3-Aminobenzamide reduces brain infarction and neutrophil infiltration after transient focal cerebral ischemia in mice.
Poly(ADP-ribose) polymerase (PARP) was shown to be detrimental in cerebral ischemia but the mechanisms whereby PARP is deleterious have yet to be determined. They may include a role in neutrophil infiltration known to aggravate ischemic damage. In this context, we investigated the effect of 3-aminobenzamide (3-AB), a PARP inhibitor, on brain damage and neutrophil infiltration after transient focal cerebral ischemia in mice. Ischemia was induced in male Swiss mice, anaesthetized with chloral hydrate (400 mg/kg, i.p.), by a 15-min-occlusion of the left middle cerebral artery using an intraluminal suture. Treatments with 3-AB were first administered intraperitoneally 15 min before reperfusion and endpoints measured at 24 h. Among the range of dosages studied (20-320 mg/kg), 40 mg/kg gave the maximal neuroprotection with a 30% decrease in the infarct volume and tended to improve the neurological score evaluated by a grip test. The same dosage was, however, devoid of effect when injection was delayed 2 or 6 h after reperfusion. Myeloperoxidase (MPO) activity used as an index of neutrophil infiltration showed that infiltration peaked 48 h after reperfusion in our model. At this time point, 3-AB (40 mg/kg given 15 min before reperfusion) markedly reduced the neutrophil infiltration, as evidenced by a 72%-decrease in MPO activity, and was still neuroprotective. Our results confirm that 3-AB reduces brain damage. Moreover, for the first time, a quantitative study shows that 3-AB decreases neutrophil infiltration elicited by cerebral ischemia.
Couturier
Jérôme Y
JY
Laboratoire de Pharmacologie, UPRES EA2510, Université René Descartes, F-75006, Paris, France.
Ding-Zhou
Li
L
Croci
Nicole
N
Plotkine
Michel
M
Margaill
Isabelle
I
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D020520:Brain Infarction / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D002546:Ischemic Attack, Transient / Q000150:complications; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009195:Peroxidase / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D015424:Reperfusion; D013997:Time Factors
D001549:Benzamides; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C025160:3-aminobenzamide; D009195:Peroxidase