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.
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.
Baydas
G
G
Department of Physiology, Faculty of Medicine, Firat University, Elazig 23119, Turkey. baydas@hotmail.com
Reiter
R J
RJ
Akbulut
M
M
Tuzcu
M
M
Tamer
S
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism*; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism; D053938:DNA Fragmentation; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006710:Homocysteine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014178:Translocation, Genetic
D006710:Homocysteine; D045304:Cytochromes c; D005979:Glutathione Peroxidase; D011065:Poly(ADP-ribose) Polymerases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D008550:Melatonin