Contribution of poly(ADP-ribose) polymerase to postischemic blood-brain barrier damage in rats.
The nuclear enzyme poly(ADP-ribose) polymerase (PARP) is activated by oxidative stress and plays a significant role in postischemic brain injury. We assessed the contribution of PARP activation to the blood-brain barrier (BBB) disruption and edema formation after ischemia-reperfusion. In male Wistar rats, global cerebral ischemia was achieved by occluding the carotid arteries and lowering arterial blood pressure for 20 mins. The animals were treated with saline or with the PARP inhibitor N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N, N-dimethylacetamide.HCl (PJ34); (10 mg/kg, i.v.) before ischemia. After 40 mins, 24, and 48 h of reperfusion, the permeability of the cortical BBB was determined after Evans Blue (EB) and Na-fluorescein (NaF) administration. The water content of the brain was also measured. The permeability of the BBB for EB increased after ischemia-reperfusion compared with the nonischemic animals after 24 and 48 h reperfusion but PARP inhibition attenuated this increase at 48 h (nonischemic: 170+/-9, saline: 760+/-95, PJ34: 472+/-61 ng/mg tissue). The extravasation of NaF showed similar changes and PJ34 post-treatment attenuated the permeability increase even at 24 h. PARP inhibition decreased the brain edema seen at 48 h. Because PARP has proinflammatory properties, the neutrophil infiltration of the cortex was determined, which showed lower values after PJ34 treatment. Furthermore, PJ34 treatment decreased the loss of the tight junction protein occludin at 24 and 48 h. The inhibition of PARP activity accompanied by reduced post-ischemic BBB disturbance and decreased edema formation suggests a significant role of this enzyme in the development of cerebral vascular malfunction
Lenzsér
Gábor
G
Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157, USA.lenzserg@hotmail.com
Kis
Béla
B
Snipes
James A
JA
Gáspár
Tamás
T
Sándor
Péter
P
Komjáti
Katalin
K
Szabó
Csaba
C
Busija
David W
DW
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000201:enzymology / Q000209:etiology; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation; D020925:Hypoxia-Ischemia, Brain / Q000150:complications / Q000201:enzymology*; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D062793:Occludin; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D010616:Phenanthrenes / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000150:complications / Q000201:enzymology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D008565:Membrane Proteins; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D062793:Occludin; C568987:Ocln protein, rat; D010616:Phenanthrenes; D018799:Intercellular Adhesion Molecule-1; D009195:Peroxidase; D011065:Poly(ADP-ribose) Polymerases