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Pioglitazone fosters neuroprotection via specific interaction with mitoNEET

Funder: Craig H Neilsen Foundation

Funding period
USD 600 K
Funding amount
The fundamental concept underlying the current proposal is based on our compelling experimental data demonstrating that mitochondrial dysfunction is pivotal to the neuropathological sequelae following both spinal cord injury (SCI) and traumatic brain injury (TBI). This is based on our published work demonstrating the loss of mitochondrial homeostasis, increased mitochondrial Ca2+ cycling/overload, reactive oxygen species (ROS) production, as well as disruption of synaptic homeostasis following SCI and TBI. We have also demonstrated that strategies which maintain mitochondrial homeostasis following both SCI and TBI are neuroprotective, solidifying the importance of mitochondria-mediated neuronal cell death. However, the therapeutic time window of these compounds appears to be limited in terms of clinical applications. Recently, we have shown that the FDA-approved diabetes drug, 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. Accordingly, our new preliminary data show that pioglitazone improves mitochondrial function after acute contusion SCI in WT mice, but not in mitoNEET knockout (KO) mice. Pioglitazone also improves recovery of long-term hindlimb locomotor function and tissue sparing in wildtype mice after SCI, but we have not yet evaluated chronically-injured mitoNEET KO mice. Accordingly, the proposed experiments are designed to test mechanistically whether pioglitazone confers functional neuroprotection following contusion SCI and directly mitigates mitochondrial dysfunction by binding to mitoNEET. Specific Aim 1 will determine the optimal dose and therapeutic window of pioglitazone that maximally maintains mitochondrial bioenergetics following injury, to then be utilized in Specific Aims 2 and 3 for assessing its neuroprotective efficacy to promote long-term recovery of hindlimb function and tissue sparing. Critically, Specific Aim 3 is designed explicitly to test the hypothesis that pioglitazone neuroprotection is directly linked to mitoNEET binding and, therefore, provides a mechanism of neuroprotection. To accomplish this we will employ, collectively, a specific mitoNEET ligand agonist (NL-1) and antagonist (NL-3), both of which lack PPAR binding, as well as mitoNEET KO mice to specifically test this novel hypothesis. The results of these studies will not only shed light on the fundamental processes involved in SCI neuropathology but also investigate a mechanism by which FDA-approved pioglitazone targets mitochondrial dysfunction underlying pathophysiology following SCI. These studies aim to move forward the repurposing of pioglitazone to target specific pathways germane to SCI neuropathology. (CHN: SCIRTS chn:wdg)
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    1109 Neurosciences

  • RCDC

    Injury (total) Accidents/Adverse Effects

  • RCDC

    Injury - Trauma - (Head and Spine)

  • RCDC

    Injury - Traumatic brain injury

  • RCDC


  • RCDC

    Spinal Cord Injury

  • RCDC

    Brain Disorders

  • RCDC





    5.1 Pharmaceuticals

  • Health Research Areas


  • Broad Research Areas

    Basic Science