Tissue-plasminogen activator-induced ischemic brain injury is reversed by melatonin: Role of iNOS and Akt

Ertugrul Kilic, Ülkan Kilic, Russel J. Reiter, Claudio L. Bassetti, Dirk M. Hermann

Research output: Contribution to journalArticlepeer-review

60 Scopus citations


In vivo studies showed that tissue-plasminogen activator (t-PA) may aggravate neuronal injury after focal cerebral ischemia. We hypothesized that t-PA impairs survival-promoting cell signaling in the ischemic brain, which may be reversed by a neuroprotectant, i.e. melatonin. We examined the effects of t-PA (10 mg/kg, i.V.), administered alone or in combination with melatonin (4 mg/kg, i.p.), on ischemic injury, inducible nitric oxide synthase (iNOS) expression as well as Akt, Bcl-XL and caspase-3 signaling following 90 min of intraluminal middle cerebral artery (MCA) occlusion in mice. t-PA, delivered immediately after reperfusion onset, increased infarct volume at 24 hr after MCA occlusion, in accordance with previous findings. Melatonin reduced infarct size when administered alone and reversed the t-PA-induced brain injury. Immunohistochemical studies showed that t-PA treatment was associated with an accumulation of iNOS positive cells in ischemic brain areas, which was abolished after co-delivery of melatonin. Western blots revealed that t-PA decreased phosphorylated Akt levels, but did not influence Bcl-XL expression and caspase-3 activity in ischemic brain lysates. Co-treatment with melatonin restored phosphorylated Akt levels, increased Bcl-XL expression and reduced caspase-3 activity. We provide evidence that t-PA-induced brain injury is accompanied by an activation of iNOS and inhibition of phosphatidylinositol-3 kinase/Akt. That melatonin reversed these signaling changes and the t-PA-induced brain injury makes this indole attractive as an add-on treatment with thrombolytics.

Original languageEnglish (US)
Pages (from-to)151-155
Number of pages5
JournalJournal of pineal research
Issue number2
StatePublished - Sep 1 2005


  • Akt
  • Melatonin
  • Middle cerebral artery occlusion
  • Neuroprotection
  • Thrombolysis

ASJC Scopus subject areas

  • Endocrinology


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