Enhanced poly(ADP-ribose) polymerase-1 activation contributes to recombinant tissue plasminogen activator-induced aggravation of ischemic brain injury in vivo
✍ Scribed by Olaf Crome; Thorsten R. Doeppner; Sönke Schwarting; Barbara Müller; Mathias Bähr; Jens Weise
- Publisher
- John Wiley and Sons
- Year
- 2007
- Tongue
- English
- Weight
- 493 KB
- Volume
- 85
- Category
- Article
- ISSN
- 0360-4012
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✦ Synopsis
Abstract
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. © 2007 Wiley‐Liss, Inc.