Mechanism of Melatonin-induced Neuroprotection in Traumatic Brain Injury

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a significant public health problem affecting millions of Americans annually and causing long-term functional impairments (e.g. memory-, learning-, and motor- deficits). Apoptotic cell death of neurons and glial cells occurs following a TBI and is associated with negative outcomes. Melatonin (MEL), an endogenously produced substance available as a drug and over-the-counter supplement, contributes to neuroprotection by reducing apoptotic cell death in a variety of central nervous system (CNS) disorders (e.g Huntington's, amyotrophic lateral sclerosis, and spinal cord injury) characterized by impairments in memory, learning, and motor function, including TBI. High numbers of MEL-specific receptors (MT1 & MT2) in the CNS, and the ability of MEL to readily cross the blood-brain-barrier, suggest it could be administered exogenously and exert protective effects within the brain. Although MEL holds promise as an anti-apoptotic agent within the CNS, the beneficial effects of MEL in the context of TBI remain understudied. While, MEL has been found to reduce apoptotic cellular death and improve functional outcomes (assessed using behavioral testing in rodents) following TBI, there remains a gap in the knowledge surrounding the underlying mechanism. Previous research using animal models of Huntington's and amyotrophic lateral sclerosis found the neuroprotective and anti-apoptotic effects of MEL were MT1 receptor-dependent. However the role of MT1 post-TBI remains unknown. This innovative study is the first to evaluate if the anti-apoptotic effect of MEL following TBI is MT1-dependent; 2x2x2 (8 group) design will be used, controlling for injury exposure (TBI vs. sham), therapy (MEL vs. vehicle) and genotype (MT1 KO vs. WT). Addressing this gap is necessary before translation of MEL to TBI clinical care can occur. This novel study explores possible moderators in TBI outcomes and also represents a beginning step in the applicant's program of research.