Department of Pharmacology, Faculty of Pharmacy, Ziauddin University, Karachi, 75600, Pakistan.
Department of Molecular Medicine, Ziauddin University, Karachi, 75600, Pakistan.
Naunyn Schmiedebergs Arch Pharmacol. 2024 Nov;397(11):9023-9032. doi: 10.1007/s00210-024-03232-2. Epub 2024 Jun 15.
Glycation is among the underlying mechanisms attributed to ageing and associated morbidities. There is no drug available to combat this deleterious phenomenon. The present study aimed to explore phloroglucinol (PHL) for its anti-glycation potential at preclinical level. The rats were treated with methylglyoxal (MGO, 17.25 mg/kg, i.p. for 14 days) to induce glvcative stress. The treatment groups received additional administration of test drug (PHL; 0.25mg/kg, 0.5mg/kg, and 1mg/kg) or standard aminoguanidine (AG, 50 mg/kg) or saline (control, 5ml/kg). During 14 days, the weight and food intake was noted. Afterwards, the cognitive function was evaluated using Morris Water Maze (MWM) while hepatic and renal functions were assessed through liver function test (bilirubin, alkaline phosphatase, SGPT, and SGOT) and creatinine respectively, using chemical analyzer. The carboxymethyllysine (CML) levels were quantified in the blood using ELISA technique. Histopathological study was performed on the brain, liver, and kidney using H&E staining. Additionally, the qPCR was used to quantify the expression of TNF-α, RAGE and BACE-1 (brain), RAGE, TNF-α, and glyoxalase-I (liver) and RAGE, TNF-α, and VEGF (kidney), while glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as a reference housekeeping gene. The data regarding weight and food intake did not reveal significant alterations. In MWM, the MGO treatment caused significant increase in the time to reach target quadrant, while decrease in the time spent in target quadrant and number of crossings through platform position. All these effects were inhibited by both AG and PHL. The navigation maps also exhibit that the retention of spatial memory. Additionally, the MGO-induced alteration in hepatic and renal function indicators was ameliorated by both AG and PHL treatments. The plasma CML levels were found to be elevated following MGO treatment, while the concomitant administration of AG and PHL has resisted this raise. Histopathological assessment revealed no specific pathology in liver kidney and brain tissues. The qPCR data revealed enhanced expression of all genes, especially TNF-α and BACE, which were found to be reduced following both AG and PHL treatments. PHL prevented the brain, hepatic, and renal impairments caused by MGO induced glycative stress. Hence, the PHL, a clinically used anti-spasmodic drug, presents itself as a potential candidate to be repurposed as anti-glycation drug.
糖基化是导致衰老和相关疾病的潜在机制之一。目前还没有药物可以对抗这种有害现象。本研究旨在探索根皮素（PHL）在临床前水平上的抗糖基化潜力。大鼠用甲基乙二醛（MGO，17.25mg/kg，腹腔注射，共 14 天）诱导糖基化应激。实验组给予额外的测试药物（PHL；0.25mg/kg、0.5mg/kg 和 1mg/kg）或标准氨基胍（AG，50mg/kg）或生理盐水（对照组，5ml/kg）。在 14 天期间，记录体重和食物摄入量。之后，使用 Morris 水迷宫（MWM）评估认知功能，同时使用化学分析仪分别通过肝功能试验（胆红素、碱性磷酸酶、SGPT 和 SGOT）和肌酐评估肝功能和肾功能。使用 ELISA 技术定量检测血液中的羧甲基赖氨酸（CML）水平。使用 H&E 染色对大脑、肝脏和肾脏进行组织病理学研究。此外，使用 qPCR 定量检测 TNF-α、RAGE 和 BACE-1（大脑）、RAGE、TNF-α和糖氧酶-I（肝脏）以及 RAGE、TNF-α和 VEGF（肾脏）的表达，同时使用甘油醛-3-磷酸脱氢酶（GAPDH）作为内参管家基因。体重和食物摄入量的数据没有显示出显著的变化。在 MWM 中，MGO 处理导致到达目标象限的时间显著增加，而在目标象限花费的时间和穿过平台位置的次数减少。AG 和 PHL 都抑制了所有这些作用。导航图还显示了空间记忆的保留。此外，AG 和 PHL 治疗改善了 MGO 诱导的肝肾功能指标的改变。发现 MGO 处理后血浆 CML 水平升高，而同时给予 AG 和 PHL 可抑制这种升高。组织病理学评估显示肝脏、肾脏和脑组织没有特定的病理变化。qPCR 数据显示所有基因的表达增强，特别是 TNF-α和 BACE，AG 和 PHL 治疗后这些基因的表达降低。PHL 可预防 MGO 诱导的糖基化应激引起的大脑、肝脏和肾脏损伤。因此，临床上使用的抗痉挛药物 PHL 可能成为抗糖基化药物的潜在候选药物。
