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Updated: Oct 9, 2026
Controlled Cortical Impact Model for Traumatic Brain Injury
Published on: August 5, 2014
Effect of serine protease inhibitors on posttraumatic brain injury and neuronal apoptosis
V A Movsesyan1, A G Yakovlev, L Fan
1Georgetown Institute for Cognitive and Computational Sciences, Department of Neurocience, Georgetown University Medical Center, Washington, DC 20007, USA.
Abstract:
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.
Insights
Chymotrypsin-like serine protease (CSP) inhibitors like TPCK did not protect against brain injury or neuronal death in rats. Instead, these inhibitors were toxic to neurons, suggesting CSPs may have a protective role in brain injury recovery.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Chymotrypsin-like serine proteases (CSPs) are implicated in cellular processes, including apoptosis.
- N-Tosyl-l-phenylalanyl chloromethyl ketone (TPCK) inhibits CSPs and has shown potential in reducing neuronal damage.
- The role of CSPs in traumatic brain injury (TBI) and neuronal cell death remains unclear.
Purpose of the Study:
- To investigate the role of CSPs in neuronal recovery after TBI in rats.
- To evaluate the effect of CSP inhibition on neuronal cell survival in various in vitro models.
Main Methods:
- Lateral fluid percussion-induced TBI model in rats.
- Intracerebroventricular administration of TPCK post-TBI.
- In vitro neuronal cell death models using cultured rat cerebellar granule cells, rat cortical neurons, and SH-SY5Y cells.
- Assessment of CSP activity, spatial learning, motor function, and cell viability.
Main Results:
- TBI induced a time-dependent increase in cortical CSP activity.
- TPCK treatment after TBI exacerbated motor dysfunction but did not improve spatial learning.
- TPCK and 3,4-dichloroisocoumarin induced cytotoxicity in neuronal cultures, independent of caspase activation or DNA fragmentation.
Conclusions:
- CSP inhibitors like TPCK do not appear to offer neuroprotection against TBI or in vitro neuronal death models.
- CSPs may play an endogenous neuroprotective role, potentially by regulating necrotic cell death pathways.
