Efficacy and safety of a new hexadentate iron chelator therapy for TBI-induced chronic disabilities in a rodent model

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Traumatic brain injury (TBI) care and rehabilitation presents significant current and future challenges to the Veterans Health System (VHS). In addition to specific disabilities, there is a growing concern that TBI may significantly elevate risk factors for long-term chronic inflammation-induced progressive disease. Currently, effective therapies to address both of these issues are hampered by the lack of a sufficient neurobiological foundation to guide refinement of therapy for disability, and prevention strategies for chronic disease. Acceleration/deceleration TBI causes micro-vessel shear injury, blood brain barrier (BBB) dysfunction, and micro-bleeding. Iron deposited by diffuse micro-bleeds fuels inflammation through reactive oxygen species (ROS), and other inflammatory pathways may further induce progressive disabilities. There is an urgent need to address both specific disabilities and risk factors for long term progressive disease, and to develop effective therapies that have excellent potential for translation. The proposed pre-clinical studies will increase our understanding of microbleed (iron)-induced inflammation and the potential therapeutic benefits provided by a new iron chelating drug to address three long-term hallmark TBI disabilities that significantly impact the quality of life. The proposal will test the preclinical evaluation of the safety and efficacy of a new hexadentate iron chelator, NaHBED, to remove microbleed-induced iron, a powerful catalyst of inflammation, and to upregulate neural and vascular trophic agents to protect and heal injured neural and vascular tissues. Accordingly, three specific aims are proposed: Specific Aim 1: To correlate TBI-induced chronic disorders with cellular/molecular changes in LC and specific neural substrates of test behaviors in three functional domains. Tests for motor, anxiety, cognitive functions, and a comprehensive safety protocol will be conducted immediately before and monthly for 3 months post-treatment to evaluate the safety and efficacy of treatment. Clinically relevant state of the art Susceptibility weighted imaging (SWI)/Quantitative Susceptibility Mapping (QSM) MRI, and histological and immunohistological experiments will be performed to chart the time course for iron removal and/or further iron deposition. Specific Aim 2: (Therapeutic efficacy). To determine the efficacy of NaHBED therapy in mitigating long-term motor, cognitive and anxiety disabilities. Chronic treatment will be initiated at 6 months post- TBI using a dose shown in preliminary work to be effective. In addition, to temporal characteristics and progress of iron elimination and/or further iron deposition following NaHBED therapy (SWI/QSM MRI), the therapeutic impact on chronic motor, anxiety, and cognitive disabilities will be assessed immediately before and monthly for 3 months following the initiation of treatment. Specific Aim 3: To determine the safety and efficacy of NaHBED in reducing iron toxicity and up-regulating of trophic factors at the cellular level in the neural regions for motor, cognitive, and anxiety behaviors, using comprehensive histological, immunohistochemical, and molecular assays. We propose that treatment will significantly decrease the magnitude of long-term motor, cognitive and anxiety disabilities and these improvements will be correlated with significant decreases in a) cell death, b) iron deposition and neurodegenerative markers for inflammation and ROS, c) normalization of BBB markers, and d) significant increases in neural and vascular protective factors in the specific neural centers that provide key neural substrates for the studied behaviors. These chronic TBI studies address specifically highlighted RR&D concerns regarding TBI-induced long-term disabilities, and long-term degenerative disease (RX-18-014). In particular, these studies will provide new insights regarding TBI-induced factors that potentially contribute to significant chronic inflammation-induced TBI disabilities. Since these risk factors are prevalent in both impact acceleration (vehicular) TBI as well as blast TBI, they affect the predominant VHS TBI population. If our proposed treatment is determined to be safe and effective in the chronic TBI setting, it is well positioned for immediate translation to clinical treatment and rehabilitation since it obtained an IND approval for other disorder.