A novel p38 alpha MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer's disease mouse model.
A novel p38 alpha MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer's disease mouse model.
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一种新型的p38 alpha MAPK抑制剂抑制了脑促炎细胞因子上调，并减轻阿尔茨海默氏病小鼠模型中的突触功能障碍和行为缺陷。
DOI：
10.1186/1742-2094-4-21
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发表时间：
2007-09-04
影响因子：
9.3
通讯作者：
Watterson, D. Martin
中科院分区：
文献类型：
--
作者：
Munoz, Lenka;Ranaivo, Hantamalala Ralay;Roy, Saktimayee M.;Hu, Wenhui;Craft, Jeffrey M.;McNamara, Laurie K.;Chico, Laura Wing;Van Eldik, Linda J.;Watterson, D. Martin
越来越多的证据支持这样一种假设，即激活的胶质细胞产生的促炎细胞因子的过度或长期增加是病理生理学进展的一个因素，而病理生理学进展与神经退行性疾病（如阿尔茨海默病（AD））的突触功能障碍和海马行为缺陷有因果关系。这为开发新型潜在的疾病改善疗法提供了机会。p38α MAPK是一个合理的候选中枢神经系统靶点，它是一个成熟的药物发现分子靶点，可以改变外周组织疾病中促炎细胞因子级联反应。激活的p38 MAPK在人AD脑组织和AD相关动物模型中可见，细胞培养研究强烈暗示p38 MAPK与被人β淀粉样蛋白（Aβ）和其他疾病相关应激源激活的胶质细胞增加促炎细胞因子的产生有关。然而，绝大多数小分子药物没有足够的血脑屏障外显率，无法用作体内研究工具或神经退行性疾病的治疗药物。本研究的目的是验证脑p38α MAPK是口服生物可利用的小分子的潜在体内靶标，能够通过激活的胶质细胞恢复稳态来抑制过度的细胞因子产生，从而改善神经系统预后。设计、合成了一种基于先前使用的分子支架的新型合成小分子，并对其进行了分析，以证明其潜在的体内生物利用度、代谢稳定性、安全性和脑摄取。使用ad相关小鼠模型测试体内功效。一种新型的、cns渗透的、无毒的、口服生物利用的p38α MAPK小分子抑制剂（MW01-2-069A-SRM）被开发出来。在动物模型中，低剂量口服该化合物（2.5 mg/kg）可使海马体内过量的促炎细胞因子产生减少，恢复正常。细胞因子产生减弱的动物突触功能障碍和海马体依赖性行为缺陷减少。p38α MAPK通路在a β诱导的海马促炎细胞因子的产生中具有重要的定量意义，脑p38α MAPK是未来开发AD和相关神经退行性疾病的潜在疾病改善疗法的可行分子靶点。
An accumulating body of evidence is consistent with the hypothesis that excessive or prolonged increases in proinflammatory cytokine production by activated glia is a contributor to the progression of pathophysiology that is causally linked to synaptic dysfunction and hippocampal behavior deficits in neurodegenerative diseases such as Alzheimer's disease (AD). This raises the opportunity for the development of new classes of potentially disease-modifying therapeutics. A logical candidate CNS target is p38α MAPK, a well-established drug discovery molecular target for altering proinflammatory cytokine cascades in peripheral tissue disorders. Activated p38 MAPK is seen in human AD brain tissue and in AD-relevant animal models, and cell culture studies strongly implicate p38 MAPK in the increased production of proinflammatory cytokines by glia activated with human amyloid-beta (Aβ) and other disease-relevant stressors. However, the vast majority of small molecule drugs do not have sufficient penetrance of the blood-brain barrier to allow their use as in vivo research tools or as therapeutics for neurodegenerative disorders. The goal of this study was to test the hypothesis that brain p38α MAPK is a potential in vivo target for orally bioavailable, small molecules capable of suppressing excessive cytokine production by activated glia back towards homeostasis, allowing an improvement in neurologic outcomes. A novel synthetic small molecule based on a molecular scaffold used previously was designed, synthesized, and subjected to analyses to demonstrate its potential in vivo bioavailability, metabolic stability, safety and brain uptake. Testing for in vivo efficacy used an AD-relevant mouse model. A novel, CNS-penetrant, non-toxic, orally bioavailable, small molecule inhibitor of p38α MAPK (MW01-2-069A-SRM) was developed. Oral administration of the compound at a low dose (2.5 mg/kg) resulted in attenuation of excessive proinflammatory cytokine production in the hippocampus back towards normal in the animal model. Animals with attenuated cytokine production had reductions in synaptic dysfunction and hippocampus-dependent behavioral deficits. The p38α MAPK pathway is quantitatively important in the Aβ-induced production of proinflammatory cytokines in hippocampus, and brain p38α MAPK is a viable molecular target for future development of potential disease-modifying therapeutics in AD and related neurodegenerative disorders.
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影响因子：
2.1
作者：
Ferrer, I.;Gomez-Isla, T.;Avila, J.
通讯作者：
Avila, J.
影响因子：
3.1
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Craft, JM;Van Eldik, LJ;Watterson, DM
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Watterson, DM
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作者：
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影响因子：
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作者：
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DURY, K
影响因子：
5.3
作者：
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通讯作者：
McLarnon, James G.