Grants and Contracts Details
Pioglitazone fosters neuroprotection via specific interaction with mitoNEET Traumatic spinal cord injury (SCI) is a serious health care problem in the United States which has led to an enormous focus on the development and discovery of neuroprotective therapies. However, there are currently limited pharmacological treatments approved for the clinical treatment of this condition. The fundamental concept underlying this proposal is that SCI-induced excitotoxicity increases mitochondrial Ca2+ cycling/overload and reactive oxygen species (ROS) production, ultimately leading to mitochondrial dysfunction and subsequent neuronal cell death, and that targeting SCI-induced mitochondrial dysfunction is a viable neuroprotective therapeutic strategy. Compelling experimental data demonstrates that mitochondrial dysfunction is a pivotal link in the neuropathological sequelae of both SCI and traumatic brain injury (TBI). This is based on our published work demonstrating loss of mitochondrial homeostasis and increased mitochondrial reactive oxygen species (ROS) production following CNS trauma. We have also demonstrated that pharmacological strategies which maintain mitochondrial homeostasis following both SCI and TBI are neuroprotective, solidifying the important role of mitochondria-mediated neuronal cell death. However, the therapeutic windows of efficacy for such compounds appear to be limited in terms of clinical applications. Recently, we have shown that pioglitazone is neuroprotective following TBI and that its mechanism of action may be directly related to its interactions with the mitochondrial protein mitoNEET, and not entirely dependent upon Peroxisome Proliferator Activated Receptor (PPAR) interaction, as previously hypothesized. Our new preliminary results in a mouse model of SCI show that pioglitazone treatment beginning at 15 min or 3 hr post-injury maintains mitochondrial respiration near normal levels at 24 hr following contusion SCI in WT mice, but not in mitoNEET knockout (KO) mice. Moreover, daily treatment with pioglitazone for 5 days post-injury improves long-term tissue sparing and hindlimb locomotor function in WT mice, but we do not yet have results in mitoNEET KO mice. Consistent with these ideas, the proposed experiments are designed to elucidate the mechanism(s) by which pioglitazone confers neuroprotection following contusion SCI by testing the novel hypothesis that it directly ameliorates mitochondrial dysfunction and, hence, functional neuroprotection. These experiments will move forward the repurposing of an FDA-approved diabetic drug, pioglitazone, to treat SCI while investigating a novel mechanism of its action with untold therapeutic applications. Specific Aim 1: Test the hypothesis that pioglitazone treatment maintains mitochondrial integrity and bioenergetics following contusion SCI. Specific Aim 2: Test the hypothesis that pioglitazone treatment increases tissue sparing and improves long-term tissue sparing functional and recovery following contusion SCI. Specific Aim 3: Determine the mechanism(s) underlying the neuroprotection afforded by pioglitazone treatment following contusion SCI. Key words: mitochondrial dysfunction, mitoNEET ligand, peroxisome proliferator activated receptor (PPAR); behavioral testing; oxidative stress, tissue sparing
|Effective start/end date||7/31/17 → 7/30/21|
- Craig H. Neilsen Foundation: $599,781.00
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