A deficiency of mitochondrial glutathione reductase (or GR2) is capable of adversely affecting the reduction of GSSG and increasing mitochondrial oxidative stress. BCNU [1, 3-bis (2-chloroethyl)-1-nitrosourea] is an anticancer agent and known inhibitor of cytosolic GR ex vivo and in vivo. Here we tested the hypothesis that a BCNU-induced GR2 defect contributes to mitochondrial dysfunction and subsequent impairment of heart function. Intraperitoneal administration of BCNU (40 mg/kg) specifically inhibited GR2 activity by 79.8±2.7% in the mitochondria of rat heart. However, BCNU treatment modestly enhanced the activities of mitochondrial Complex I and other ETC components. The cardiac function of BCNU-treated rats was analyzed by echocardiography, revealing a systolic dysfunction associated with decreased ejection fraction, decreased cardiac output, and an increase in left ventricular internal dimension and left ventricular volume in systole. The respiratory control index of isolated mitochondria from the myocardium was moderately decreased after BCNU treatment, whereas NADH-linked uncoupling of oxygen consumption was significantly enhanced. Extracellular flux analysis to measure the fatty acid oxidation of myocytes indicated a 20% enhancement after BCNU treatment. When the mitochondria were immunoblotted with antibodies against GSH and UCP3, both protein S-glutathionylation of Complex I and expression of UCP3 were significantly up-regulated. Overexpression of SOD2 in the myocardium significantly reversed BCNU-induced GR2 inhibition and mitochondrial impairment. In conclusion, BCNU-mediated cardiotoxicity is characterized by the GR2 deficiency that negatively regulates heart function by impairing mitochondrial integrity, increasing oxidative stress with Complex I S-glutathionylation, and enhancing uncoupling of mitochondrial respiration.
Rosmarinic acid (RA) is a naturally occurring polyphenolic compound. It is found in several herbs in the Lamiaceae family, such as Perilla frutescens. RA has been reported to exert anti-oxidative effects on rat erythrocyte, liver, and kidney cells. However, little is known about the effects of RA on dopaminergic cells. In the present study, we investigated whether RA could protect MES23.5 dopaminergic cells from 6-hydroxydopamine (6-OHDA)-induced neurotoxicity. The results showed that RA pretreatment significantly prevented 6-OHDA-induced cell viability reduction. Further experiments demonstrated that 6-OHDA induced intracellular reactive oxygen species generation and decreased the mitochondria membrane potential (DeltaPsim). These effects could be partially reversed by RA pretreatment. However, RA had no direct chemical reaction with 6-OHDA extracellularly in a cell-free system. Taken together, these results suggest that RA could exert its protective effects against 6-OHDA-induced neurotoxicity through its anti-oxidation properties. Thus, we propose that RA should be viewed as a potential chemotherapeutic in Parkinson's disease patients.
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