Moderate-severe traumatic brain injury (TBI) often causes neuronal death and neurocognitive impairments, with both immature and mature neurons being vulnerable to the injury. The endoplasmic reticulum (ER) plays a major role in the folding of membrane and secreted proteins and in calcium storage and intracellular calcium homeostasis. Its function can disrupted in response to decreased in response to a number of stimuli including reduced glucose levels, hypoxia, and altered calcium levels, all of which have been observed after TBI. Disrupted ER function (often referred to as ER stress) can result in the accumulation of misfolded proteins. One of the signaling pathways activated in response to ER stress is double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (Perk). Once activated, Perk phosphorylates the translation initiation factor eIF2a, which acts to reduce global protein synthesis while permitting the synthesis of chaperones involved in protein folding. If ER function cannot be restored, Perk leads to the increased expression of CCAAT/enhancer-binding protein homologous protein (CHOP), a mediator of cell death. We have observed that TBI increases eIF2a phosphorylation and enhances CHOP expression. In order to examine the translational potential of targeting Perk-eIF2a-CHOP pathway, we have obtained preliminary experimental results to indicate that post injury administration of guanabenz (a FDA-approved drug that acts to inhibit eIF2a phosphatase) reduces neuronal loss and improves neurocognitive outcome. Furthermore, post-injury administration a chemical chaperone (4-phenylbuteric acid (4-PBA), an FDA-approved drug) also improved outcome. Based on these and other observations, we propose to test the hypothesis that post-TBI administration of guanabenz, 4-PBA, and their combination will effectively reduce loss of both mature and immature neurons and improve neurocognitive function.
Aim 1 : To determine efficacy of guanabenz and its therapeutic time window.
Aim 2 : To define the optimal dose and therapeutic time window for 4-PBA.
Aim 3 : To evaluate if the combination of guanabenz and 4-PBA is more efficacious. The results from these studies provide the basis for future clinical studies to determine if individual drugs alone or in combination can be used to improve outcome after TBI.

Public Health Relevance

Persons who experience traumatic brain injury often have lasting difficulties with learning and memory, reasoning, and other cognitive problems. While injury-related cell death is known to contribute to these deficits, there are no clinically proven strategies to reduce neuronal loss and improve cognitive function. The objective of this research is to test two compounds that resolve ER stress for their ability to improve outcome after TBI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS090935-04
Application #
9519055
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Bellgowan, Patrick S F
Project Start
2015-07-15
Project End
2020-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Neurosciences
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77030
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
Hill, Julia L; Kobori, Nobuhide; Zhao, Jing et al. (2016) Traumatic brain injury decreases AMP-activated protein kinase activity and pharmacological enhancement of its activity improves cognitive outcome. J Neurochem 139:106-19
Dash, Pramod K; Hylin, Michael J; Hood, Kimberly N et al. (2015) Inhibition of Eukaryotic Initiation Factor 2 Alpha Phosphatase Reduces Tissue Damage and Improves Learning and Memory after Experimental Traumatic Brain Injury. J Neurotrauma 32:1608-20