer’s. We investigated the relevance of the prostaglandin D2 pathway in Alzheimer’s disease, because prostaglandin D2 is a major prostaglandin in the brain. Thus, its contribution to Alzheimer’s disease merits attention, given the known impact of the prostaglandin E2 pathway in Alzheimer’s disease. We used the TgF344-AD transgenic rat model because it exhibits age-dependent and progressive Alzheimer’s disease pathology. Prostaglandin D2 levels in hippocampi of TgF344-AD and wild-type littermates were significantly higher than prostaglandin E2. Prostaglandin D2 signals through DP1 and DP2 receptors. Microglial DP1 receptors were more abundant and neuronal DP2 receptors were fewer in TgF344-AD than in wild-type rats. Expression of the major brain prostaglandin D2 synthase (lipocalin-type PGDS) was the highest among 33 genes involved in the prostaglandin D2 and prostaglandin E2 pathways. We treated a subset of rats (wild-type and TgF344-AD males) with timapiprant, a potent highly selective DP2 antagonist in development for allergic inflammation treatment. Timapiprant significantly mitigated Alzheimer’s disease pathology and cognitive deficits in TgF344-AD males. Thus, selective DP2 antagonists have potential as therapeutics to treat Alzheimer’s disease.
影响因子：
4
作者：
Avila JA;Zanca RM;Shor D;Paleologos N;Alliger AA;Figueiredo-Pereira ME;Serrano PA
通讯作者：
Serrano PA
DOI：
10.1016/j.jchromb.2013.11.041
发表时间：
2014-01-15
影响因子：
3
作者：
Shaik, Jafar Sadik B.;Miller, Tricia M.;Graham, Steven H.;Manole, Mioara D.;Poloyac, Samuel M.
通讯作者：
Poloyac, Samuel M.
影响因子：
5.8
作者：
Cudaback, Eiron;Jorstad, Nikolas L.;Yang, Yue;Montine, Thomas J.;Keene, C. Dirk
通讯作者：
Keene, C. Dirk