Investigation of the role of mitochondrial damage and oxidative stress in manganase induced cytotoxicity

Manganese (Mn), an essential dietary element, has important roles in several physiological processes in the body. However, accumulation of Mn due to excessive environmental and occupational exposure leads to movement abnormalities and cognitive impairment. Although oxidative stress has been hypothesized to play a role in this dysfunction, the underlying mechanisms still need to be elucidated. In the present study, we aim to investigate the effects of chronic Mn toxicity in brain and its relation with mitochondrial oxidative stress. Also, we examined whether edaravone (EDA), a radical scavenger, exerts cytoprotective effects against Mn neurotoxicity. Forty adult male Sprague Dawley rats were included in the study. Study groups were designed as follows: Group 1: Saline, Group 2: Mn (10 mg/kg), Group 3: Mn + EDA 1mg/kg and Group 4: Mn + EDA 5 mg/kg. All treatments were performed intraperitoneally (Mn) and intramuscularly (EDA) through 28 days. At the end of the treatment period, gross motor performance was measured and distribution of Mn in brain regions was detected using MR imaging. Then, brain tissues were dissected and and electron transport chain enzyme complex I activity, lipid peroxide and protein carbonyl levels were determined in mitochondrial fractions. All data were analyzed by one way ANOVA and post-hoc Bonferonni test. According to our findings, complex I activity was significantly decreased in Mn + saline group compared to saline group (p<0.0005) whereas lipid peroxide and protein carbonyl levels were significantly increased (p<0.0005). Administration of edaravone significantly and dose-dependently prevented cytotoxicity against Mn exposure. Overall, our results reveal that chronic Mn exposure may lead to cytotoxicity in rat brain through mitochondrial oxidative stress. Moreover, edaravone, as an antioxidant agent, may have cytoprotective effects against Mn exposure.