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Mild traumatic brain injury (mTBI), such as mild blast injuries due to improvised exploding devices, result in long term impairment of cognition and behavior. Our hypothesis is that there are inflammatory outcomes, via the IL-1 / and TNF signaling pathways, to mTBI over time that cause the neuropathogenesis responsible for the clinical outcomes. We developed and characterized an adaptation of the rat moderate brain lateral fluid percussion brain injury model (mLFP injury) and a mild blast brain injury model (mBBI) developed by us with similar resulting righting reflex response times (RRRT). Both showed increased IL-1 and TNF levels, macrophage/ microglial and astrocytic activation, blood brain barrier disruption, neuronal losses and behavioral impairment. mBBI showed increased phosphorylated Tau protein (p-Tau) levels, a neuroencephalopathy marker. For mLFP injury, we showed beneficial outcomes after IL-1 receptor blockade with FDA-approved Kineret and of TNF receptor with FDA-approved Etanercept, singly or in combination, decreased neuropathology and improved outcomes. We determined an optimal time course of treatment. For mBBI, we showed that there were increases in IL-1 and TNF levels, macrophage/ microglial and astrocytic activation, and phosphorylated Tau (p-Tau) levels, the latter indicative of neuroencephalopathy, in the injured cortex, hippocampus, thalamus and amygdala. Whereas there was an apparent correlation between the RRRT values and the p-Tau levels, general inflammatory responses were more threshold-triggered. For mBBI we showed a beneficial outcome after blockade of IL-1 receptor (IL-1R) with Kineret. These results suggest potential therapies for mild blast injuries., The original document contains color images.

Mild traumatic brain injury (mTBI), particularly mild blast injuries due to improvised exploding devices, result in long term impairment of cognition and behavior. Our hypothesis is that there are inflammatory consequences to mTBI that persist over time and in part cause the resultant pathogenesis and clinical outcomes. We used an adaptation (1 atm pressure) of the moderate to severe brain lateral fluid percussion (LFP) brain injury rat model. Our mild LFP (mLFP) injury resulted in acute increases in IL-1 / and TNF levels, macrophage/ microglial and astrocytic activation, and blood brain barrier (BBB) disruption; which may contribute to brain pathology. These results suggest therapeutic opportunities to treat mTBI via blockade of the IL-1 / and TNF receptors. We further hypothesize that blockade of these receptors, IL-1 and IL-1 , both bind to the IL- 1R receptor, will block inflammatory cytokine signaling after mTBI and improve outcomes by ameliorating inflammation. Our goal is to develop, implement and assess interventions with two FDA-approved drugs (Kineret or Interleukin-1 Receptor Antagonist, IL-1Ra and Etanercept or antibody to the Tumor Necrosis Factor Receptor alpha, TNF ) singly or in combination in a rat model of mTBI (mild lateral fluid percussion or mLFP) that will ameliorate the mTBI-induced inflammation and therefore the resultant neuropathology and neurological deficits. We also proposed to test our hypothesis on a blast model of mTBI on two models. An earlier model relied on an injury consisting of a primary blast exposure followed by blunt impact injury, the Vanderberg model. The other more recently implemented model is the Advanced Blast Simulator. During this last year, we assessed the beneficial effects of individual vs combined treatment with Kineret and Etanercept; we also determined an optimal time course of treatment., The original document contains color images.

Brain injury, particularly mild "blast" injuries due to improvised exploding devices, have long term cognitive and behavioral deficits. Key inflammatory cytokine levels (IL-1 and TNFalpha) usually increase after traumatic insults to the brain and contribute to the development of long-term deficits via activation of infiltrated monocytes and resident microglia and astrocytes and impaired vascular function; both resulting in persistent inflammation. Our central hypothesis is that blocking inflammatory cytokine signaling after mild traumatic brain injury (mTBI) will improve outcomes by ameliorating inflammation. Our goal is to develop, implement and assess interventions with two FDA approved drugs in two rat models of mTBI that will ameliorate the mTBI-induced cognitive and behavioral deficits. We have validated the use of a number of biomarkers that characterize mTBI injury as early as 6h and demonstrated significant behavioral impairment, such as working memory, in our lateral fluid percussion model of mTBI. We have also performed a pilot intervention via ip injection of Kineret, an IL-1 receptor antagonist, at 30 minutes and 6 hours post-mTBI. Preliminary assessments show improvement in working memory and amelioration of the glial inflammation biomarker GFAP. Improved administration and dosages are underway. While our first year focused on outcomes at 6h, this second year focuses on outcomes at 18 days., The original document contains color images.

Brain injury, particularly mild 'blast type' injuries due to improvised exploding devices are difficult to detect clinically, although there are long term cognitive and behavioral deficits. Key inflammatory cytokines are unregulated after traumatic insults that play a role in the development of long-term deficits. Early events are increased IL-1 and TNFalpha cytokine levels, that contribute to cell death and inflammation, and microglial and astrocytic activation, mediators dysfunction via persistent inflammation. Our central hypothesis is that blocking inflammatory cytokine signaling after mild traumatic brain injury (MTBI) will improve outcomes by ameliorating inflammation and the resultant neuronal dysfunction. Our goal is to develop, implement and assess interventions to ameliorate the long term neurological deficits caused by MTBI by ameliorating injury-induced brain inflammation. We used lateral fluid percussion model of MTBI in rat. The results are that we have an appropriate injury that provides detectable damage as early as 6h after injury. We showed by immunohistochemistry that TBI induced significant astrocytic and microglial activation and increased IL-1alpha and TNFalpha in brain 6 hours and 18 days. We saw corresponding behavioral deficits based on beam balance and footfall assays. Thus, we have biomarkers to assess therapeutic strategies designed to minimize outcomes associated with MTBI., The original document contains color images.