Traumatic brain injury (TBI) causes severe complications to the estimated 1.7 million Americans who are injured annually. This has precipitated a major focus on the discovery and development of neuroprotective and pro-regenerative therapeutic agents. One potential neuroprotective target, which has been well supported in the literature, is mitochondrial dysfunction resulting from TBI induced excitotoxicity This excitotoxicity is caused by excessive synaptic glutamate and the consequent over-excitation of neurons at the site of injury leading to large increases in mitochondrial Ca2+ cycling/Ca2+ overload. Ca2+ overload precedes a notable decrease in mitochondrial respiration, which has been documented in the first 3 to 48 hours post-injury. This decreased mitochondrial respiration, which is an indication of decreased mitochondrial bioenergetics (ability to generate ATP), leads to the initiation of cell death pathways. As the injured neurons die, the extent of tissue damage increases and functional (motor and cognitive) abilities decrease. We believe mitochondrial dysfunction to be a pivotal component to the neuropathological sequelae of brain injury and an important therapeutic target for drug discovery research in TBI. An overall goal of our laboratory is to determine whether amelioration of mitochondrial dysfunction will decrease the neuronal cell death associated with TBI. Findings from our lab and others show that pioglitazone, a known PPAR-? agonist, is neuroprotective and increases functional recovery following TBI. In support of this and the goals of our lab, pioglitazone not only reduces mitochondrial dysfunction following TBI, but also binds to mitoNEET, a novel mitochondrial membrane protein. However, the contribution of mitoNEET to pioglitazone- mediated neuroprotection is unknown. Preliminary results indicate that pioglitazone-mediated neuroprotection is absent in mitoNEET knockout mice and a specific mitoNEET ligand (NL-1) is neuroprotective following TBI. Taken together, these data suggest that mitoNEET is an essential component of pioglitazone mediated neuroprotection. Therefore, in order to understand the mechanisms of pioglitazone, I will test the hypothesis that pioglitazone's ability to improve mitochondrial bioenergetics, thereby decreasing tissue loss and improving functional recovery following TBI, hinges on binding mitoNEET. I further hypothesize that the protective effects of pioglitazone can be reproduced by NL-1, an exogenous mitoNEET ligand.

Public Health Relevance

Traumatic brain injury (TBI) is a devastating healthcare problem in the United States, with no pharmacological treatments currently approved for clinical intervention following injury. Improved TBI treatment options are urgently needed. This proposal examines the potential of pioglitazone, an FDA approved drug, in limiting the brain damage and dysfunction resulting from TBI via maintenance of mitochondrial function.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Bellgowan, Patrick S F
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University of Kentucky
Anatomy/Cell Biology
Schools of Medicine
United States
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Yonutas, Heather M; Pandya, Jignesh D; Sullivan, Patrick G (2015) Changes in mitochondrial bioenergetics in the brain versus spinal cord become more apparent with age. J Bioenerg Biomembr 47:149-54
Pandya, Jignesh D; Readnower, Ryan D; Patel, Samir P et al. (2014) N-acetylcysteine amide confers neuroprotection, improves bioenergetics and behavioral outcome following TBI. Exp Neurol 257:106-13
Patel, Samir P; Sullivan, Patrick G; Pandya, Jignesh D et al. (2014) N-acetylcysteine amide preserves mitochondrial bioenergetics and improves functional recovery following spinal trauma. Exp Neurol 257:95-105