The nuclear factor erythroid 2-like 2 activator, tert-butylhydroquinone, improves cognitive performance in mice after mild traumatic brain injury.
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.
Laboratory of Molecular Biology, Research and Development 151, Bay Pines VA Healthcare System, Bay Pines, FL 33744, United States.
J N
JN
Saykally
L
L
Rachmany
H
H
Hatic
A
A
Shaer
V
V
Rubovitch
C G
CG
Pick
B A
BA
Citron
D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000150:complications* / Q000188:drug therapy; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006873:Hydroquinones / Q000627:therapeutic use*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D011684:Purine Nucleosides / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects; D045442:Rotarod Performance Test; D013997:Time Factors
D000975:Antioxidants; D005904:Glial Fibrillary Acidic Protein; D018840:HSP70 Heat-Shock Proteins; D006873:Hydroquinones; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D016755:Proto-Oncogene Proteins c-jun; D011684:Purine Nucleosides; D012333:RNA, Messenger; C550733:VER 155008; C018855:2-tert-butylhydroquinone; D053148:Caspase 3