Kryl'skii E D, Chupandina E E, Popova T N, Shikhaliev Kh S, Mittova V O, Popov S S, Verevkin A N, Filin A A
Department of Medical Biochemistry and Microbiology, Voronezh State University, Voronezh, Russia.
Department of Pathological Anatomy, Voronezh State Medical University named after N.N. Burdenko, Voronezh, Russia.
Biochimie. 2021 Jul;186:130-146. doi: 10.1016/j.biochi.2021.04.010. Epub 2021 May 5.
The aim of the study was the assessment of the neuroprotective potential of 6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline (DHQ) and its effect on inflammation, apoptosis, and transcriptional regulation of the antioxidant system in cerebral ischemia/reperfusion (CIR) in rats. The CIR rat model was constructed using the bilateral common carotid artery occlusion followed by reoxygenation. DHQ was administered at a dose of 50 mg/kg for three days. Histological staining was performed using hematoxylin and eosin. The level of S100B protein, 8-hydroxy-2-deoxyguanosine, and 8-isoprostane was assessed using an enzyme immunoassay. The intensity of apoptosis was assessed based on the activity of caspases and DNA fragmentation. The activity of enzymes was measured spectrophotometrically, the level of gene transcripts was assessed by real-time PCR. DHQ reduced the histopathological changes and normalized levels of S100B, lactate, pyruvate, and HIF-1 mRNA in the CIR rat model. In addition, DHQ decreased the oxidative stress markers in animals with a pathology. The tested compound also inhibited inflammation by decreasing the activity of myeloperoxidase, expression of interleukins and Nfkb2. DHQ-treated rats with CIR showed decreased caspase activity, DNA fragmentation, and AIF expression. DHQ changed activity of antioxidant enzymes to the control values, decreased the expression of Cat, Gsr, and Nfe2l2, which was overexpressed in CIR, and activated the expression of Sod1, Gpx1, Gsta2, and Foxo1. DHQ showed a neuroprotective effect on CIR in rats. The neuroprotective effect involve mechanisms such as the inhibition of oxidative stress, leading to a reduction in the inflammatory response and apoptosis and the modulation of the antioxidant defense components.
本研究的目的是评估6-羟基-2,2,4-三甲基-1,2-二氢喹啉（DHQ）的神经保护潜力及其对大鼠脑缺血/再灌注（CIR）炎症、凋亡和抗氧化系统转录调控的影响。采用双侧颈总动脉闭塞后再给氧的方法构建CIR大鼠模型。以50 mg/kg的剂量给予DHQ，持续三天。使用苏木精和伊红进行组织学染色。采用酶免疫测定法评估S100B蛋白、8-羟基-2-脱氧鸟苷和8-异前列腺素的水平。根据半胱天冬酶的活性和DNA片段化评估凋亡强度。通过分光光度法测量酶的活性，通过实时PCR评估基因转录本的水平。DHQ减轻了CIR大鼠模型中的组织病理学变化，并使S100B、乳酸、丙酮酸和HIF-1 mRNA水平恢复正常。此外，DHQ降低了患病动物的氧化应激标志物。所测试的化合物还通过降低髓过氧化物酶的活性、白细胞介素和Nfkb2的表达来抑制炎症。经DHQ处理的CIR大鼠半胱天冬酶活性、DNA片段化和AIF表达降低。DHQ将抗氧化酶的活性改变至对照值，降低了CIR中过表达的Cat、Gsr和Nfe2l2的表达，并激活了Sod1、Gpx1、Gsta2和Foxo1的表达。DHQ对大鼠CIR具有神经保护作用。这种神经保护作用涉及抑制氧化应激等机制，从而导致炎症反应和凋亡减少以及对抗氧化防御成分的调节。
