Melatonin inhibits neural apoptosis induced by homocysteine in hippocampus of rats via inhibition of cytochrome c translocation and caspase-3 activation and by regulating pro- and anti-apoptotic protein levels

• DOI: 10.1016/j.neuroscience.2005.05.048
• Publication Date: 2005-11-07T15:44:29Z
• Authors: G. Baydas; R.J. Reiter; M. Akbulut; M. Tuzcu; S. Tamer
• Keywords: Male; Neurons; 0301 basic medicine; Glutathione Peroxidase; Caspase 3; Blotting, Western; Cytochromes c; Apoptosis; DNA Fragmentation; Hippocampus; Mitochondria; Rats; 3. Good health; Enzyme Activation; 03 medical and health sciences; Cytosol; Gene Expression Regulation; Caspases; Animals; Lipid Peroxidation; Poly(ADP-ribose) Polymerases; Homocysteine; Melatonin

In the present study, we examined the molecular mechanism by which homocysteine causes neuronal cell apoptosis. We further investigated the mechanisms of melatonin's ability to reduce homocysteine-induced apoptosis. Consistent with its antioxidant properties, melatonin reduced homocysteine-induced lipid peroxidation and stimulated glutathione peroxidase enzyme activity in hippocampus of rats with hyperhomocysteinemia. Furthermore, melatonin treatment diminished cytochrome c release from mitochondria and reduced caspase 3 and caspase 9 activation induced by hyperhomocysteinemia. Chronic hyperhomocysteinemia also led to poly(ADP-ribose) polymerase cleavage and subsequently DNA fragmentation. Treatment with melatonin markedly inhibited poly(ADP-ribose) polymerase cleavage and reduced DNA damage. Hyperhomocysteinemia caused an elevation of pro-apoptotic Bax levels while reducing anti-apoptotic protein, Bcl-2, levels. Daily administration of melatonin up-regulated Bcl-2 and down-regulated Bax levels. We propose that, in addition to its antioxidant properties, melatonin has the ability to protect neuronal cells against apoptosis mediated homocysteine neurotoxicity by modulating apoptosis-regulatory proteins in the hippocampus of rats.