Mechanistic studies into the cognitive rescue effect of pioglitazone in chronic TBI

Traumatic Brain Injury (TBI) is a leading cause of long-term disability in people of all ages. Although the full pathophysiology that leads to brain dysfunction in long-term TBI is not well understood, it is becoming clear that changes in brain metabolic function, with the accompanying activation of brain cellular stress responses likely play a role. Thus, brain injury leads to metabolic dysfunction, which in turn induces cellular stress mechanisms such as endoplasmic reticulum stress. Activation of cellular stress pathways leads to impaired brain function, including cognitive impairment, which is a leading cause of long-term disability after TBI. At this time there are no approved treatments known to ameliorate brain metabolic changes or cellular stress responses to improve functional outcomes after TBI. In a rat lateral fluid percussion model of TBI, we found evidence of chronic brain metabolic changes, as well as impaired performance on cognitive behavioral tasks. Importantly, behavioral measures of cognitive dysfunction are improved by treatment with pioglitazone, which has effects on cellular metabolism and endoplasmic reticulum stress in other systems. However, the specific processes impacted by pioglitazone in TBI are not known. We hypothesize that the actions of pioglitazone in chronic experimental TBI are mediated by its effects on redox balance, energy substrate metabolism, and ER stress. We will test this hypothesis using two specific aims:

1. To determine the effect of pioglitazone treatment on metabolic markers of redox balance and energy metabolism, and on markers of ER stress activation in TBI animals compared to controls.
2. To determine the effect of pioglitazone treatment on expression of genes relevant to redox balance and ER stress in animals with TBI compared to controls.

The results of the proposed experiments will reveal the effects of pioglitazone on metabolic and cell stress pathways in animals with chronic TBI. In addition, the data from the proposed experiments will identify candidate cellular and molecular pathways to explain the mechanism of action for pioglitazone in improving cognitive performance in chronic TBI. These experiments will provide critical data to support future, larger studies to confirm the relevant mechanisms of pioglitazone. They are also expected to ultimately lead to potential treatment targets in chronic TBI-associated cognitive impairment.

Grant Recipients

Nathan Evanson, MD PhD

Dr. Nathan Evanson is an assistant professor in the Division of Pediatric Rehabilitation Medicine at Cincinnati Children’s Hospital and the Department of Pediatrics at the University of Cincinnati College of Medicine. He completed his MD and PhD degrees in the University of Cincinnati Physician Scientist Training Program and Neuroscience Graduate Program. In graduate school he studied the neurobiology of stress, specifically in rapid regulation of hypothalamus-pituitary-adrenal responses to stress. This was followed by a combined residency program in Pediatrics and Physical Medicine & Rehabilitation at Cincinnati Children’s Hospital Medical Center. He currently has a clinical practice in acquired brain injury rehabilitation in children, and works primarily in outpatient multidisciplinary clinical teams. In his clinical practice he works with many children who have long-term disability due to traumatic brain injury. These long-term deficits have motivated his research program, which has foci on the brain metabolic response to traumatic injury, and the role of cellular stress mechanisms in optic nerve injury after head trauma. In a collaborative effort with Dr. McGuire, they have shown long-term metabolic dysregulation after traumatic brain injury in a rat fluid percussion injury model. This metabolic dysregulation co-exists with cognitive and working memory deficits. The core hypothesis of this work is that optimizing brain metabolic function in chronic brain injury will improve cognitive performance.

Jennifer McGuire, PhD

Dr. Jennifer McGuire is a Research Instructor in the Department of Neurosurgery in the University of Cincinnati College of Medicine. Dr. McGuire completed her Ph.D. in the Molecular and Developmental Biology Program based at Cincinnati Children’s Hospital. Dr. McGuire’s doctoral work focused on stress resilience and the role of Neuropeptide Y in mitigating the effects of traumatic stress. In her Postdoctoral Fellowship at the Uniformed Services University in Bethesda, MD she began studying traumatic brain injury and its effects on associative learning as well as the interactions of fearfulness and glucocorticoid circadian rhythms. Dr. McGuire’s current research focuses on the coordination of metabolism and neurotransmission in traumatic brain injury, in particular whether strategies to restore metabolic function and efficiency can maximize recovery potential and improve cognitive function in chronic stages of injury. Drs McGuire and Evanson are long-time collaborators, using a lateral fluid percussion model of chronic traumatic brain injury. In their work together they have shown that there are widespread metabolic changes in the chronically injured brain in a model that produces chronic cognitive deficits. More importantly, cognitive deficits improved and glucose metabolism increased when chronically injured animals were given the diabetes drug pioglitazone. The goal of this project is to dig deeper into the mechanisms and cell types that are increasing glucose utilization in the brain after pioglitazone treatment and whether pioglitazone also restores downstream metabolic pathways that support cognition.