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Attenuated neurological deficit, cell death and lesion volume in Fas-mutant mice is associated with altered neuroinflammation following traumatic brain injury

Citation

Ziebell, JM and Bye, N and Semple, BD and Kossmann, T and Morganti-Kossmann, MC, Attenuated neurological deficit, cell death and lesion volume in Fas-mutant mice is associated with altered neuroinflammation following traumatic brain injury, Brain research, 1414 pp. 94-105. ISSN 0006-8993 (2011) [Refereed Article]

Copyright Statement

Copyright 2011 Elsevier B.V.

DOI: doi:10.1016/j.brainres.2011.07.056

Abstract

Progressive neurodegeneration following traumatic brain injury (TBI) involves the Fas and TNF-receptor1 protein systems which have been implicated in mediating delayed cell death. In this study, we used two approaches to assess whether inhibition of these pathways reduced secondary brain damage and neurological deficits after TBI. Firstly, we investigated whether the expression of non-functional Fas in lpr mice subjected to TBI altered tissue damage and neurological outcome. Compared to wild-type, lpr mice showed improved neurological deficit (p=0.0009), decreased lesion volume (p=0.017), number of TUNEL+ cells (p=0.011) and caspase-3+ cells (p=0.007). Changes in cellular inflammation and cytokine production were also compared between mouse strains. Accumulation of macrophages/microglia occurred earlier in lpr mice, likely due to enhanced production of the chemotactic mediators IL-12(p40) and MCP-1 (p<0.05). Cortical production of IL-1α and IL-6 increased after injury to a similar extent regardless of strain (p<0.05), while TNF and G-CSF were significantly higher in lpr animals (p<0.05). Secondly, we assessed whether therapeutic inhibition of FasL and TNF via intravenous injection of neutralizing antibodies in wild-type mice post-TBI could reproduce the beneficial effects observed in lpr animals. No differences were found with this approach in animals treated with anti-FasL and anti-TNF antibodies alone or the combination of both. Altogether, reduced neurological deficits and lesion volume in lpr mice was associated with altered cellular and humoral inflammation, possibly contributing to neuroprotection, whereas neutralization of FasL and TNF had no effect. In future studies, the lpr mouse strain may be utilized as a model to further characterize molecular and cellular mechanisms protecting against secondary brain damage after TBI.

Item Details

Item Type:Refereed Article
Keywords:cell death, cytokine, caspase, Fas, neuroinflammation, traumatic brain injury
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Neurosciences not elsewhere classified
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Nervous System and Disorders
Author:Ziebell, JM (Dr Jenna Ziebell)
Author:Bye, N (Dr Nicole Bye)
ID Code:101787
Year Published:2011
Web of Science® Times Cited:25
Deposited By:Wicking Dementia Research and Education Centre
Deposited On:2015-07-08
Last Modified:2017-11-07
Downloads:0

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