LEX032, a novel recombinant serpin, protects the brain after transient focal ischemia.
This investigation examined the effectiveness of a serine protease inhibitor (LEX032) when used as a cerebral protective agent after ischemia. Focal cerebral ischemia in the rat was produced by intravascular occlusion of the middle cerebral artery for a period of 30 min. Just prior to thread withdrawal (i.e., reperfusion), rats received an iv bolus administration of either vehicle or LEX032 (50 mg/kg), an optimal dose chosen based on previous studies. Somatosensory evoked potentials (SSEP's) were monitored prior to, during, and for a period of 60 min after removal of occlusion. The animals were allowed to recover for 24 h after the ischemic insult. Cortical activity in the occluded region, as assessed by SSEPs, returned much sooner in the LEX032-treated animals (10 +/- 6 min) than in the untreated animals (40 +/- 25 min). On a scale ranging from 0 to 3, with three indicating the most severely injured, the LEX032 animals had a significantly better neurologic score (1.0 +/- 0.9) than the untreated animals (2.3 +/- 0.5) 24 h after ischemia. The improved neurobehavior was related to a 55% reduction in brain injury as assessed by TTC staining. LEX032-treated animals had significantly (P < 0.01) smaller infarcts (115 +/- 40 mm3) compared to vehicle-treated animals (263 +/- 13 mm3). In a separate group of animals (n = 6/group), leukocyte infiltration, as evaluated by tissue myeloperoxidase activity (MPO U/g tissue wt), was also significantly (P < 0.05) lower in the LEX032-treated animals (1.4 +/- 0.3) compared to vehicle-treated animals (3.6 +/- 0.7). This data demonstrates that LEX032 reduces brain injury and suggests that serine protease inhibitors may reduce ischemia/reperfusion injury by decreasing leukocyte activation and migration.
Weaver
Michael
M
Department of Physiology, Temple University School of Medicine, 3420 N. Broad St., Philadelphia, Pennsylvania 19140, USA.
Leshley
Karin
K
Sands
Howard
H
Gritman
Kurt R
KR
Legos
Jeffrey J
JJ
Tuma
Ronald F
RF
D000818:Animals; D001921:Brain / Q000473:pathology*; D002545:Brain Ischemia; D002448:Cell Adhesion; D002465:Cell Movement; D005071:Evoked Potentials; D006801:Humans; D009504:Neutrophils / Q000201:enzymology; D009195:Peroxidase / Q000096:biosynthesis / Q000378:metabolism*; D011480:Protease Inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000517:prevention & control; D015843:Serpins / Q000378:metabolism* / Q000494:pharmacology*; D013696:Temperature; D013997:Time Factors
C095800:LEX 032; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D015843:Serpins; D009195:Peroxidase