Tissue plasminogen activator-induced ischemic injury is reversed by NMDA antagonist MK-801 in vivo.
In vitro studies suggested that tissue plasminogen activator (t-PA) may aggravate ischemic injury by enhancing N-methyl-D-aspartate (NMDA) receptor signalling. It remained unclear whether NMDA signalling is also relevant for t-PA toxicity in vivo. We herein examined effects of intravenous t-PA (10 mg/kg), administered alone or in combination with the NMDA antagonist MK-801 (0.2 mg/kg), following 90 min of middle cerebral artery occlusion in mice. In our study, MK-801 alone, administered intraperitoneally, neither affected infarct volume nor brain swelling at 24 h after reperfusion. t-PA significantly increased infarct size, in accordance with previous findings. t-PA-induced ischemic injury was completely abolished and brain swelling markedly reduced when t-PA-treated animals received additional MK-801 injections. To elucidate how t-PA influences brain damage, we examined actions of t-PA on the expression of NO synthases by immunohistochemistry, showing that t-PA does not influence neuronal NO synthase, but increases inducible NO synthase in ischemic areas. The effect of t-PA on inducible NO synthase levels was completely reversed after cotreatment with MK-801. Our study provides in vivo evidence in a model of focal cerebral ischemia that t-PA-induced brain injury involves an NMDA receptor-dependent mechanism.
Kilic
Ertugrul
E
Department of Neurology, University Hospital Zurich, Zurich, Switzerland. ertugrul.kilic@usz.ch
Kilic
Ulkan
U
Bahr
Mathias
M
Hermann
Dirk M
DM
D000704:Analysis of Variance; D000818:Animals; D001784:Blood Gas Analysis / Q000379:methods; D001929:Brain Edema / Q000188:drug therapy / Q000209:etiology; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000209:etiology*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000627:therapeutic use*; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000627:therapeutic use*; D007150:Immunohistochemistry / Q000379:methods; D017078:Laser-Doppler Flowmetry / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000009:adverse effects*
D018690:Excitatory Amino Acid Agonists; D016291:Dizocilpine Maleate; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D010959:Tissue Plasminogen Activator