Long-term intracerebral inflammatory response after traumatic brain injury

Gentleman, Steve; Leclercq, Pascale D.; Moyes, LH; Graham, David I.; Smith, Colin; Griffin, W. Sue T.; Nicoll, James A. R.

doi:10.1016/j.forsciint.2004.06.027

Cited by 232 publications

(186 citation statements)

References 44 publications

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“…34,37,38,[66][67][68][69] These results indicate that the persistence of post-traumatic anxiety may reflect chronic neuroinflammatory neuropathy, a possibility supported by the observation of activated microglia and astrocytes, key cells mediating inflammatory processes, many years after injury in long-term survivors of TBI. [9][10][11][12] Chronic post-traumatic neuroinflammation suggests the presence of a self-perpetuating positive feedback loop, possibly involving reactivation and further promotion of inflammatory mediators after injury in an inflammation-damage-inflammation cycle. 70 Stressed, damaged, and injured cells release endogenous danger signals, which trigger local inflammatory responses needed for tissue repair and regeneration.…”

Section: Discussionmentioning

confidence: 99%

“…Extensive research has shown that chronic neuroinflammation continues for months to years after injury, [9][10][11][12] and evidence for chronic inflammation has been observed in a number of studies examining patients with PTSD, panic disorder, obsessive-compulsive disorder (OCD), and generalized anxiety disorder. [13][14][15][16][17][18] Glial activation may be involved in the development and maintenance of PTSD, [9][10][11][12] and mounting evidence supports the role of inflammatory processes in both TBI and anxiety disorders. After injury, immune cells rapidly produce endogenous danger signals or ''alarmins,'' which function as potent effectors of innate defense and promote immune system activation by recruiting antigen-presenting cells (APCs) that relay and amplify the inflammatory response.…”

mentioning

confidence: 99%

“…inflammatory response in the brain that exceeds early neuroprotection and results in neurodegenerative changes capable of continuing the inflammatory cycle. 9,27,90 Chronic inflammation has been observed in a number of studies examining patients with trauma-related anxiety disorders, reporting increases in downstream mediators, such as peripheral elevations of TNF-a, interferon-gamma (IFN-c), IL-1b, and IL-6, in patients with PTSD, [13][14][15][16] elevations of TNF-a and IL-6 in patients with OCD, 17 and elevations in proinflammatory cytokines and chemokines (monocyte chemoattractant protein 1, macrophage inflammatory protein 1 alpha, IL-1a, IL-1b, IL-6, IL-8, Eotaxin, granulocyte macrophage colony-stimulating factor, and IFN-c) in individuals with panic disorder and PTSD. 18 Despite compelling evidence implicating excessive inflammatory actions and a generalized inflammatory state in the development of anxiety disorders after TBI, central measures of proinflammatory cytokine elevations specifically related to human PTSD and other anxiety disorders have not yet been performed.…”

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confidence: 99%

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Reversal of Established Traumatic Brain Injury-Induced, Anxiety-Like Behavior in Rats after Delayed, Post-Injury Neuroimmune Suppression

Rodgers

Deming

Bercum

et al. 2014

Journal of Neurotrauma

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Traumatic brain injury (TBI) increases the risk of neuropsychiatric disorders, particularly anxiety disorders. Yet, there are presently no therapeutic interventions to prevent the development of post-traumatic anxiety or effective treatments once it has developed. This is because, in large part, of a lack of understanding of the underlying pathophysiology. Recent research suggests that chronic neuroinflammatory responses to injury may play a role in the development of post-traumatic anxiety in rodent models. Acute peri-injury administration of immunosuppressive compounds, such as Ibudilast (MN166), have been shown to prevent reactive gliosis associated with immune responses to injury and also prevent lateral fluid percussion injury (LFPI)-induced anxiety-like behavior in rats. There is evidence in both human and rodent studies that post-traumatic anxiety, once developed, is a chronic, persistent, and drug-refractory condition. In the present study, we sought to determine whether neuroinflammation is associated with the long-term maintenance of post-traumatic anxiety. We examined the efficacy of an anti-inflammatory treatment in decreasing anxiety-like behavior and reactive gliosis when introduced at 1 month after injury. Delayed treatment substantially reduced established LFPI-induced freezing behavior and reactive gliosis in brain regions associated with anxiety and continued neuroprotective effects were evidenced 6 months post-treatment. These results support the conclusion that neuroinflammation may be involved in the development and maintenance of anxiety-like behaviors after TBI.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Reversal of Established Traumatic Brain Injury-Induced, Anxiety-Like Behavior in Rats after Delayed, Post-Injury Neuroimmune Suppression

Rodgers

Deming

Bercum

et al. 2014

Journal of Neurotrauma

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“…164,170,171 In addition, head injury, epilepsy, and AIDS include early overexpression of βAPP and increases in neuroinflammatory cytokines, such as IL-1 and S100B. 82,[172][173][174][175][176][177] In several of the conditions mentioned above, glial activation has been associated with neuropathological changes similar to those in AD; glial activation is sometimes present long before frank neurodegeneration is noted.…”

Section: Environmental Events That Contribute To Precocious (Age-inapmentioning

confidence: 99%

Neuroinflammatory Cytokines—The Common Thread in Alzheimer Pathogenesis

Griffin¹,

Barger²

2010

US Neurology

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This article discusses the potential role of the cytokine cycle and its corollary as drivers of the relentless progression of Alzheimer's neuropathologies, whether they are the result of gene mutations, gene polymorphisms, and/or environmental and comorbid conditions. Based on the discovery of cytokine overexpression as an accompaniment to the dementia-related glial activation, the cytokine hypothesis wasproposed. This states that in response to the negative impact on neurons of known and unknown risk factors-which include genetic inheritance, comorbid and environmental factors-microglia and astrocytes become activated and produce excess amounts of the immune-modulating cytokine interleukin-1 (IL-1) and the neuritogenic cytokine S100B, respectively. Finding that these glial events occur in fetuses and neonates with Down syndrome provided the first evidence that productive immune responses by activated glia precede rather than follow overt AD-related pathology. This finding can be added to the demonstration of IL-1 induction of amyloid β (Aβ) precursor protein and astrocyte activation with excess production of neuritogenic factor S100B. This combination suggests that IL-1 and S100B overexpression would favor the Aβ production and dystrophic neurite growth necessary for laying down neuritic Aβ plaques. This, together with demonstration of IL-1 induction of excessive production of the precursors of other features common in AD prompted a corollary to the cytokine hypothesis. The corollary states that regardless of the primary cause of the neuronal insult, the result will be chronic glial activation, which in turn will result in further neuronal injury, still more glial activation with excess cytokine expression and so on. This article discusses known causes, genetic and environmental risk factors, and comorbid conditions, and the potential contribution of glial activation with excessive cytokine expression to each. KeywordsAlzheimer's disease (AD), amyloid β (Aβ), apolipoprotein E (ApoE), β−amyloid precursor protein (βAPP), cytokines, Down syndrome (DS), excitotoxicity, glutamate, interleukin-1 (IL-1), S100B, tumor necrosis factor alpha (TNFα) Disclosure: The authors have no conflicts of interest to declare. Acknowledgments:Much of the work cited in this article was supported by National Institutes of Health (NIH) grants P01AG12411 (to WSTG) and R01AG17498 (to SWB). The authors thank Orwa Aboud, MD, for helpful comments and editing. A progression of these neuropathological events seems apparent. For example, the plethora of Aβ plaques at end stages-from several to many-and an inclusion of neurofibrillary tangles-in a few to numerous neurons-strongly suggests that these neuropathological Received

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“…In primates, microglia activation was found to persist for at least 12 months (Nagamoto-Combs et al, 2007). Post-mortem studies in humans have shown persistent elevated microglial activity several years after TBI (Gentleman et al, 2004). In addition, a recent PET imaging study in humans using a ligand that binds to activated microglia revealed increased microglial activation for up to 17 years after TBI (Ramlackhansingh et al, 2011).…”

Section: Innate Immunitymentioning

confidence: 99%