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 journalArticle

56 Citations (Scopus)

Abstract

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
Volume39
Issue number2
DOIs
StatePublished - Sep 2005

Fingerprint

Nitric Oxide Synthase Type II
Tissue Plasminogen Activator
Melatonin
Brain Injuries
Caspase 3
Middle Cerebral Artery Infarction
Brain
Phosphatidylinositol 3-Kinase
Wounds and Injuries
Neuroprotective Agents
Brain Ischemia
Reperfusion
Cell Survival
Western Blotting

Keywords

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

ASJC Scopus subject areas

  • Endocrinology

Cite this

Tissue-plasminogen activator-induced ischemic brain injury is reversed by melatonin : Role of iNOS and Akt. / Kilic, Ertugrul; Kilic, Ülkan; Reiter, Russel J; Bassetti, Claudio L.; Hermann, Dirk M.

In: Journal of Pineal Research, Vol. 39, No. 2, 09.2005, p. 151-155.

Research output: Contribution to journalArticle

Kilic, Ertugrul ; Kilic, Ülkan ; Reiter, Russel J ; Bassetti, Claudio L. ; Hermann, Dirk M. / Tissue-plasminogen activator-induced ischemic brain injury is reversed by melatonin : Role of iNOS and Akt. In: Journal of Pineal Research. 2005 ; Vol. 39, No. 2. pp. 151-155.
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