Studies performed in rats, mice, non-human primates, and human patients have demonstrated that the hippocampus, a structure within the temporal lobe, plays a critical role in learning and memory, and damage to this structure can result in profound impairments. As this basic cognitive function is critical for day-to-day activities, learning and memory dysfunction makes it difficult to hold a job, manage one's finances, and plan daily activities. These problems severely compromise the quality of life for persons with traumatic brain injury, can hamper the effectiveness of rehabilitation, and hinder a return to an independent lifestyle. Using experimental models of brain injury, a number of investigators including us have shown that traumatic brain injury causes hippocampal cell death and dysfunction that underlies learning and memory deficits. Through a series of experimentats, we have identified two compounds that are capable of increasing the expression of cytoprotective genes, which are endogenous to a number of cell types including neurons and are activated by the transcription factor Nrf2. Our working hypothesis is that post-TBI administration of these newly identified compounds will reduce secondary pathologies and improve learning and memory by increasing the expression of Nrf2-driven genes. We will use a combination of biochemical, molecular, genetic and behavioral tests to examine if post-injury administration of these compounds can decrease blood-brain barrier permeability, offer neuroprotection, and improve learning and memory. If successful, the results from this mechanism-based study may pave the way for clinical testing in patients who have sustained a traumatic brain injury.

Public Health Relevance

Learning and memory impairments are common consequences of traumatic brain injury (TBI), and can profoundly influence quality of life. Secondary damage, occurring hours to days after the injury, can contribute to lasting cognitive and behavioral problems. The present study aims to investigate the therapeutic potential of two compounds for their capacity to alleviate secondary brain damage and improve outcome.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-IFCN-T (02))
Program Officer
Hicks, Ramona R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Health Science Center Houston
Schools of Medicine
United States
Zip Code
Boehning, Alexandra L; Essien, Safia A; Underwood, Erica L et al. (2018) Cell type-dependent effects of ellagic acid on cellular metabolism. Biomed Pharmacother 106:411-418
Hylin, Michael J; Zhao, Jing; Tangavelou, Karthikeyan et al. (2018) A role for autophagy in long-term spatial memory formation in male rodents. J Neurosci Res 96:416-426
Hood, Kimberly N; Zhao, Jing; Redell, John B et al. (2018) Endoplasmic Reticulum Stress Contributes to the Loss of Newborn Hippocampal Neurons after Traumatic Brain Injury. J Neurosci 38:2372-2384
Hergenroeder, Georgene W; Moore, Anthony N; Schmitt, Karl M et al. (2016) Identification of autoantibodies to glial fibrillary acidic protein in spinal cord injury patients. Neuroreport 27:90-3
Fischer, Tara D; Hylin, Michael J; Zhao, Jing et al. (2016) Altered Mitochondrial Dynamics and TBI Pathophysiology. Front Syst Neurosci 10:29
Dash, Pramod K; Zhao, Jing; Kobori, Nobuhide et al. (2016) Activation of Alpha 7 Cholinergic Nicotinic Receptors Reduce Blood-Brain Barrier Permeability following Experimental Traumatic Brain Injury. J Neurosci 36:2809-18
Kobori, Nobuhide; Moore, Anthony N; Dash, Pramod K (2015) Altered regulation of protein kinase a activity in the medial prefrontal cortex of normal and brain-injured animals actively engaged in a working memory task. J Neurotrauma 32:139-48
Rozas, Natalia S; Redell, John B; Pita-Almenar, Juan D et al. (2015) Intrahippocampal glutamine administration inhibits mTORC1 signaling and impairs long-term memory. Learn Mem 22:239-46
Rozas, Natalia S; Redell, John B; McKenna 3rd, James et al. (2015) Prolonging the survival of Tsc2 conditional knockout mice by glutamine supplementation. Biochem Biophys Res Commun 457:635-9
Rozas, Natalia S; Redell, John B; Hill, Julia L et al. (2015) Genetic activation of mTORC1 signaling worsens neurocognitive outcome after traumatic brain injury. J Neurotrauma 32:149-58

Showing the most recent 10 out of 12 publications