ver-155008 and Brain-Injuries

Traumatic Brain injury affects at least 1.7 million people in the United States alone each year. The majority of injuries are categorized as mild but these still produce lasting symptoms that plague the patient and the medical field. Currently treatments are aimed at reducing a patient's symptoms, but there is no effective method to combat the source of the problem, neuronal loss. We tested a mild, closed head traumatic brain injury model for the effects of modulation of the antioxidant transcription factor Nrf2 by the chemical activator, tert-butylhydroquinone (tBHQ). We found that post-injury visual memory was improved by a 7 day course of treatment and that the level of activated caspase-3 in the hippocampus was reduced. The injury-induced memory loss was also reversed by a single injection at 30 min after injury. Since the protective stress response molecule, HSP70, can be upregulated by Nrf2, we examined protein levels in the hippocampus, and found that HSP70 was elevated by the injury and then further increased by the treatment. To test the possible role of HSP70, model neurons in culture exposed to a mild injury and treated with the Nrf2 activator displayed improved survival that was blocked by the HSP70 inhibitor, VER155008. Following mild traumatic brain injury, there may be a partial protective response and patients could benefit from directed enhancement of regulatory pathways such as Nrf2 for neuroprotection.

Topics: Analysis of Variance; Animals; Antioxidants; Avoidance Learning; Brain; Brain Injuries; Caspase 3; Cell Line, Tumor; Cell Survival; Cognition Disorders; Disease Models, Animal; Gene Expression Regulation; Glial Fibrillary Acidic Protein; HSP70 Heat-Shock Proteins; Humans; Hydroquinones; Male; Maze Learning; Mice; Mice, Inbred ICR; Motor Activity; Neuroblastoma; NF-E2-Related Factor 2; Proto-Oncogene Proteins c-jun; Purine Nucleosides; Recognition, Psychology; RNA, Messenger; Rotarod Performance Test; Time Factors