Plotnikov Mark B, Chernysheva Galina A, Smol'yakova Vera I, Aliev Oleg I, Anishchenko Anna M, Ulyakhina Olga A, Trofimova Eugene S, Ligacheva Anastasia A, Anfinogenova Nina D, Osipenko Anton N, Kovrizhina Anastasia R, Khlebnikov Andrei I, Schepetkin Igor A, Drozd Anastasia G, Plotnikov Evgenii V, Atochin Dmitriy N, Quinn Mark T
Department of Pharmacology, Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634028, Russia.
Faculty of Radiophysics, National Research Tomsk State University, Tomsk 634050, Russia.
Pharmaceuticals (Basel). 2023 Jul 25;16(8):1057. doi: 10.3390/ph16081057.
The activation of -Jun N-terminal kinase (JNK) plays an important role in stroke outcomes. Tryptanthrin-6-oxime (TRYP-Ox) is reported to have high affinity for JNK and anti-inflammatory activity and may be of interest as a promising neuroprotective agent. The aim of this study was to investigate the neuroprotective effects of TRYP-Ox in a rat model of transient focal cerebral ischemia (FCI), which involved intraluminal occlusion of the left middle cerebral artery (MCA) for 1 h. Animals in the experimental group were administered intraperitoneal injections of TRYP-Ox 30 min before reperfusion and 23 and 47 h after FCI. Neurological status was assessed 4, 24, and 48 h following FCI onset. Treatment with 5 and 10 mg/kg of TRYP-Ox decreased mean scores of neurological deficits by 35-49 and 46-67% at 24 and 48 h, respectively. At these doses, TRYP-Ox decreased the infarction size by 28-31% at 48 h after FCI. TRYP-Ox (10 mg/kg) reduced the content of interleukin (IL) 1β and tumor necrosis factor (TNF) in the ischemic core area of the MCA region by 33% and 38%, respectively, and attenuated cerebral edema by 11% in the left hemisphere, which was affected by infarction, and by 6% in the right, contralateral hemisphere 24 h after FCI. TRYP-Ox reduced -Jun phosphorylation in the MCA pool at 1 h after reperfusion. TRYP-Ox was predicted to have high blood-brain barrier permeability using various calculated descriptors and binary classification trees. Indeed, reactive oxidant production was significantly lower in the brain homogenates from rats treated with TRYP-Ox versus that in control animals. Our data suggest that the neuroprotective activity of TRYP-Ox may be due to the ability of this compound to inhibit JNK and exhibit anti-inflammatory and antioxidant activity. Thus, TRYP-Ox may be considered a promising neuroprotective agent that potentially could be used for the development of new treatment strategies in cerebral ischemia.
c-Jun氨基末端激酶（JNK）的激活在中风预后中起着重要作用。据报道，靛玉红-6-肟（TRYP-Ox）对JNK具有高亲和力且具有抗炎活性，可能是一种有前景的神经保护剂。本研究的目的是在大鼠短暂性局灶性脑缺血（FCI）模型中研究TRYP-Ox的神经保护作用，该模型涉及左大脑中动脉（MCA）腔内闭塞1小时。实验组动物在再灌注前30分钟以及FCI后23小时和47小时腹腔注射TRYP-Ox。在FCI发作后4、24和48小时评估神经功能状态。5和10mg/kg的TRYP-Ox治疗分别在24小时和48小时使神经功能缺损平均评分降低35-49%和46-67%。在这些剂量下，TRYP-Ox在FCI后48小时使梗死面积减少28-31%。TRYP-Ox（10mg/kg）使MCA区域缺血核心区白细胞介素（IL）-1β和肿瘤坏死因子（TNF）的含量分别降低33%和38%，并使梗死所累及的左半球脑水肿减轻11%，对侧右半球脑水肿在FCI后24小时减轻6%。TRYP-Ox在再灌注后1小时降低了MCA区c-Jun的磷酸化水平。使用各种计算描述符和二元分类树预测TRYP-Ox具有高血脑屏障通透性。事实上，与对照动物相比，用TRYP-Ox治疗的大鼠脑匀浆中的活性氧化剂产生明显更低。我们的数据表明，TRYP-Ox的神经保护活性可能归因于该化合物抑制JNK以及表现出抗炎和抗氧化活性的能力。因此，TRYP-Ox可能被认为是一种有前景的神经保护剂，有可能用于开发脑缺血的新治疗策略。
