High Ca2+ Influx During Traumatic Brain Injury Leads to Caspase-1-Dependent Neuroinflammation and Cell Death

Authors

P. M. Abdul-Muneer, Newark College of Engineering
Mathew Long, Newark College of Engineering
Adriano Andrea Conte, Newark College of Engineering
Vijayalakshmi Santhakumar, Rutgers New Jersey Medical School
Bryan J. Pfister, Newark College of Engineering

Document Type

Article

Publication Date

8-1-2017

Abstract

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.

Identifier

85024107049 (Scopus)

Publication Title

Molecular Neurobiology

External Full Text Location

https://doi.org/10.1007/s12035-016-9949-4

e-ISSN

15591182

ISSN

08937648

PubMed ID

27289225

First Page

3964

Last Page

3975

Issue

6

Volume

54

Grant

R01NS069861

Fund Ref

National Institute of Neurological Disorders and Stroke

Recommended Citation

Abdul-Muneer, P. M.; Long, Mathew; Conte, Adriano Andrea; Santhakumar, Vijayalakshmi; and Pfister, Bryan J., "High Ca2+ Influx During Traumatic Brain Injury Leads to Caspase-1-Dependent Neuroinflammation and Cell Death" (2017). Faculty Publications. 9404.
https://digitalcommons.njit.edu/fac_pubs/9404