Kryl'skii E D, Chupandina E E, Popova T N, Shikhaliev Kh S, Medvedeva S M, Verevkin A N, Popov S S, Mittova V O
Department of Medical Biochemistry and Microbiology, Voronezh State University, Universitetskaya sq. 1, 394018, Voronezh, Russia.
Department of Pathological Anatomy, Voronezh State Medical University named after N.N. Burdenko, Voronezh, Russia.
Metab Brain Dis. 2022 Apr;37(4):1271-1282. doi: 10.1007/s11011-022-00928-3. Epub 2022 Feb 24.
Ischemia is one of the main etiological factors of stroke and is associated with the development of energy deficiency, oxidative stress, and inflammation. An abrupt restoration of blood flow, called reperfusion, can worsen the effects of ischemia. In our study, we assessed the neuroprotective potential of 1-benzoyl-6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline (BHDQ) in cerebral ischemia/reperfusion (CIR) in rats. Wistar rats, divided into 4 groups were used in the study: sham-operated animals; animals with CIR caused by occlusion of the common carotid arteries and subsequent removal of the occlusions; rats treated with BHDQ at a dose of 50 mg/kg in the presence of pathology; sham-operated animals treated with BHDQ. The analysis of the state of energy metabolism in the brain, the level of the S100B protein and the histological assessment of the brain tissue were carried out. The antioxidant potential of BHDQ was assessed by measuring biochemiluminescence parameters, analysing the level of 8-isoprostane, products of lipid and protein oxidation, concentration of α-tocopherol and citrate, and aconitate hydratase activity during CIR in rats. A study of the effect of BHDQ on the regulation of the enzymatic antioxidant system and the inflammatory processes was performed. We demonstrated that BHDQ has a neuroprotective effect in CIR, reducing histopathological changes in the brain, normalizing pyruvate and lactate concentrations, and the transcripts level of Hif-1α gene. The positive effect of BHDQ was probably due to its antioxidant and anti-inflammatory activity, manifested in a decrease in the parameters of the oxidative stress, decreased mRNA of proinflammatory cytokines and NF-κB factor genes. In addition, BHDQ reduced the load on antioxidant protection enzymes, contributing to a change in their activities, decreased the level of antioxidant gene transcripts and expression of Nrf2 and Foxo1 factors toward control. Thus, BHDQ exhibited a neuroprotective effect due to a decrease in the level of oxidative stress and inflammation and the normalization of redox homeostasis on CIR in rats.
缺血是中风的主要病因之一，与能量缺乏、氧化应激和炎症的发展相关。血流的突然恢复，即再灌注，会使缺血的影响恶化。在我们的研究中，我们评估了1-苯甲酰基-6-羟基-2,2,4-三甲基-1,2-二氢喹啉（BHDQ）对大鼠脑缺血/再灌注（CIR）的神经保护潜力。将Wistar大鼠分为4组用于该研究：假手术动物；通过结扎颈总动脉并随后解除结扎导致CIR的动物；在出现病理情况时用50mg/kg剂量的BHDQ治疗的大鼠；用BHDQ治疗的假手术动物。对大脑能量代谢状态、S100B蛋白水平以及脑组织进行了组织学评估。通过测量生物发光参数、分析8-异前列腺素水平、脂质和蛋白质氧化产物、α-生育酚和柠檬酸盐浓度以及大鼠CIR期间乌头酸水合酶活性来评估BHDQ的抗氧化潜力。进行了BHDQ对酶促抗氧化系统调节和炎症过程影响的研究。我们证明BHDQ在CIR中具有神经保护作用，减少大脑中的组织病理学变化，使丙酮酸和乳酸浓度以及Hif-1α基因的转录水平正常化。BHDQ的积极作用可能归因于其抗氧化和抗炎活性，表现为氧化应激参数降低、促炎细胞因子和NF-κB因子基因的mRNA减少。此外，BHDQ减轻了抗氧化保护酶的负担，导致其活性发生变化，降低了抗氧化基因转录物水平以及Nrf2和Foxo1因子的表达，使其趋向于对照水平。因此，由于氧化应激和炎症水平降低以及大鼠CIR中氧化还原稳态的正常化，BHDQ表现出神经保护作用。
