Thursday, April 25, 2024
4/25/2024
ABSTRACT Alcohol is the most used and abused drug in the United States. Chronic alcohol abuse results in neuronal degeneration and functional deficits in sensorimotor, memory, psychological, and cognitive functions. We and others have demonstrated that oxidative signaling is the central mechanism in alcohol-induced injury that leads to neurological and functional deficits. Remediation of accumulating oxidative radicals may serve as an effective strategy for preventing the progression of neurological damage in alcoholics. Thus, this proposal will study a novel hypothesis that the brain injury and associated neuroinflammation and neurodegeneration caused by alcohol-induced oxidative damage can be repaired by activating the antioxidant signaling Nrf2 (nuclear factor E2-related factor 2) pathway. The Nrf2 transcriptional system is an endogenous defense mechanism that boosts the expression of many detoxifying, cytoprotective and anti-inflammatory genes by interacting with the antioxidant response element (ARE) in their regulatory regions. Nrf2 has the potential to be a novel and therapeutic target to mitigate alcohol-induced neural damage. Our central hypothesis is that activation of antioxidant-promoting transcription factor Nrf2 alleviates oxidative stress-induced pathophysiological changes associated with excessive alcohol ingestion. These changes include activation of transforming growth factor ß1 (TGF-ß1) and matrix metalloproteinases (MMPs), neuroinflammatory responses, and neurodegeneration. Activation of Nrf2 transcription factor and up-regulation of endogenous antioxidant enzymes will be achieved by treating animals with Nrf2 activator III TAT peptide (Nrf2 peptide). We will administer Nrf2 peptide to the alcohol ingested mice systemically (subcutaneous) and evaluate its therapeutic potential in alleviating alcohol-associated neurological impairments in defined regions such as the prefrontal cortex, hippocampus, and cerebellum. The proposed study not only validates the cause and effect of Nrf2 peptide in mitigating oxidative stress in AUD but also identifies the mechanistic regulation of Nrf2 transcription factor activated antioxidant genes and their interactions with Nrf2 by ChIP-qPCR, and ChIP-Seq. The protective role of Nrf2 will be determined by assessing its effects on gene expression and protein levels of the major antioxidant, inflammatory, and apoptotic proteins. We will validate the effect of Nrf2 peptide in Nrf2 knock-out (KO) mice (Nrf2-/-). We will also use a cohort of behavioral tests that will utilize to assess cognitive, sensory-motor feedback, and psychological behavioral recovery associated with Nrf2 peptide treatment following alcohol exposure in wild type and Nrf2-/- mice. We will compare the results with control peptide (random sequence with TAT) treated animals. We anticipate that the findings from this study will have extensive clinical relevance.
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