Effect of serine protease inhibitors on posttraumatic brain injury and neuronal apoptosis.
N-Tosyl-l-phenylalanyl chloromethyl ketone (TPCK), an inhibitor of chymotrypsin-like serine protease (CSP), prevents DNA fragmentation and apoptotic cell death in certain blood cell lines and was reported to reduce hippocampal neuronal damage caused by cerebral ischemia. We examined the role of CSP on recovery after lateral fluid percussion-induced traumatic brain injury (TBI) in rats, as well as on cell survival in various in vitro models of neuronal cell death. TBI caused significant time-dependent upregulation of CSP activity, but not trypsin-like serine protease activity in injured cortex. Intracerebroventricular administration of TPCK to rats after TBI did not significantly affect deficits of spatial learning but exacerbated motor dysfunction after injury. Moreover, TPCK did not prevent apoptotic neuronal cell death caused by serum/K(+) deprivation or by application of staurosporine or etoposide in cultured rat cerebellar granule cells, rat cortical neurons, or in the human neuroblastoma SH-SY5Y cell line. Instead, at doses from 10 to 100 microM, TPCK was cytotoxic in all cultures tested. Similar results were obtained in cultures treated with another CSP inhibitor, 3,4-dichloroisocoumarin. Cell death caused by CSP inhibitors was neither caspase-dependent nor associated with oligonucleosomal DNA fragmentation. Taken together, these data do not support a neuroprotective role for CSP inhibitors. Rather, they suggest that CSPs may serve an endogenous neuroprotective role, possibly by modulating necrotic cell death.
Movsesyan
V A
VA
Georgetown Institute for Cognitive and Computational Sciences, Department of Neurocience, Georgetown University Medical Center, Washington, DC 20007, USA.
Yakovlev
A G
AG
Fan
L
L
Faden
A I
AI
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003374:Coumarins / Q000008:administration & dosage; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007276:Injections, Intraventricular; D049934:Isocoumarins; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012697:Serine Endopeptidases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage*; D013037:Spatial Behavior / Q000187:drug effects; D019311:Staurosporine / Q000494:pharmacology; D014107:Tosyllysine Chloromethyl Ketone / Q000008:administration & dosage; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000008:administration & dosage; D014949:Wounds, Nonpenetrating
D003374:Coumarins; D016895:Culture Media, Serum-Free; D049934:Isocoumarins; D019384:Nucleic Acid Synthesis Inhibitors; D015842:Serine Proteinase Inhibitors; D014107:Tosyllysine Chloromethyl Ketone; D014108:Tosylphenylalanyl Chloromethyl Ketone; C046235:3,4-dichloroisocoumarin; D012697:Serine Endopeptidases; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D019311:Staurosporine; D011188:Potassium