PARP Inhibitor for Improving Functional Recovery After TBI & Binge Alcohol Intoxication

The long-term goal of this research is to provide better therapeutic options for US veterans with traumatic brain injury (TBI) that misuse alcohol prior to TBI injury. Alcohol misuse is a high priority for the VA because of its high prevalence in the US military, which continues into civilian life as veterans. An alarming statistic, highly relevant to veterans with alcohol misuse disorder, is that 1.2 million TBIs occur annually with blood alcohol levels exceeding the 0.08% legal driving limit. While debilitating consequences challenge many survivors, patients that misused alcohol before TBI face worse clinical outcomes due to neuroinflammation arising from alcohol misuse. Current therapies include cognitive, physical, speech, and occupational therapy, with headache or anxiety medication, but no effective pharmacological treatment exists to improve functional neurological recovery, especially after alcohol misuse. To address this therapeutic gap and provide better therapeutic options to improve long-term neurological functional recovery for US veterans, this study will investigate the effectiveness of repurposing an oncology therapeutic, a poly(ADP)ribose polymerase (PARP) inhibitor, for TBI exacerbated by alcohol misuse. Our recent results indicate that PARP inhibitors can prevent neuroinflammatory/degenerative responses to binge alcohol exposure. Thus, PARP inhibitors may augment functional recovery in TBI exacerbated by alcohol misuse. The overall objective of this proposal is to test the in vivo feasibility and effectiveness of a novel pharmacological approach (an orally administered PARP inhibitor) in improving neurological functional recovery after binge alcohol intoxication and TBI. The central hypothesis is that PARP inhibition will diminish TBI neuroinflammation exacerbated by alcohol to improve functional recovery. This central hypothesis will be tested in rats by the following specific aims: 1) Determine if oral PARP inhibitor treatment after injury improves functional recovery after binge alcohol intoxication and TBI by measuring spatial memory, a hippocampus-dependent function, through Morris water maze (MWM) tasks. Brain regions supporting learning and memory (hippocampus and entorhinal cortex) are highly vulnerable to binge alcohol intoxication and to TBI. 2) Determine if PARP inhibitor treatment after binge alcohol intoxication and TBI improves the neuroinflammation/degeneration in these brain regions and the perilesional area by quantifying neurodegeneration (FluoroJade B) and neuroinflammation markers. Neuroinflammation markers will consist of fibrillary acid protein (GFAP) and vimentin for astrogliosis, and ionized calcium-binding adapter molecule 1 (Iba1) and cluster of differentiation molecule 11B (CD11b) for microglia activation. Responses to TBI and alcohol will be compared in rats receiving the PARP inhibitor, veliparib (ABT-888), to those without at 1 week (neuroinflammation/degeneration) and at six weeks (functional recovery) after injury. This proposal is innovative by focusing on a novel pharmacological approach to improve neurological functional recovery after binge alcohol intoxication and TBI where none exist. Testing neuroinflammatory responses will also advance our efforts to improve functional outcomes because neuroinflammation is linked to impaired functional recovery. Given that PARP inhibitors have been recently FDA-approved for oncology indications, repurposing PARP inhibitors for binge alcohol intoxication and TBI represent a promising avenue to augment functional recovery that is easily translatable. This work is expected have a positive impact on US veterans with TBI impairments exacerbated by alcohol misuse, and will also generate the pilot data needed for future VA Merit and NIH funding for clinical trials to ultimately improve their therapeutic options.

The long-term goal of this research is to provide better therapeutic options for US veterans with traumatic brain injury (TBI) that misuse alcohol prior to TBI injury. Alcohol misuse is a high priority for the VA because of its high prevalence in the US military, which continues into civilian life as veterans. An alarming statistic, highly relevant to veterans with alcohol misuse disorder, is that 1.2 million TBIs occur annually with blood alcohol levels exceeding the 0.08% legal driving limit. While debilitating consequences challenge many survivors, patients that misused alcohol before TBI face worse clinical outcomes due to neuroinflammation arising from alcohol misuse. Current therapies include cognitive, physical, speech, and occupational therapy, with headache or anxiety medication, but no effective pharmacological treatment exists to improve functional neurological recovery, especially after alcohol misuse. To address this therapeutic gap and provide better therapeutic options to improve long-term neurological functional recovery for US veterans, this study will investigate the effectiveness of repurposing an oncology therapeutic, a poly(ADP)ribose polymerase (PARP) inhibitor, for TBI exacerbated by alcohol misuse. Our recent results indicate that PARP inhibitors can prevent neuroinflammatory/degenerative responses to binge alcohol exposure. Thus, PARP inhibitors may augment functional recovery in TBI exacerbated by alcohol misuse. The overall objective of this proposal is to test the in vivo feasibility and effectiveness of a novel pharmacological approach (an orally administered PARP inhibitor) in improving neurological functional recovery after binge alcohol intoxication and TBI. The central hypothesis is that PARP inhibition will diminish TBI neuroinflammation exacerbated by alcohol to improve functional recovery. This central hypothesis will be tested in rats by the following specific aims: 1) Determine if oral PARP inhibitor treatment after injury improves functional recovery after binge alcohol intoxication and TBI by measuring spatial memory, a hippocampus-dependent function, through Morris water maze (MWM) tasks. Brain regions supporting learning and memory (hippocampus and entorhinal cortex) are highly vulnerable to binge alcohol intoxication and to TBI. 2) Determine if PARP inhibitor treatment after binge alcohol intoxication and TBI improves the neuroinflammation/degeneration in these brain regions and the perilesional area by quantifying neurodegeneration (FluoroJade B) and neuroinflammation markers. Neuroinflammation markers will consist of fibrillary acid protein (GFAP) and vimentin for astrogliosis, and ionized calcium-binding adapter molecule 1 (Iba1) and cluster of differentiation molecule 11B (CD11b) for microglia activation. Responses to TBI and alcohol will be compared in rats receiving the PARP inhibitor, veliparib (ABT-888), to those without at 1 week (neuroinflammation/degeneration) and at six weeks (functional recovery) after injury. This proposal is innovative by focusing on a novel pharmacological approach to improve neurological functional recovery after binge alcohol intoxication and TBI where none exist. Testing neuroinflammatory responses will also advance our efforts to improve functional outcomes because neuroinflammation is linked to impaired functional recovery. Given that PARP inhibitors have been recently FDA-approved for oncology indications, repurposing PARP inhibitors for binge alcohol intoxication and TBI represent a promising avenue to augment functional recovery that is easily translatable. This work is expected have a positive impact on US veterans with TBI impairments exacerbated by alcohol misuse, and will also generate the pilot data needed for future VA Merit and NIH funding for clinical trials to ultimately improve their therapeutic options.