N-tosyl-L-phenylalanyl-chloromethylketone reduces hypoxic-ischemic brain injury in rat pups.
N-tosyl-L-phenylalanyl-chloromethylketone (TPCK) in vitro blocks apoptotic pathways leading to cell death. We wished to see if TPCK would reduce brain injury in vivo. Seven-day-old rat pups had the right carotid artery ligated and then received either vehicle or TPCK (5 to 100 mg/kg i.p.). They were then given 8% oxygen for 2.25 h. Twenty-two days later, the cerebral hemispheres were weighed to determine the reduction in size in the right hemisphere. TPCK decreased the reduction in right hemisphere weight from 15+/-3% (vehicle, n=20), to 4+/-2% (10 mg/kg, n = 19, P<0.01). TPCK reduced the number of cells staining for DNA breaks 3 days after injury from 1729+/-275 mm(-2) (vehicle, n = 8) to 550+/-236 mm(-2) (10 mg/kg TPCK, n = 9, P<0.01), decreased the amount of DNA fragmentation 3 days after injury by gel electrophoreses (20 mg/kg, n = 16, P<0.01) and eliminated the increase in nitric oxide metabolites 6 h after injury (vehicle 1.5+/-0.4, n = 10; and 20 mg/kg TPCK 0.0+/-0.1 nM/mg protein, n = 10, P<0.001). TPCK pretreatment in the newborn rat model of hypoxic-ischemic brain injury reduces DNA fragmentation, nitric oxide production and brain injury.
LeBlanc
M H
MH
Department of Pediatrics, University of Mississippi Medical Center, 2500 North State Street, Jackson, MI 39216-4505, USA. mleblanc@ped.umsmed.edu
Feng
Y
Y
Fratkin
J D
JD
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000517:prevention & control*; D004247:DNA / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D002534:Hypoxia, Brain / Q000517:prevention & control*; D020287:In Situ Nick-End Labeling; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology*
D009566:Nitrates; D009573:Nitrites; D015842:Serine Proteinase Inhibitors; D014108:Tosylphenylalanyl Chloromethyl Ketone; D004247:DNA