Grants and Contracts Details


The goal of the proposed study is to elucidate the neuroprotective mechanisms of pioglitazone following traumatic brain injury (TBI). Presently, no pharmacological treatment is approved for TBI in part due to the overall complexity and an incomplete understanding of the fundamental pathways involved in TBI-induced cell death. This proposed study will test a novel usage of an FDA-approved drug, pioglitazone (Actos), which has been developed for the treatment of type 2 diabetes mellitus, as an effective TBI treatment. Several pathological events including mitochondrial dysfunction, oxidative stress, apoptosis, and inflammation are known to precipitate neuronal death following TBI. Therapeutic compounds that can target these multiple pathophysiological mechanisms can be extremely useful in preventing post-TBI neuronal death. We recently demonstrated that pioglitazone protects against neuroinflammation-induced neuronal damage by restoring mitochondrial bioenergetics and reducing inflammatory response and oxidative stress. Our preliminary studies also show that TBI induced by the midline fluid percussion injury can cause marked inflammation in the medial forebrain bundle, a tract that connects the striatum and substantia nigra (SN), followed by dopaminergic loss in the SN, and that pioglitazone treatments significantly reversed both microglial activation in MFB and dopaminergic neuron loss in the SN. We therefore hypothesize that pioglitazone protects neuronal structure and function by improving mitochondria function, inhibiting neuroinflammation and regulating the phenotypic polarization of microglia following TBI. We propose three specific aims: Aim 1. To test the hypothesis that pioglitazone can attenuate TBI-induced dopaminergic neuronal damage and locomotor deficits; Aim 2. To test the hypothesis that pioglitazone can inhibit pro-inflammatory responses, and reduce diffuse axonal injury in the MFB following TBI; and Aim 3. To test the hypothesis that pioglitazone may regulate the phenotypic polarization of microglia from a proinflammatory M1 state into an anti-inflammatory M2 state after TBI. Thus the proposed studies will allow us to determine whether pioglitazone plays an important role in the mitochondrial and inflammatory events following TBI. Knowledge of this potential role that could lead to potentially novel interventions and novel targets for the treatment of TBI and, perhaps, other neurological condition such as PD and Alzheimer’s disease.
Effective start/end date1/15/181/14/22


  • KY Spinal Cord and Head Injury Research Trust: $300,000.00


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