Use of a poly(ADP-ribose) polymerase inhibitor to suppress inflammation and neuronal death after cerebral ischemia-reperfusion.
OBJECTIVE
Most stroke patients do not present for medical treatment until several hours after onset of brain ischemia. Consequently, neuroprotective strategies are required with comparably long therapeutic windows. Poly(ADP-ribose) polymerase inhibitors such as PJ34 are known to suppress microglial activation, a postischemic event that may contribute to neuronal death. We evaluated the effects of PJ34 administered 8 hours after transient forebrain ischemia.


METHODS
Rats were subjected to 10 minutes of forebrain ischemia and treated with PJ34 for 7 days beginning 8 hours after reperfusion. Activated microglia and infiltrating macrophages were evaluated at serial time points between zero and 14 days after ischemia by immunostaining for CD11b. CA1 neuronal survival was evaluated 7 days after ischemia.


RESULTS
Rats treated with PJ34 showed a near-complete inhibition of microglia/macrophage activation (evaluated on day 5) and an 84% reduction in CA1 neuronal death.


CONCLUSIONS
Administration of PJ34 as late as 8 hours after transient ischemia-reperfusion has a large protective effect on CA1 survival. This effect may be mediated by suppression of the postischemic brain inflammatory response.
Hamby
Aaron M
AM
Department of Neurology, University of California, San Francisco, and Veterans Affairs Medical Center, San Francisco, California, USA.
Suh
Sang Won
SW
Kauppinen
Tiina M
TM
Swanson
Raymond A
RA
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D007249:Inflammation / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D010616:Phenanthrenes / Q000494:pharmacology / Q000627:therapeutic use; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion / Q000379:methods*
C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases