Enhanced poly(ADP-ribose) polymerase-1 activation contributes to recombinant tissue plasminogen activator-induced aggravation of ischemic brain injury in vivo.
Recombinant tissue plasminogen activator (rt-PA) treatment improves functional outcome after acute ischemic stroke, inducing reperfusion by its thrombolytic activity. Conversely, there is evidence that rt-PA can mediate neuronal damage after ischemic brain injury in vivo. In addition to other mechanisms, enhancement of N-methyl-D-aspartate (NMDA) receptor signalling has been proposed to underlie rt-PA-mediated neurotoxicity. However, the role of poly(ADP-ribose) polymerase-1 (PARP-1) activation, which mediates postischemic excitotoxic cell death, in rt-PA-mediated aggravation of ischemic brain injury has not been established and was therefore addressed in this study. After permanent focal cerebral ischemia, intravenous rt-PA application significantly increased early postischemic PARP-1 activation within ischemic hemispheres and infarct volumes compared with control mice without affecting cerebral blood flow. Rt-PA induced increase in PARP-1 activation, and infarct volumes could be blocked by the PARP inhibitor 3-aminobenzamide. Moreover, the rt-PA-induced increase in PARP-1 activation was also prevented by the NMDA antagonist MK-801. In summary, we demonstrate that rt-PA treatment enhances postischemic PARP-1 activation, which contributes to rt-PA induced aggravation of ischemic brain injury in vivo. Furthermore, we provide evidence that NMDA receptor activation is required for rt-PA-mediated effects on postischemic PARP-1 activation.
Crome
Olaf
O
Department of Neurology, University of Goettingen Medical School, Goettingen, Germany.
Doeppner
Thorsten R
TR
Schwarting
Sönke
S
Müller
Barbara
B
Bähr
Mathias
M
Weise
Jens
J
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000473:pathology; D020520:Brain Infarction / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D002545:Brain Ischemia / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004789:Enzyme Activation; D002546:Ischemic Attack, Transient / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D010959:Tissue Plasminogen Activator / Q000009:adverse effects* / Q000627:therapeutic use
D001549:Benzamides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D016291:Dizocilpine Maleate; C025160:3-aminobenzamide; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D010959:Tissue Plasminogen Activator