Inhibition of poly(ADP-ribose) polymerase suppresses inflammation and promotes recovery after ischemic injury.
The brain inflammatory response induced by stroke contributes to cell death and impairs neurogenesis. Poly(ADP-ribose) polymerase-1 (PARP-1) is a coactivator of the transcription factor NF-kappaB and required for NF-kappaB-mediated inflammatory responses. Here we evaluated PARP inhibition as a means of suppressing post-stroke inflammation and improving outcome after stroke. Rats were subjected to bilateral carotid occlusion-reperfusion, and treatment with the PARP inhibitor N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide (PJ34) was begun 48 h later. PJ34 was found to rapidly suppress the ischemia-induced microglial activation and astrogliosis. Behavioral tests performed 6 to 8 weeks after ischemia showed deficits in spatial memory and learning that were lessened by the PJ34 treatment. Immunohistochemical evaluation of hippocampus at 8 weeks after ischemia showed increased neuronal density in CA1 layer of PJ34-treated animals relative to vehicle-treated animals. Bromodeoxyuridine labeling showed formation of new neurons in hippocampal CA1 area in PJ34-treated animals, but not in vehicle-treated animals. Together, these results suggest that treatment with a PARP inhibitor for several days after ischemia enhances long-term neuronal survival and neurogenesis by reducing inflammation.
Kauppinen
Tiina M
TM
Department of Neurology, University of California San Francisco, San Francisco, California 94121, USA. Tiina.Kauppinen@ucsf.edu
Suh
Sang Won
SW
Berman
Ari E
AE
Hamby
Aaron M
AM
Swanson
Raymond A
RA
D000818:Animals; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy*; D002470:Cell Survival; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006624:Hippocampus / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy / Q000517:prevention & control*; D007858:Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D009474:Neurons; D010616:Phenanthrenes / Q000494:pharmacology / Q000627:therapeutic use; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D020521:Stroke / Q000150:complications / Q000188:drug therapy; D016896:Treatment Outcome
D004791:Enzyme Inhibitors; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors