Ramli Fitri Fareez, Rejeki Purwo Sri, Ibrahim Nurul 'Izzah, Abdullayeva Gulnar, Halim Shariff
Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, 56000 Kuala Lumpur, Malaysia.
Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK.
Int J Med Sci. 2025 Jan 1;22(3):482-507. doi: 10.7150/ijms.99159. eCollection 2025.
Persistent methamphetamine use causes many toxic effects in various organs, including the brain, heart, liver, kidney and eyes. The extent of its toxicity depends on numerous pharmacological factors, including route of administration, dose, genetic polymorphism related to drug metabolism and polysubstance abuse. Several molecular pathways have been proposed to activate oxidative stress, inflammation and apoptosis: B-cell lymphoma protein 2 (Bcl-2)-associated X (Bax)/Bcl2/caspase-3, nuclear factor erythroid 2-related factor (Nrf2)/heme oxygenase-1 (HO-1), protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/p70S6K, trace amine-associated receptor 1 (TAAR1)/cAMP/lysyl oxidase, Sigmar1/ cAMP response element-binding protein (CREB)/mitochondrial fission-1 protein (Fis1), NADPH-Oxidase-2 (NOX-2), renal autophagy pathway, vascular endothelial growth factor (VEGF)/phosphatidylinositol-3-kinase (PI3K)/ protein kinase B (Akt)/endothelial nitric oxide synthase (eNOS), Nupr1/Chop/P53/PUMA/Beclin1 and Toll-like receptor (TLR)4/MyD88/TRAF6 pathways. The activation promotes pathological changes, including the disruption of the blood-brain barrier, myocardial infarction, cardiomyopathy, acute liver failure, acute kidney injury, chronic kidney disease, keratitis, retinopathy and vision loss. This review revisits the pharmacological profiles of methamphetamine and its effects on the brain, heart, liver, eyes, kidneys and endothelium. Understanding the mechanisms of methamphetamine toxicity is essential in developing treatment strategies to reverse or attenuate the progress of methamphetamine-associated organ damage.
长期使用甲基苯丙胺会对包括大脑、心脏、肝脏、肾脏和眼睛在内的各种器官造成多种毒性影响。其毒性程度取决于众多药理学因素，包括给药途径、剂量、与药物代谢相关的基因多态性以及多药滥用情况。已提出多种分子途径可激活氧化应激、炎症和细胞凋亡：B细胞淋巴瘤蛋白2（Bcl-2）相关X蛋白（Bax）/Bcl2/半胱天冬酶-3、核因子红细胞2相关因子（Nrf2）/血红素加氧酶-1（HO-1）、蛋白激酶B（Akt）/雷帕霉素靶蛋白（mTOR）/p70核糖体蛋白S6激酶（p70S6K）、痕量胺相关受体1（TAAR1）/环磷酸腺苷（cAMP）/赖氨酰氧化酶、西格玛-1受体（Sigmar1）/cAMP反应元件结合蛋白（CREB）/线粒体分裂蛋白1（Fis1）、烟酰胺腺嘌呤二核苷酸磷酸氧化酶2（NOX-2）、肾脏自噬途径、血管内皮生长因子（VEGF）/磷脂酰肌醇-3激酶（PI3K）/蛋白激酶B（Akt）/内皮型一氧化氮合酶（eNOS）、核蛋白1（Nupr1）/C/EBP同源蛋白（Chop）/P53/p53上调凋亡调节因子（PUMA）/自噬相关蛋白Beclin1以及Toll样受体（TLR）4/髓样分化因子88（MyD88）/肿瘤坏死因子受体相关因子6（TRAF6）途径。这些激活作用会促进病理变化，包括血脑屏障破坏、心肌梗死、心肌病、急性肝衰竭、急性肾损伤、慢性肾病、角膜炎、视网膜病变和视力丧失。本综述重新审视了甲基苯丙胺的药理学特征及其对大脑、心脏、肝脏、眼睛、肾脏和内皮的影响。了解甲基苯丙胺毒性机制对于制定治疗策略以逆转或减轻甲基苯丙胺相关器官损伤的进展至关重要。
