Studies show that inflammation contributes significantly to the pathophysiology of secondary insults after traumatic brain injury (TBI). However, a comprehensive evaluation of chronic inflammatory dysregulation following TBI is lacking. Development of animal models that will allow specific modulation of the peripheral and central innate response to enhance injury recovery, facilitate regeneration and prevent long-term neurodegeneration is critical. Experiments will use the fluid-percussion injury model of non-penetrating head injury in rats. Acute and chronic changes in peripheral and central immune functions will be evaluated by flow cytometry, PCR, ELISA, histology and motor and behavioral analyses. The overall hypothesis is that dysregulated innate immune activity following TBI underlies poor recovery. Furthermore, chronic dysregulation and loss of central nervous system (CNS) maintenance may represent a common link between combat-related brain injury and neurodegenerative conditions such as Alzheimer's disease (AD). In order to avoid detrimental effects, homeostatic balances must be attained following injury and to prevent secondary disease progression. The specific objectives and hypotheses of this proposal are:
Aim 1 : Tumor Necrosis Factor-alpha (TNFa) modulation of inflammation and cellular infiltrates into the CNS following TBI in rats: impact on TBI recovery and neurodegeneration. Hypothesis (H)1: Peripheral and central TNFa will rise rapidly following TBI and will demonstrate a persistent elevation following TBI. H2: Chemokine modulations at the injury site will increase recruitment of peripheral leukocytes into the CNS. H3: Rats subjected to moderate TBI will demonstrate dysregulated inflammation characterized by CNS infiltration of peripheral leukocytes. H4: CNS infiltrating leukocytes will establish a local inflammatory response in the CNS that persists over many months.
Aim 2 : Reprogramming the inflammatory cascade with small molecule TNFa inhibitors to improve TBI outcome and reduce AD risk. H1: The initial spike in TNFa following TBI is important for recruiting inflammatory infiltrates into the CNS while the continued elevation in TNFa contributes to poor TBI recovery through the persistence of CNS inflammation. H1a: Short duration TNFa inhibitor treatment immediately following TBI (days 1-7) will worsen TBI outcome by downregulating peripheral infiltrates. H1b: Attenuating the prolonged increase in TNFa levels following TBI (day 8 onward) will improve TBI outcome by resolving persistent/dysregulated CNS inflammation. H2: Centrally acting TNFa inhibitors (PD-2015 and -2016) will be more effective at resolving inflammatory dysregulation than the peripherally acting TNFa inhibitor (PD-2024). H3: Rats subjected to TBI will demonstrate exacerbation of beta- amyloid infusion-induced AD pathology (Beta-amyloid deposition and inflammation) and memory impairments. H4: Treatment of rats with TNFa inhibitors following TBI will reduce the risk of development of AD pathology and memory impairments. The findings from this proposal will inform the development of targeted immunotherapeutic windows to improve immune function and benefit long-term recovery, facilitate neurorepair mechanisms and prevent secondary outcomes such as AD. )

Public Health Relevance

to Veteran Health. TBI is one of the Veterans Affairs medical research priorities. Due to continuing conflicts in Iraq and Afghanistan, TBI accounts for a large proportion of combat-related injuries. We anticipate that findings from this study will have the potential for development of innovative therapies for TBI. )

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Neurobiology C (NURC)
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VA Greater Los Angels Healthcare System
Los Angeles
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Hensley, Kenneth; Harris-White, Marni E (2015) Redox regulation of autophagy in healthy brain and neurodegeneration. Neurobiol Dis 84:50-9
Hensley, Kenneth; Gabbita, S Prasad; Venkova, Kalina et al. (2013) A derivative of the brain metabolite lanthionine ketimine improves cognition and diminishes pathology in the 3 × Tg-AD mouse model of Alzheimer disease. J Neuropathol Exp Neurol 72:955-69