Pharmacology, Faculty of Biochemical and Pharmaceutical Sciences. National University of Rosario, CONICET, Rosario, Argentina.
Pharmacology. 2021;106(5-6):332-340. doi: 10.1159/000514843. Epub 2021 Apr 13.
The presence of mercury in the environment is a worldwide concern. Inorganic mercury is present in industrial materials, is employed in medical devices, is widely used in batteries, is a component of fluorescent light bulbs, and it has been associated with human poisoning in gold mining areas. The nephrotoxicity induced by inorganic mercury is a relevant health problem mainly in developing countries. The primary mechanism of mercury toxicity is oxidative stress. Trimetazidine (TMZ) is an anti-ischemic drug, which inhibits cellular oxidative stress, eliminates oxygen-free radicals, and improves lipid metabolism. The aim of this study was to evaluate whether the administration of TMZ protects against mercuric chloride (HgCl2) kidney damage.
Adult male Wistar rats received only HgCl2 (4 mg/kg bw, sc) (Hg group, n = 5) or TMZ (3 mg/kg bw, ip) 30 min before HgCl2 administration (4 mg/kg bw, sc) (TMZHg group, n = 7). Simultaneously, a control group of rats (n = 4) was studied. After 4 days of HgCl2 injection, urinary flow, urea and creatinine (Cr) plasma levels, Cr clearance, urinary glucose, and sodium-dicarboxylate cotransporter 1 (NaDC1) in urine were determined. Lipid peroxidation (MDA) and glutathione (GSH) levels were measured in kidney homogenates.
Rats only treated with HgCl2 showed an increase in urea and Cr plasma levels, urinary flow, fractional excretion of water, glucosuria, and NaDC1 urinary excretion as compared with the control group and a decrease in Cr clearance. TMZHg group showed a decrease in urea and Cr plasma levels, urinary flow, fractional excretion of water, glucosuria, NaDC1 urinary excretion, and an increase in Cr clearance when compared to the Hg group. Moreover, MDA and GSH levels observed in Hg groups were decreased and increased, respectively, by TMZ pretreatment.
TMZ exerted a renoprotective action against HgCl2-induced renal injury, which might be mediated by the reduction of oxidative stress. Considering the absence of toxicity of TMZ, its clinical application against oxidative damage due to HgCl2-induced renal injury should be considered. The fact that TMZ is commercially available should simplify and accelerate the translation of the present data "from bench to bedside." In this context, TMZ become an interesting new example of drug repurposing.
汞在环境中的存在是一个全球性的问题。无机汞存在于工业材料中，被用于医疗器械，广泛用于电池，是荧光灯泡的组成部分，并且与金矿地区的人类中毒有关。无机汞引起的肾毒性是一个主要的健康问题，主要在发展中国家。汞毒性的主要机制是氧化应激。曲美他嗪（TMZ）是一种抗缺血药物，可抑制细胞氧化应激，消除氧自由基，并改善脂质代谢。本研究旨在评估 TMZ 是否可预防氯化汞（HgCl2）引起的肾脏损伤。
成年雄性 Wistar 大鼠仅接受 HgCl2（4 mg/kg bw，sc）（Hg 组，n = 5）或 TMZ（3 mg/kg bw，ip）30 分钟前给予 HgCl2 （4 mg/kg bw，sc）（TMZHg 组，n = 7）。同时，研究了一组对照大鼠（n = 4）。HgCl2 注射 4 天后，测定尿流量，尿素和肌酐（Cr）血浆水平，Cr 清除率，尿葡萄糖和尿中二羧酸共转运蛋白 1（NaDC1）。测量肾匀浆中的脂质过氧化（MDA）和谷胱甘肽（GSH）水平。
仅用 HgCl2 治疗的大鼠与对照组相比，尿素和 Cr 血浆水平，尿流量，水的分数排泄，糖尿和 NaDC1 尿排泄增加，而 Cr 清除率降低。与 Hg 组相比，TMZHg 组的尿素和 Cr 血浆水平，尿流量，水的分数排泄，糖尿，NaDC1 尿排泄减少，Cr 清除率增加。此外，TMZ 预处理可降低 Hg 组中观察到的 MDA 和 GSH 水平。
TMZ 对 HgCl2 诱导的肾损伤具有肾保护作用，这可能是通过减少氧化应激介导的。考虑到 TMZ 无毒性，应考虑将其用于治疗 HgCl2 诱导的肾损伤引起的氧化损伤。TMZ 可商购，这应简化并加速从“基础到临床”的翻译。在这种情况下，TMZ 成为药物再利用的一个有趣的新范例。
