Ghanbarinejad Vahid, Ahmadi Asrin, Niknahad Hossein, Ommati Mohammad Mehdi, Heidari Reza
Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
Adv Pharm Bull. 2019 Jun;9(2):294-301. doi: 10.15171/apb.2019.034. Epub 2019 Jun 1.
Manganese (Mn) is a neurotoxic chemical which induces a wide range of complications in the brain tissue. Impaired locomotor activity and cognitive dysfunction are associated with high brain Mn content. At the cellular level, mitochondria are potential targets for Mn toxicity. Carnosine is a dipeptide abundantly found in human brain. Several pharmacological properties including mitochondrial protecting and antioxidative effects have been attributed to carnosine. The current study aimed to evaluate the effect of carnosine treatment on Mn-induced mitochondrial dysfunction in isolated brain mitochondria. Mice brain mitochondria were isolated based on the differential centrifugation method and exposed to increasing concentrations of Mn (10 µM-10 mM). Carnosine (1 mM) was added as the protective agent. Mitochondrial indices including mitochondrial depolarization, reactive oxygen species (ROS) formation, mitochondrial dehydrogenases activity, ATP content, and mitochondrial swelling and permeabilization were assessed. Significant deterioration in mitochondrial indices were evident in Mn-exposed brain mitochondria. On the other hand, it was found that carnosine (1 mM) treatment efficiently prevented Mn-induced mitochondrial impairment. These data propose mitochondrial protection as a fundamental mechanism for the effects of carnosine against Mn toxicity. Hence, this peptide might be applicable against Mn neurotoxicity with different etiologies (e.g., in cirrhotic patients).
锰（Mn）是一种神经毒性化学物质，可在脑组织中引发多种并发症。运动活动受损和认知功能障碍与脑中高含量的锰有关。在细胞水平上，线粒体是锰毒性的潜在靶点。肌肽是一种在人脑中大量存在的二肽。肌肽具有多种药理特性，包括线粒体保护和抗氧化作用。本研究旨在评估肌肽处理对分离的脑线粒体中锰诱导的线粒体功能障碍的影响。采用差速离心法分离小鼠脑线粒体，并将其暴露于浓度不断增加的锰（10 μM - 10 mM）中。添加肌肽（1 mM）作为保护剂。评估线粒体指标，包括线粒体去极化、活性氧（ROS）形成、线粒体脱氢酶活性、ATP含量以及线粒体肿胀和通透性。在暴露于锰的脑线粒体中，线粒体指标明显恶化。另一方面，发现肌肽（1 mM）处理可有效预防锰诱导的线粒体损伤。这些数据表明线粒体保护是肌肽对抗锰毒性作用的基本机制。因此，这种肽可能适用于治疗不同病因的锰神经毒性（例如，肝硬化患者）。
