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

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-X(L) 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-X(L) expression and caspase-3 activity in ischemic brain lysates. Co-treatment with melatonin restored phosphorylated Akt levels, increased Bcl-X(L) 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.
AuthorsErtugrul Kilic, Ulkan Kilic, Russel J Reiter, Claudio L Bassetti, Dirk M Hermann
JournalJournal of pineal research (J Pineal Res) Vol. 39 Issue 2 Pg. 151-5 (Sep 2005) ISSN: 0742-3098 [Print] Denmark
PMID16098092 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Proto-Oncogene Proteins
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Tissue Plasminogen Activator
  • Melatonin
  • Animals
  • Blotting, Western
  • Brain Ischemia (chemically induced, drug therapy)
  • Immunohistochemistry
  • Laser-Doppler Flowmetry
  • Male
  • Melatonin (pharmacology)
  • Mice
  • Mice, Inbred C57BL
  • Nitric Oxide Synthase (physiology)
  • Nitric Oxide Synthase Type II
  • Protein-Serine-Threonine Kinases (physiology)
  • Proto-Oncogene Proteins (physiology)
  • Proto-Oncogene Proteins c-akt
  • Tissue Plasminogen Activator (pharmacology)

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