Jiang Shangqian, Ding Yuchuan, Wang Hongrui, Kim Enoch, Geng Xiaokun
Neuroscience Institute, Beijing Luhe Hospital Capital Medical University Beijing China.
Department of Neurology, Beijing Luhe Hospital Capital Medical University Beijing China.
J Am Heart Assoc. 2024 Dec 17;13(24):e035382. doi: 10.1161/JAHA.124.035382. Epub 2024 Nov 22.
Glyceryl trinitrate (GTN), also known as nitroglycerin, is predominantly recognized as a vasodilator for ischemic heart disease, and its potential neuroprotective properties in acute ischemic stroke remain under exploration. We sought to discover the therapeutic advantages and mechanisms of post-recanalization GTN administration in acute ischemic stroke.
A total of 118 male Sprague-Dawley rats were divided into groups: sham, transient/permanent middle cerebral artery occlusion (MCAO) with or without GTN treatment, and transient/permanent MCAO treated with both GTN and KT5823, an inhibitor of PKG. Acute ischemic stroke was induced by transient MCAO for 2 hours followed by 6 or 24 hours of reperfusion and permanent MCAO (28-hour MCAO without reperfusion). The study assessed infarct volumes, neurological deficits, glucose metabolism metrics, NO, and cGMP levels via ELISA. mRNA and protein expression of key molecules of hyperglycolysis, gluconeogenesis, endoplasmic reticulum stress as well as signaling molecules (PKG, AMPK) were conducted via reverse transcription polymerase chain reaction and Western blotting, and cell death was assessed with TUNEL and ELISA. GTN significantly reduced cerebral infarct volumes, neurological deficits, and cell death only after transient MCAO. GTN led to a significant reduction in the expression of NO and cGMP levels, key glucose metabolism, endoplasmic reticulum stress-related genes and proteins, and phosphorylated AMPK while boosting PKG expression, in transient MCAO but not permanent MCAO. The GTN-induced reduction in glucose metabolites, lactate, and reactive oxygen species was exclusive to transient MCAO groups. Coadministration of GTN and PKG inhibitors reversed the observed GTN benefits.
GTN induced neuroprotection in transient MCAO by improving glucose metabolism and potentially controlling endoplasmic reticulum stress through the NO-cGMP-PKG signaling cascade to inhibit AMPK phosphorylation.
甘油三硝酸酯（GTN），也被称为硝酸甘油，主要被认为是一种用于缺血性心脏病的血管扩张剂，其在急性缺血性卒中中的潜在神经保护特性仍在探索中。我们试图发现急性缺血性卒中再通后给予GTN的治疗优势和机制。
总共118只雄性Sprague-Dawley大鼠被分为以下几组：假手术组、短暂性/永久性大脑中动脉闭塞（MCAO）组（有无GTN治疗）以及同时接受GTN和PKG抑制剂KT5823治疗的短暂性/永久性MCAO组。通过短暂性MCAO 2小时，随后再灌注6或24小时以及永久性MCAO（28小时MCAO且无再灌注）诱导急性缺血性卒中。该研究通过酶联免疫吸附测定法评估梗死体积、神经功能缺损、葡萄糖代谢指标、一氧化氮（NO）和环磷酸鸟苷（cGMP）水平。通过逆转录聚合酶链反应和蛋白质免疫印迹法检测糖酵解、糖异生、内质网应激关键分子以及信号分子（PKG、AMPK）的mRNA和蛋白质表达，并用末端脱氧核苷酸转移酶介导的缺口末端标记法（TUNEL）和酶联免疫吸附测定法评估细胞死亡情况。仅在短暂性MCAO后，GTN显著减少了脑梗死体积、神经功能缺损和细胞死亡。在短暂性MCAO而非永久性MCAO中，GTN导致NO和cGMP水平、关键葡萄糖代谢、内质网应激相关基因和蛋白质的表达以及磷酸化AMPK显著降低，同时提高了PKG表达。GTN诱导的葡萄糖代谢产物、乳酸和活性氧的减少仅在短暂性MCAO组中出现。联合给予GTN和PKG抑制剂可逆转所观察到的GTN的益处。
GTN通过改善葡萄糖代谢并可能通过NO-cGMP-PKG信号级联控制内质网应激以抑制AMPK磷酸化，从而在短暂性MCAO中诱导神经保护作用。
