Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common forms of neurodegenerative disorders. Dehydroepiandrosterone (DHEA) has been reported as a neuroprotective steroid useful in the therapeutic management of neurodegenerative disorders such as AD and PD. Herein we report the synthesis and evaluation of a new series of 16,17-pyrazolinyl DHEA analogues 2–4a–d as neuroprotective agents using LPS-induced neuroinflammation animal models. Treatment with the pyrazoline substituted steroids considerably improved the LPS-induced learning, memory and movement deficits in animal models. Suppression of biochemical parameters of oxidative and nitrosative stress, acetylcholinesterase activity, and TNF-α levels was also observed. 16,17-Pyrazolinyl steroids 2c–4c substituted with a 4-pyridyl moiety at the 5-position of the heterocyclic ring were found to be the most potent agents and produced neuroprotective effects better than standard drugs celecoxib and dexamethasone. Of these pyrazoline substituted steroids, the N-acetyl analogue 3c displayed neuroprotective effects better than N-phenyl (4c), which in turn showed potency more than N-unsubstituted analogue 2c.

中文翻译：

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用LPS诱导的小鼠和大鼠神经炎症模型研究16,17-吡唑啉取代的杂类固醇作为抗阿尔茨海默病和抗帕金森病的药物

阿尔茨海默氏病（AD）和帕金森氏病（PD）是神经退行性疾病的最常见形式。据报道，脱氢表雄酮（DHEA）是一种神经保护性类固醇，可用于治疗神经退行性疾病（例如AD和PD）。在此，我们报告了一系列新的16,17-吡唑啉基DHEA类似物2 – 4a – d的合成和评估。使用LPS诱导的神经炎症动物模型作为神经保护剂。用吡唑啉取代的类固醇治疗可大大改善LPS诱导的动物模型中的学习，记忆和运动缺陷。还观察到氧化和亚硝化应激，乙酰胆碱酯酶活性和TNF-α水平的生化参数的抑制。发现在杂环的5位上被4-吡啶基部分取代的16,17-吡唑啉基类固醇2c - 4c是最有效的药物，其神经保护作用优于标准药物celecoxib和地塞米松。在这些吡唑啉取代的类固醇中，N-乙酰基类似物3c的神经保护作用优于N苯基（图4c），其又表现出效力超过ñ -未取代的类似物2c中。