Treatment of traumatic brain injury with anti-inflammatory drugs

Bergold, Peter J.

doi:10.1016/j.expneurol.2015.05.024

Cited by 135 publications

(103 citation statements)

References 137 publications

(273 reference statements)

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“…Baratz used a small molecule drug protein synthesis inhibitor of TNF-alpha, the pro-inflammatory early phase cytokine, as a pre-injury and post-injury treatment and observed benefits to TBI-induced behavioral deficits, accompanied by mitigation of neuronal loss and neuroinflammation, with a drug therapeutic window of up to 12 hours after the injury (Baratz et al, 2011; 2015). Interestingly numerous models of diverse forms of TBI implicate inflammation as a favorable target for drug development (Kovesdi et al, 2012; Naseem and Parvez, 2014; Tuttolomondo et al, 2014; Bergold 2015); however, the key question has related to the choice of the specific element within the process to best inhibit.…”

Section: Discussionmentioning

confidence: 99%

Mild traumatic brain injury-induced hippocampal gene expressions: The identification of target cellular processes for drug development

Tweedie

Rachmany

Kim

et al. 2016

Journal of Neuroscience Methods

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Background Neurological dysfunction after traumatic brain injury (TBI) poses short-term or long-lasting health issues for family members and health care providers. Presently there are no approved medicines to treat TBI. Epidemiological evidence suggests that TBI may cause neurodegenerative disease later in life. In an effort to illuminate target cellular processes for drug development, we examined the effects of a mild TBI on hippocampal gene expression in mouse. Methods mTBI was induced in a closed head, weight drop-system in mice (ICR). Animals were anesthetized and subjected to mTBI (30 g). Fourteen days after injury the ipsilateral hippocampus was utilized for cDNA gene array studies. mTBI animals were compared with sham-operated animals. Genes regulated by TBI were identified to define TBI-induced physiological/pathological processes. mTBI regulated genes were divided into functional groupings to provide gene ontologies. Genes were further divided to identify molecular/cellular pathways regulated by mTBI. Results Numerous genes were regulated after a single mTBI event that mapped to many ontologies and molecular pathways related to inflammation and neurological physiology/pathology, including neurodegenerative disease. Conclusions These data illustrate diverse transcriptional changes in hippocampal tissues triggered by a single mild injury. The systematic analysis of individual genes that lead to the identification of functional categories, such as gene ontologies and then molecular pathways, illustrate target processes of relevance to TBI pathology. These processes may be further dissected to identify key factors that can be evaluated at the protein level to highlight possible treatments for TBI in human disease and potential biomarkers of neurodegenerative processes.

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Section: Discussionmentioning

confidence: 99%

Mild traumatic brain injury-induced hippocampal gene expressions: The identification of target cellular processes for drug development

Tweedie

Rachmany

Kim

et al. 2016

Journal of Neuroscience Methods

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“…Here, we observed extensive decreases of pro-inflammatory cytokines and chemokines, but an increase of anti-inflammatory cytokine after fingolimod treatment on the 3rd day after TBI. A large number of anti-inflammatory agents have shown to be effective in preclinical studies but few drugs have shown clinical efficacy after TBI [14]. One reason for this lack of transplantation is that the inflammatory responses after TBI involves a great variety of immune cells, cytokines, and chemokines which all play important roles in the pathology.…”

Section: Cd25-pementioning

confidence: 98%

“…However, recent studies demonstrate that CD4+ T lymphocyte protected injured neurons [9]. Although a large number of anti-inflammatory drugs including nonsteroidal antiinflammatory drugs (NSAIDS) [10], TNF-α inhibitors [11], IL-1 inhibitors [12], and corticosteroids [13] have been tested in both preclinical and clinical experiments, but few efficient treatments have been developed [14]. Therefore, the immunoinflammatory responses after TBI and how to modulate them appropriately require further investigations.…”

Section: Introductionmentioning

confidence: 99%

A Three-Day Consecutive Fingolimod Administration Improves Neurological Functions and Modulates Multiple Immune Responses of CCI Mice

Gao

Huang

et al. 2016

Mol Neurobiol

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Excessive inflammation after traumatic brain injury (TBI) is a major cause of secondary TBI. Though several inflammatory biomarkers have been postulated as the risk factors of TBI, there has not been any comprehensive description of them. Fingolimod, a new kind of immunomodulatory agent which can diminish various kinds of inflammatory responses, has shown additional therapeutic effects in the treatment of intracranial cerebral hematoma (ICH), ischemia, spinal cord injury (SCI), and many other CNS disorders. However, its therapeutic application has not been confirmed in TBI. Thus, we hypothesized that a 3-day consecutive fingolimod administration could broadly modulate the inflammatory reactions and improve the outcomes of TBI. The TBI models of C57/BL6 mice were established with the controlled cortical impact injury (CCI) system. A 3-day consecutive fingolimod therapy (given at 1, 24, and 48 h post injury) was performed at a dose of 1 mg/kg. The flow cytometry, immunoflourence, cytokine array, and ELISA were all applied to evaluate the immune cells and inflammatory markers in the injured brains. Immunohistochemical staining with anti-APP antibody was performed to assess the axonal damage. The neurological functions of these TBI models were assessed by mNSS/Rota-rod and Morris water maze (MWM). The brain water content and integrity of the blood-brain barrier (BBB) were also observed. On the 3rd day after TBI, the accumulation of inflammatory cytokines and chemokines reached the peak and administration of fingolimod reduced as many as 20 kinds of cytokines and chemokines. Fingolimod decreased infiltrated T lymphocytes and NK cells but increased the percentage of regulatory T (Treg) cells, and the concentration of IL-10 on the 3rd day after TBI. Fingolimod also notably attenuated the general activated microglia but augmented the M2/M1 ratio accompanied by decreased axonal damage. The neurological functions were improved after the fingolimod treatment accompanied with alleviation of the brain edema and BBB damage. This study suggests that the 3-day consecutive fingolimod administration extensively modulates multiple immuno-inflammatory responses and improves the neurological deficits after TBI, and therefore, it may be a new approach to the treatment of secondary TBI.

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“…Many drugs with anti-inflammatory properties—such as corticosteroids, nonsteroidals, statins, and specific cytokine inhibitors—have been tested in different TBI animal models (6). Although many of these treatments were effective in lessening pathology and improving neurological function, the results varied according to the injury model and/or treatment window.…”

Section: Immunosuppressive Clinical Trialsmentioning

confidence: 99%

Inflammatory neuroprotection following traumatic brain injury

Russo

McGavern

2016

Science

310

209

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Traumatic brain injury (TBI) elicits an inflammatory response in the central nervous system (CNS) that involves both resident and peripheral immune cells. Neuroinflammation can persist for years following a single TBI and may contribute to neurodegeneration. However, administration of anti-inflammatory drugs shortly after injury was not effective in the treatment of TBI patients. Some components of the neuroinflammatory response seem to play a beneficial role in the acute phase of TBI. Indeed, following CNS injury, early inflammation can set the stage for proper tissue regeneration and recovery, which can, perhaps, explain why general immunosuppression in TBI patients is disadvantageous. Here, we discuss some positive attributes of neuroinflammation and propose that inflammation be therapeutically guided in TBI patients rather than globally suppressed.

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Treatment of traumatic brain injury with anti-inflammatory drugs

Cited by 135 publications

References 137 publications

Mild traumatic brain injury-induced hippocampal gene expressions: The identification of target cellular processes for drug development

Mild traumatic brain injury-induced hippocampal gene expressions: The identification of target cellular processes for drug development

A Three-Day Consecutive Fingolimod Administration Improves Neurological Functions and Modulates Multiple Immune Responses of CCI Mice

Inflammatory neuroprotection following traumatic brain injury

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