Inhibition of poly(ADP-ribose) polymerase suppresses inflammation and promotes recovery after ischemic injury.

Abstract

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.

• Authors: Tiina M Kauppinen, Sang Won Suh, Ari E Berman, Aaron M Hamby, Raymond A Swanson
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 29 Issue 4 Pg. 820-9 (Apr 2009) ISSN: 1559-7016 [Electronic] United States
• PMID: 19190653 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Enzyme Inhibitors
• N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
• Phenanthrenes
• Poly(ADP-ribose) Polymerase Inhibitors

Topics

• Animals
• Brain Ischemia (complications, drug therapy)
• Cell Survival
• Enzyme Inhibitors (therapeutic use)
• Hippocampus (pathology)
• Inflammation (drug therapy, prevention & control)
• Learning (drug effects)
• Memory (drug effects)
• Neurons
• Phenanthrenes (pharmacology, therapeutic use)
• Poly(ADP-ribose) Polymerase Inhibitors
• Rats
• Stroke (complications, drug therapy)
• Treatment Outcome