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探索一种具有胆碱酯酶抑制特性的新型苯氧乙基哌啶衍生物作为痴呆症治疗方法的潜力:来自痴呆症的链脲佐菌素动物模型的见解。

Exploring the potential of a novel phenoxyethyl piperidine derivative with cholinesterase inhibitory properties as a treatment for dementia: Insights from STZ animal model of dementia.

作者信息

Abolhasani Fatemeh, Pourshojaei Yaghoub, Mohammadi Fatemeh, Esmaeilpour Khadijeh, Asadipour Ali, Ilaghi Mehran, Shabani Mohammad

机构信息

Department of Medicinal Chemistry, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran.

Department of Medicinal Chemistry, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran; Extremophile and Productive Microorganisms Research Center, Kerman University of Medical Sciences, Kerman, Iran.

出版信息

Neurosci Lett. 2023 Jul 27;810:137332. doi: 10.1016/j.neulet.2023.137332. Epub 2023 Jun 9.

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease, often characterized by progressive deficits in memory and cognitive functions. Cholinesterase inhibitors have been introduced as promising agents to enhance cognition and memory in both human patients and animal models of AD. In the current study, we assessed the effects of a synthetic phenoxyethyl piperidine derivative, compound 7c, as a novel dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), on learning and memory, as well as serum and hippocampal AChE levels in an animal model of AD. The model of dementia was induced by intracerebroventricular injection of streptozotocin (STZ, 2 mg/kg) to male Wistar rats. STZ-treated rats received compound 7c (3, 30, and 300 µg/kg) for five consecutive days. ​Passive avoidance (PA) learning and memory, as well as spatial learning and memory using Morris water maze, were evaluated. The level of AChE was measured in the serum and the left and right hippocampus. Findings demonstrated that compound 7c (300 µg/kg) was able to reverse STZ-induced impairments in PA memory, while also reduced the increased AChE level in the left hippocampus. Taken together, compound 7c appeared to act as a central AChE inhibitor, and its role in alleviating cognitive deficits in the AD animal model suggests that it may have therapeutic potential in AD dementia. Further research is required to assess the effectiveness of compound 7c in more reliable models of AD in light of these preliminary findings.

摘要

阿尔茨海默病(AD)是一种神经退行性疾病,通常表现为记忆和认知功能的进行性衰退。胆碱酯酶抑制剂已被视为有望改善AD患者及动物模型认知和记忆的药物。在本研究中,我们评估了一种合成苯氧乙基哌啶衍生物化合物7c作为乙酰胆碱酯酶(AChE)和丁酰胆碱酯酶(BuChE)新型双重抑制剂,对AD动物模型学习记忆以及血清和海马体AChE水平的影响。通过向雄性Wistar大鼠脑室内注射链脲佐菌素(STZ,2mg/kg)诱导痴呆模型。STZ处理的大鼠连续五天接受化合物7c(3、30和300μg/kg)。评估被动回避(PA)学习记忆以及使用莫里斯水迷宫的空间学习记忆。测定血清以及左右海马体中AChE的水平。结果表明,化合物7c(三百μg/kg)能够逆转STZ诱导的PA记忆损伤,同时还降低了左海马体中升高的AChE水平。综上所述,化合物7c似乎起到中枢AChE抑制剂的作用,其在减轻AD动物模型认知缺陷中的作用表明它可能对AD痴呆具有治疗潜力。鉴于这些初步发现,需要进一步研究以评估化合物7c在更可靠的AD模型中的有效性。

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