Effect of serine protease inhibitors on posttraumatic brain injury and neuronal apoptosis

N-Tosyl-L-phenylalanyl chloromethyl ketone (TPCK), an inhibitor of chymotry psin-like serine protease (CSP), prevents DNA fragmentation and apoptotic c ell death in certain blood cell lines and was reported to reduce hippocampa l 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 neu ronal 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 s ignificantly affect deficits of spatial learning but exacerbated motor dysf unction after injury, Moreover, TPCK did not prevent apoptotic neuronal cel l death caused by serum/K+ deprivation or by application of staurosporine o r 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 muM, TPCK was cytotoxic in all cultures tested. Similar results wer e obtained in cultures treated with another CSP inhibitor, 3,4-dichloroisoc oumarin. Cell death caused by CSP inhibitors was neither caspase-dependent nor associated with oligonucleosomal DNA fragmentation. Taken together, the se data do not support a neuroprotective role for CSP inhibitors. Rather, t hey suggest that CSPs may serve an endogenous neuroprotective role, possibl y by modulating necrotic cell death, (C) 2001 Academic Press.