PGE2 EP1 受体在缺血性脑卒中和阿尔茨海默病小鼠模型中加重神经毒性。
PGE2 EP1 receptor exacerbated neurotoxicity in a mouse model of cerebral ischemia and Alzheimer's disease.
机构信息
Department of Anesthesiology/Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
出版信息
Neurobiol Aging. 2012 Sep;33(9):2215-9. doi: 10.1016/j.neurobiolaging.2011.09.017. Epub 2011 Oct 19.
Abstract
Stroke and Alzheimer's disease (AD) are major age-related neurodegenerative diseases that may worsen the prognosis of each other. Our study was designed to delineate the prostaglandin E(2) EP1 receptor role in AD and in the setting of cerebral ischemia. Genetic deletion of the prostaglandin EP1 receptor significantly attenuated the more severe neuronal damage (38.5 ± 10.6%) and memory loss induced by ischemic insult observed in AD transgenic mice (percentage of viable hippocampal CA1 neurons: 11.2 ± 2.9%) when compared with wild type mice (45.1 ± 9.1%). In addition, we found that the amyloid plaques were reduced in EP1 deleted AD mice. β-amyloid-induced toxicity (18.0 ± 7.1%) and Ca(2+) response (91.8 ± 12.9%) were also reduced in EP1(-/-) neurons compared with control neurons in in vitro. Hence, EP1 might mediate most of the toxicity associated with cyclooxygenase-2 and contribute substantially to the cell death pathways in AD and stroke. Exploring potential therapeutic agent targeting EP1 receptor could potentially benefit treatments for stroke and AD patients.
摘要
中风和阿尔茨海默病（AD）是两种主要的与年龄相关的神经退行性疾病，它们可能相互加重预后。我们的研究旨在描绘前列腺素 E2（EP1）受体在 AD 及脑缺血中的作用。与野生型小鼠（45.1±9.1%）相比，EP1 受体基因缺失显著减轻了 AD 转基因小鼠缺血性损伤引起的更严重的神经元损伤（38.5±10.6%）和记忆丧失（海马 CA1 区存活神经元百分比：11.2±2.9%）。此外，我们发现 EP1 缺失的 AD 小鼠中的淀粉样斑块减少。在体外，与对照神经元相比，β-淀粉样蛋白诱导的毒性（18.0±7.1%）和 Ca2+反应（91.8±12.9%）也在 EP1（-/-）神经元中降低。因此，EP1 可能介导与环氧化酶-2 相关的大部分毒性，并在 AD 和中风的细胞死亡途径中起重要作用。探索针对 EP1 受体的潜在治疗药物可能有助于治疗中风和 AD 患者。
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