Inhibition of 12/15-LOX hyperactivation mitigates cognitive decline in a chronic cerebral hypoperfusion mouse model and in H2O2-induced HT22 cells: therapeutic effects of brozopine.

IF 5.4 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Xuening Wang, Zhizai Lu, Qiuji Shao, Yi Wang, Zixin Zhang, Zhiyu Wang, Qingran Jia, Jinpeng Zhu, Yiran Song, Lingxu Yuan, Yiming Wang, Shaoyang Xu, Lirou He, Junbiao Chang, Yuan Gao
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引用次数: 0

Abstract

Brozopine (BZP), a novel inhibitor of 12/15-lipoxygenase (12/15-LOX), has previously demonstrated efficacy in mitigating inflammatory and oxidative stress-related injury in cerebral ischaemia models. This study aimed to evaluate the therapeutic potential and underlying mechanisms of BZP in a mouse model of vascular dementia induced by chronic cerebral hypoperfusion. BZP was administered for 28 days following right unilateral common carotid artery occlusion (rUCCAO) in mice. BZP significantly alleviated cognitive impairment, behavioural deficits, and fine motor function. Mechanistically, BZP inhibited 12/15-LOX, cPLA2, p-p38 MAPK/p38 MAPK ratio, tumour necrosis factor-α, interlukin-1β, Aβ1-42 deposition, and Tau hyperphosphorylation in the brain and serum of rUCCAO mice. Similar protective effects were observed in both 12/15-LOX-overexpressed and H2O2-induced HT22 cell models. These findings suggest that BZP exerts its neuroprotective effects by targeting the 12/15-LOX/cPLA2/p38 MAPK pathway, offering a promising therapeutic strategy for mitigating the progression of cognitive impairment.

抑制12/15-LOX过度激活减轻慢性脑灌注不足小鼠模型和h2o2诱导的HT22细胞的认知能力下降:溴佐平的治疗作用
溴佐平(BZP)是一种新型的12/15-脂氧合酶(12/15-LOX)抑制剂,先前在脑缺血模型中显示出减轻炎症和氧化应激相关损伤的疗效。本研究旨在评估BZP对慢性脑灌注不足致血管性痴呆小鼠模型的治疗潜力及其机制。小鼠右单侧颈总动脉闭塞(rUCCAO)后给予BZP 28天。BZP显著缓解认知障碍、行为缺陷和精细运动功能。在机制上,BZP抑制rUCCAO小鼠脑和血清中12/15-LOX、cPLA2、p-p38 MAPK/p38 MAPK比值、肿瘤坏死因子-α、白介素-1β、a - β1-42沉积和Tau过度磷酸化。在12/15- lox过表达和h2o2诱导的HT22细胞模型中观察到类似的保护作用。这些发现表明,BZP通过靶向12/15-LOX/cPLA2/p38 MAPK通路发挥其神经保护作用,为缓解认知障碍的进展提供了一种有希望的治疗策略。
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来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
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