一种新烯丙基吗啉衍生物对大鼠创伤性脑损伤模型神经保护活性的评价

Q3 Pharmacology, Toxicology and Pharmaceutics Drug Development and Registration Pub Date : 2021-12-25 DOI:10.33380/2305-2066-2021-10-4(1)-179-187
V. Prikhodko, A. V. Kan, Yurii I. Sysoev, I. A. Titovich, N. Anisimova, S. Okovityi
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引用次数: 2

摘要

介绍寻找和开发能够降低创伤性脑损伤神经功能缺损严重程度的新药是药理学研究的一项关键任务。含色酮的烯丙基吗啉是一组新的神经保护候选药物,已被证明在体外抑制乙酰胆碱酯酶和丁酰胆碱酯酶,并阻断N-甲基-D-天冬氨酸受体。目标本研究旨在使用大鼠创伤性脑损伤模型评估烯丙基吗啉衍生物(E)-4-[3-(8-溴-6-甲基-4-氧代-4H-色烯-3-基)-1-环己基烯丙基]吗啉-4-氯化铵(33b)的体内神经保护活性。材料和方法。采用可控皮层撞击模型诱发创伤性脑损伤。烯丙基吗啉衍生物在创伤诱导后1小时以1、10或50 mg×kg-1 b.w.腹膜内给药,然后在接下来的6天内每天给药。使用肢体放置、开阔场地、高架迷宫、光束行走和圆柱体测试评估神经功能缺损。结果和讨论。在所有给药剂量下,烯丙基吗啉衍生物对创伤性脑损伤后的运动功能或探索行为没有积极影响。在Elevated Plus Maze中,10 mg×kg-1 b.w.的该化合物进一步抑制了受伤动物的探索行为,这似乎与之前在斑马鱼中观察到的其镇静特性一致。结论尽管先前描述了烯丙基吗啉对脑损伤发病机制和创伤后功能恢复至关重要的几个分子靶点的体外亲和力,但在本研究中,烯丙基吗啶衍生物在大鼠创伤性脑损伤模型中没有神经保护作用。这些结果进一步强调了体内评估潜在神经保护候选药物的重要性。
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Evaluation of the neuroprotective activity of a new allylmorpholine derivative in a rat model of traumatic brain injury
Introduction. The search for and development of new drugs capable of reducing the severity of neurological deficit in traumatic brain injury are a critical task for investigational pharmacology. Chromone-containing allylmorpholines are a new group of neuroprotective drug candidates that have been shown to inhibit acetylcholinesterase and butyrylcholinesterase, and block N-methyl-D-aspartate receptors in vitro.Aim. This study aimed to evaluate the neuroprotective activity of the allylmorpholine derivative (E)-4-[3-(8-bromo-6-methyl-4-oxo-4H-chromen- 3-yl)-1-cyclohexylallyl]morpholin-4-ium chloride (33b) in vivo using a rat model of traumatic brain injury.Materials and methods. Traumatic brain injury was induced using the controlled cortical impact model. The allylmorpholine derivative was administered intraperitoneally at 1, 10, or 50 mg × kg-1 b.w. at 1 h after trauma induction, and then daily for the next 6 d. The neurological deficit was assessed using the Limb Placing, Open Field, Elevated Plus Maze, Beam Walking, and Cylinder tests.Results and discussion. At all doses administered, the allylmorpholine derivative had no positive effect on the motor function or exploratory behavior following traumatic brain injury. In the Elevated Plus Maze, 10 mg × kg-1 b.w. of the compound further suppressed exploratory behaviour in the injured animals, which appears to be consistent with its sedative properties observed previously in zebrafish.Conclusion. Despite the previously described in vitro affinity of allylmorpholines towards several molecular targets crucial for the pathogenesis of brain trauma and posttraumatic functional recovery, an allylmorpholine derivative had no neuroprotective effect in a rat model of traumatic brain injury in this study. These results further emphasize the importance of in vivo evaluation of potential neuroprotective drug candidates.
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来源期刊
Drug Development and Registration
Drug Development and Registration Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
1.20
自引率
0.00%
发文量
61
审稿时长
8 weeks
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