AlAsmari Abdullah F, Alshehri Mohammed M, Ali Nemat, AlAsmari Fawaz, Sari Youssef, Childers Wayne E, Abou-Gharbia Magid, Alharbi Metab, Elnagar Doaa M, Al-Qahtani Wejdan S
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, USA.
Saudi Pharm J. 2024 Sep;32(9):102148. doi: 10.1016/j.jsps.2024.102148. Epub 2024 Jul 21.
Drug addiction is considered a worldwide concern and one of the most prevailing causes of death globally. Opioids are highly addictive drugs, and one of the most common opioids that is frequently used clinically is fentanyl. The potential harmful effects of chronic exposure to opioids on the heart are still to be elucidated. Although β-lactam antibiotics are well recognized for their ability to fight bacteria, its protective effect in the brain and liver has been reported. In this study, we hypothesize that β-lactam antibiotic, ceftriaxone, and the novel synthetic non-antibiotic β-lactam, MC-100093, are cardioprotective against fentanyl induced-cardiac injury by upregulating xCT expression. Mice were exposed to repeated low dose (0.05 mg/kg, i.p.) of fentanyl for one week and then challenged on day 9 with higher dose of fentanyl (1 mg/kg, i.p.). This study investigated cardiac histopathology and target genes and proteins in serum and cardiac tissues in mice exposed to fentanyl overdose and β-lactams. We revealed that fentanyl treatment induced cardiac damage as evidenced by elevated cardiac enzymes (troponin I). Furthermore, fentanyl treatment caused large aggregations of inflammatory cells and elevation in the areas and volumes of myocardial fibers, indicating hypertrophy and severe cardiac damage. Ceftriaxone and MC-100093 treatment, However, induced cardioprotective effects as evidenced by marked reduction in cardiac enzymes (troponin I) and changes in histopathology. Furthermore, ceftriaxone and MC-100093 treatment decreased the levels of hypertrophic genes (α-MHC & β-MHC), apoptotic (caspase-3), and inflammatory markers (IL-6 & NF-κB). This study reports for the first time the cardioprotective effect of β-lactams against fentanyl-induced cardiac injury. Further studies are greatly encouraged to completely identify the cardioprotective properties of ceftriaxone and MC-100093.
药物成瘾被视为一个全球性问题，也是全球最主要的死亡原因之一。阿片类药物是极易成瘾的毒品，临床上常用的最常见阿片类药物之一是芬太尼。长期接触阿片类药物对心脏的潜在有害影响仍有待阐明。尽管β-内酰胺类抗生素因其抗菌能力而广为人知，但已有报道称其对大脑和肝脏具有保护作用。在本研究中，我们假设β-内酰胺类抗生素头孢曲松和新型合成非抗生素β-内酰胺类药物MC-100093通过上调xCT表达对芬太尼诱导的心脏损伤具有心脏保护作用。小鼠连续一周接受低剂量（0.05 mg/kg，腹腔注射）芬太尼，然后在第9天接受高剂量芬太尼（1 mg/kg，腹腔注射）刺激。本研究调查了芬太尼过量和β-内酰胺类药物作用下小鼠的心脏组织病理学以及血清和心脏组织中的靶基因和蛋白质。我们发现芬太尼治疗导致心脏损伤，心肌酶（肌钙蛋白I）升高就是证据。此外，芬太尼治疗导致炎症细胞大量聚集，心肌纤维面积和体积增加，表明心肌肥大和严重心脏损伤。然而，头孢曲松和MC-100093治疗具有心脏保护作用，心肌酶（肌钙蛋白I）显著降低和组织病理学变化就是证据。此外，头孢曲松和MC-100093治疗降低了肥大基因（α-肌球蛋白重链和β-肌球蛋白重链）、凋亡（半胱天冬酶-3）和炎症标志物（白细胞介素-6和核因子-κB）的水平。本研究首次报道了β-内酰胺类药物对芬太尼诱导的心脏损伤的心脏保护作用。强烈鼓励进一步研究以全面确定头孢曲松和MC-100093的心脏保护特性。
