Melatonin reduces disseminate neuronal death after mild focal ischemia in mice via inhibition of caspase-3 and is suitable as an add-on treatment to tissue-plasminogen activator.
The effects of i.p. melatonin (4 + 4 mg/kg, after induction of ischemia and at reperfusion onset) administered either alone or in combination with the thrombolytic tissue-plasminogen activator (t-PA, 10 mg/kg), on cerebral laser Doppler flow (LDF) and ischemic injury were studied after 30 min of middle cerebral artery (MCA) thread occlusion in male C57BL/6 mice. Thread occlusions resulted in reproducible focal ischemias, followed by hyperperfusion reactions immediately after thread withdrawal, as revealed by LDF measurements. Compared with animals receiving normal saline (peak LDF after reperfusion: 172.0 +/- 24.2%), postischemic LDF was significantly attenuated in animals treated with melatonin (105.1 +/- 6.7%, P < 0.05). Delivery of t-PA (132.8 +/- 22.3%) or t-PA plus melatonin (164.7 +/- 36.7%), on the contrary, did not influence postischemic LDF recordings. Twenty-four hours after reperfusion, melatonin treated mice had significantly increased neuronal survival and decreased disseminate cell injury in the ischemia-vulnerable striatum, as investigated by cresyl violet and terminal transferase biotinylated-dUTP nick end labeling stainings. The protective effects were associated with inhibition of caspase-3 activity. Melatonin administration also increased neuronal survival after 30 min MCA occlusion in animals treated with t-PA, although t-PA itself already decreased the degree of injury in a significant manner. Our data demonstrate that melatonin reduces disseminated neuronal injury in the striatum after mild focal ischemia. Brain protection is independent of hemodynamic changes and involves inhibition of caspase-3.
Kilic
Ertugrul
E
Department of Neurology, University Hospital Zürich, Zürich, Switzerland. ertugrul.kilic@usz.ch
Kilic
Ulkan
U
Yulug
Burak
B
Hermann
Dirk M
DM
Reiter
Russel J
RJ
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy; D053148:Caspase 3; D061945:Caspase Inhibitors; D016923:Cell Death / Q000187:drug effects; D003327:Coronary Disease; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D004357:Drug Synergism; D007511:Ischemia / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020768:Middle Cerebral Artery / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D015427:Reperfusion Injury; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
D061945:Caspase Inhibitors; D018696:Neuroprotective Agents; D010959:Tissue Plasminogen Activator; C505409:Casp3 protein, mouse; D053148:Caspase 3; D008550:Melatonin