High Ca2+Influx During Traumatic Brain Injury Leads to Caspase-1-Dependent Neuroinflammation and Cell Death.
We investigated the hypothesis that high Ca2+influx during traumatic brain injury induces the activation of the caspase-1 enzyme, which triggers neuroinflammation and cell apoptosis in a cell culture model of neuronal stretch injury and an in vivo model of fluid percussion injury (FPI). We first established that stretch injury causes a rapid increase in the intracellular Ca2+level, which activates interleukin-converting enzyme caspase-1. The increase in the intracellular Ca2+level and subsequent caspase-1 activation culminates into neuroinflammation via the maturation of IL-1β. Further, we analyzed caspase-1-mediated apoptosis by TUNEL staining and PARP western blotting. The voltage-gated sodium channel blocker, tetrodotoxin, mitigated the stretch injury-induced neuroinflammation and subsequent apoptosis by blocking Ca2+influx during the injury. The effect of tetrodotoxin was similar to the caspase-1 inhibitor, zYVAD-fmk, in neuronal culture. To validate the in vitro results, we demonstrated an increase in caspase-1 activity, neuroinflammation and neurodegeneration in fluid percussion-injured animals. Our data suggest that neuronal injury/traumatic brain injury (TBI) can induce a high influx of Ca2+to the cells that cause neuroinflammation and cell death by activating caspase-1, IL-1β, and intrinsic apoptotic pathways. We conclude that excess IL-1β production and cell death may contribute to neuronal dysfunction and cognitive impairment associated with TBI.
Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ, 07102, USA. pmamuneer@gmail.com.|Neuroscience Institute, JFK Medical Center, Edison, NJ, 08820, USA. pmamuneer@gmail.com.
P M Abdul
PMA
Muneer
Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ, 07102, USA.
Mathew
M
Long
Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ, 07102, USA.
Adriano Andrea
AA
Conte
Department of Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA.
Vijayalakshmi
V
Santhakumar
Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ, 07102, USA. bryan.j.pfister@njit.edu.
Bryan J
BJ
Pfister
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000070642:Brain Injuries, Traumatic / Q000201:enzymology* / Q000473:pathology*; D002118:Calcium / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D007249:Inflammation / Q000201:enzymology* / Q000473:pathology*; D053583:Interleukin-1beta / Q000378:metabolism; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017207:Rats, Sprague-Dawley; D013779:Tetrodotoxin / Q000633:toxicity
D053583:Interleukin-1beta; D013779:Tetrodotoxin; D020170:Caspase 1; D002118:Calcium
Apoptosis; Ca2+ influx; Caspase-1; Fluid percussion injury; IL-1β; Neuroinflammation; Neuronal stretch injury; Traumatic brain injury