cytochrome-c-t and Amphetamine-Related-Disorders

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

Drug abuse is associated with brain dysfunction and neurodegeneration, and various recreational drugs induce apoptotic cell death. This study examined the role of the mitochondrial apoptotic pathway in psychostimulant-induced neuronal dysfunction. Using primary neuronal cultures, we observed that amphetamine (IC50=1.40 mM) was more potent than cocaine (IC50=4.30 mM) in inducing cell toxicity. Apoptotic cell death was further evaluated using cocaine and amphetamine concentrations that moderately decreased cell reduction capacity but did not affect plasma membrane integrity. Compared to cocaine, amphetamine highly decreased the mitochondrial membrane potential, as determined using the fluorescent probe rhodamine-123, whereas both drugs decreased mitochondrial cytochrome c. In contrast to amphetamine, cocaine cytotoxicity was partly mediated through effects on the electron transport chain, since cocaine toxicity was ameliorated in mitochondrial DNA-depleted cells lacking mitochondrially encoded electron transport chain subunits. Cocaine and amphetamine induced activation of caspases-2, -3 and -9 but did not affect activity of caspases-6 or -8. In addition, amphetamine, but not cocaine, was associated with the appearance of evident nuclear apoptotic morphology. These events were not accompanied by differences in the release of the apoptosis-inducing factor (AIF) from mitochondria. Our results demonstrate that although both amphetamine and cocaine activate the mitochondrial apoptotic pathway in cortical neurons, amphetamine is more likely to promote apoptosis.

Topics: Amphetamine; Amphetamine-Related Disorders; Animals; Apoptosis; Caspases; Cell Line, Tumor; Central Nervous System Stimulants; Cerebral Cortex; Cocaine; Cocaine-Related Disorders; Cytochromes c; Disease Models, Animal; Electron Transport Chain Complex Proteins; Energy Metabolism; Humans; Membrane Potentials; Mitochondria; Mitochondrial Membranes; Nerve Degeneration; Neurons; Rats