cytochrome-c-t and mephedrone

Mephedrone (4-methylmethcathinone) is a new and popular drug of abuse and also widely available on the internet and still legal in some parts of the world. The central nervous system is the target of mephedrone and recent evidence suggested that mephedrone could affect mitochondria in brain tissue. However, the underlying mechanisms of mephedrone toxicity in brain mitochondria have not yet been well understood. In this study, mitochondria from three separate parts of rat brain hippocampus, cortex, and cerebellum were obtained using differential centrifugation and were incubated with different concentrations of mephedrone (3, 6 and 12 μM). Then, the mitochondrial parameters toxicity were determined. The results showed that mephedrone (3, 6 and 12 μM) induced impairment in the activity of the mitochondrial complex II and IV. Also, mephedrone (3, 6 and 12 μM) increased mitochondrial reactive oxygen species (ROS) level, collapsed mitochondria membrane potential (MMP), induced swelling in the mitochondria and damaged the mitochondrial outer membrane (MOM) in the mitochondria obtained from hippocampus, cortex, and cerebellum, which in all cases is associated with the cytochrome c release. Furthermore, increased disturbance in oxidative phosphorylation was also shown by the decrease in ATP level in mephedrone-treated mitochondria indicating mitochondrial dysfunction in separate parts of the brain. This study suggests that mephedrone via increasing oxidative stress and impairment of the mitochondrial respiratory chain in the hippocampus, cortex, and cerebellum may play a key role in the neurotoxicity.

Topics: Animals; Cerebellum; Cerebral Cortex; Cytochromes c; Dose-Response Relationship, Drug; Electron Transport Complex II; Electron Transport Complex IV; Hippocampus; Illicit Drugs; Male; Membrane Potential, Mitochondrial; Methamphetamine; Mitochondria; Mitochondrial Swelling; Oxidative Phosphorylation; Oxidative Stress; Rats, Wistar; Reactive Oxygen Species; Risk Assessment

1. Mephedrone, a new and popular amphetamine drug, is widely abused and is still legal in some parts around the world. Little data on mechanisms involved in mephedrone induced cardiotoxicity are available. 2. Therefore, we decided to explain the mechanisms of mephedrone cardiotoxicity by using mitochondria isolated from rat heart. The isolated heart mitochondria were incubated with different concentrations of mephedrone (5, 10 and 20 µM). 3. Results showed that mephedrone induced mitochondrial dysfunction via an increase in mitochondrial reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) collapse, mitochondrial swelling and damage in the mitochondrial outer membrane (MOM) which is associated with the cytochrome c release. Our results showed that decrease of ATP levels is an indicator of disturbance in oxidative phosphorylation. Also, mephedrone increased the caspase-3 activity. 4. According to the results, we suggest that mephedrone induced cardiotoxicity is the result of a disruptive effect on the mitochondrial respiratory chain and induction of ROS-mediated apoptosis signaling in heart cardiomyocytes.

Topics: Amphetamine-Related Disorders; Animals; Caspase 3; Cytochromes c; Electron Transport; Male; Methamphetamine; Mitochondria, Heart; Mitochondrial Proteins; Myocytes, Cardiac; Rats; Rats, Wistar; Reactive Oxygen Species