Strain influences on inflammatory pathway activation, cell infiltration and complement cascade after traumatic brain injury in the rat

Nimer, Faiez Al; Lindblom, Rickard P F; Ström, Mikael; Guerreiro-Cacais, André Ortlieb; Parsa, Roham; Aeinehband, Shahin; Mathiesen, Tiit; Lidman, Olle; Piehl, Fredrik

doi:10.1016/j.bbi.2012.10.002

Cited by 45 publications

(31 citation statements)

References 49 publications

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“…For example, as in flies, human studies suggest that age and the severity of primary injury are important factors in CTE development (30,31). In addition, studies in different rodent strains as well as genetic association studies in TBI patients indicate that, as in flies, TBI outcomes depend on genetic background (26,32).…”

Section: Discussionmentioning

confidence: 99%

A Drosophila model of closed head traumatic brain injury

Katzenberger¹,

Loewen

Wassarman³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

112

233

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Traumatic brain injury (TBI) is a substantial health issue worldwide, yet the mechanisms responsible for its complex spectrum of pathologies remains largely unknown. To investigate the mechanisms underlying TBI pathologies, we developed a model of TBI in Drosophila melanogaster. The model allows us to take advantage of the wealth of experimental tools available in flies. Closed head TBI was inflicted with a mechanical device that subjects flies to rapid acceleration and deceleration. Similar to humans with TBI, flies with TBI exhibited temporary incapacitation, ataxia, activation of the innate immune response, neurodegeneration, and death. Our data indicate that TBI results in death shortly after a primary injury only if the injury exceeds a certain threshold and that age and genetic background, but not sex, substantially affect this threshold. Furthermore, this threshold also appears to be dependent on the same cellular and molecular mechanisms that control normal longevity. This study demonstrates the potential of flies for providing key insights into human TBI that may ultimately provide unique opportunities for therapeutic intervention.concussion | insect | chronic traumatic encephalopathy T raumatic brain injury (TBI) is a leading cause of neurological deficits and mortality worldwide (1, 2). TBI outcomes result from primary and secondary injuries that cause cell damage and death in the brain. Primary injuries occur during the initial impact and are triggered by external mechanical forces that deform the brain, whereas secondary injuries are triggered by cellular and molecular responses that occur over time in reaction to the primary injuries. TBI outcomes are heterogeneous in the human population owing to variation in the location and strength of primary injuries as well as genetic and environmental factors that affect the severity of primary and secondary injuries. This heterogeneity is one of the most significant barriers to the development of therapeutic interventions (3-5). Therefore, research aimed at determining the genetic and environmental factors that affect the severity of primary and secondary injuries is essential for developing treatments for TBI.To investigate the underlying cellular and molecular basis of TBI, we developed a Drosophila melanogaster model. Key advantages of flies are that (i) large numbers of animals can be rapidly and inexpensively analyzed to establish causality between injuries and outcomes, (ii) many molecular and genetic tools are available to investigate the molecules and pathways that underlie injuries, and (iii) outcomes can readily be evaluated over the entire animal lifespan. Thus, flies provide unique opportunities to understand TBI.It is reasonable to expect that TBI can be modeled in flies because Drosophila has already proved to be an extremely useful model for studying other human neurodegenerative disorders (6). In fact, research in flies has already provided novel insights into neurodegeneration, memory, and sleep, all of which are affected in human TBI (6-8)...

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Section: Discussionmentioning

confidence: 99%

A Drosophila model of closed head traumatic brain injury

Katzenberger¹,

Loewen

Wassarman³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

112

233

View full text Add to dashboard Cite

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“…Importantly, the dynamic of NF-L observed in this study also fits well with the implication that all axonal injury lesions may not occur or may not be visible on brain CT in the initial stages of TBI, but evolves over hours or days as the axonal swelling progresses 22 . Secondary effects of injury such as inflammation, as well as genetic variability have previously been shown in an animal model study of TBI to effect NF-L concentration 23 . However, we found no significant difference in the levels of either NF-L or S100B between the APOE ε 4 carriers and non-carriers.…”

Section: Discussionmentioning

confidence: 99%

P3‐193: Serum Neurofilament Light Protein Predicts Clinical Outcome in Traumatic Brain Injury

Shahim

Gren

Liman

et al. 2016

Alzheimer's & Dementia

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Axonal white matter injury is believed to be a major determinant of adverse outcomes following traumatic brain injury (TBI). We hypothesized that measurement of neurofilament light protein (NF-L), a protein found in long white-matter axons, in blood samples, may serve as a suitable biomarker for neuronal damage in TBI patients. To test our hypotheses, we designed a study in two parts: i) we developed an immunoassay based on Single molecule array technology for quantification of NF-L in blood, and ii) in a proof-of-concept study, we tested our newly developed method on serial serum samples from severe TBI (sTBI) patients (n = 72) and controls (n = 35). We also compared the diagnostic and prognostic utility of NF-L with the established blood biomarker S100B. NF-L levels were markedly increased in sTBI patients compared with controls. NF-L at admission yielded an AUC of 0.99 to detect TBI versus controls (AUC 0.96 for S100B), and increased to 1.00 at day 12 (0.65 for S100B). Importantly, initial NF-L levels predicted poor 12-month clinical outcome. In contrast, S100B was not related to outcome. Taken together, our data suggests that measurement of serum NF-L may be useful to assess the severity of neuronal injury following sTBI.

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“…Overall, the mechanism leading to the recruitment is not clear; nonetheless, it seems that the genetic background might influence this phenomenon. Thus, Nimer et al (95) found that the influx of CD3 2 CD161 bright NK cells in experimental traumatic brain contusion in DA rats was more marked than in PVG rats. This interindividual genetic heterogeneity might influence the outcome and treatment response following CNS pathology and partially explain the differences observed between studies.…”

Section: Nk Cell Modifications Associated With Cns Disordersmentioning

confidence: 99%

NK Cells in Central Nervous System Disorders

Poli

Kmiecik

Domingues

et al. 2013

The Journal of Immunology

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NK cells are important players in immunity against pathogens and neoplasms. As a component of the innate immune system, they are one of the first effectors on sites of inflammation. Through their cytokine production capacities, NK cells participate in the development of a potent adaptive immune response. Furthermore, NK cells were found to have regulatory functions to limit and prevent autoimmunity via killing of autologous immune cells. These paradoxical functions of NK cells are reflected in CNS disorders. In this review, we discuss the phenotypes and functional features of peripheral and brain NK cells in brain tumors and infections, neurodegenerative diseases, acute vascular and traumatic damage, as well as mental disorders. We also discuss the implication of NK cells in neurotoxicity and neuroprotection following CNS pathology, as well as the crosstalk between NK cells and brain-resident immune cells.

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Strain influences on inflammatory pathway activation, cell infiltration and complement cascade after traumatic brain injury in the rat

Cited by 45 publications

References 49 publications

A Drosophila model of closed head traumatic brain injury

A Drosophila model of closed head traumatic brain injury

P3‐193: Serum Neurofilament Light Protein Predicts Clinical Outcome in Traumatic Brain Injury

NK Cells in Central Nervous System Disorders

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