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

Ertugrul Kilic, Ülkan Kilic, Burak Yulug, Dirk M. Hermann, Russel J Reiter

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)171-176
Number of pages6
JournalJournal of Pineal Research
Volume36
Issue number3
StatePublished - Apr 2004

Fingerprint

Tissue Plasminogen Activator
Melatonin
Caspase 3
Ischemia
Lasers
Reperfusion
Middle Cerebral Artery Infarction
Wounds and Injuries
Transferases
Inbred C57BL Mouse
Hemodynamics
Staining and Labeling
Brain

Keywords

  • Caspase-3 activity
  • Free radical scavenging
  • Intraluminal thread occlusion
  • Ischemia/reperfusion
  • Melatonin
  • Thrombolysis
  • Tissue plasminogen activator

ASJC Scopus subject areas

  • Endocrinology

Cite this

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. / Kilic, Ertugrul; Kilic, Ülkan; Yulug, Burak; Hermann, Dirk M.; Reiter, Russel J.

In: Journal of Pineal Research, Vol. 36, No. 3, 04.2004, p. 171-176.

Research output: Contribution to journalArticle

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abstract = "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.",
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