The Small-Molecule TrkB Agonist 7, 8-Dihydroxyflavone Decreases Hippocampal Newborn Neuron Death After Traumatic Brain Injury

• Published in: Journal of neuropathology and experimental neurology Vol. 74; no. 6; pp. 557 - 567
• Main Authors: Chen, Liang, Gao, Xiang, Zhao, Shu, Hu, Weipeng, Chen, Jinhui
• Format: Journal Article
• Language: English
• Published: England American Association of Neuropathologists, Inc 01.06.2015; by American Association of Neuropathologists, Inc
• Subjects: Animals; Animals, Newborn; Azepines - pharmacology; Benzamides - pharmacology; Brain Injuries - drug therapy; Brain Injuries - pathology; Cell Death - drug effects; Disease Models, Animal; Dose-Response Relationship, Drug; Flavones - therapeutic use; Fluoresceins; Hippocampus - drug effects; Hippocampus - pathology; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins - metabolism; Neurons - drug effects; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Phosphorylation - drug effects; Receptor, trkB - agonists; Receptor, trkB - antagonists & inhibitors; Receptor, trkB - metabolism; Signal Transduction - drug effects; Newborn neuron; Neuroprotection; 7, 8-dihydroxyflavone; Brain-derived neurotrophic factor; Traumatic brain injury; Cell death
• ISSN: 0022-3069; 1554-6578; 1554-6578
• DOI: 10.1097/NEN.0000000000000199

Previous studies in rodents have shown that after a moderate traumatic brain injury (TBI) with a controlled cortical impact (CCI) device, the adult-born immature granular neurons in the dentate gyrus are the most vulnerable cell type in the hippocampus. There is no effective approach for preventing immature neuron death after TBI. We found that tyrosine-related kinase B (TrkB), a receptor of brain-derived neurotrophic factor (BDNF), is highly expressed in adult-born immature neurons. We determined that the small molecule imitating BDNF, 7, 8-dihydroxyflavone (DHF), increased phosphorylation of TrkB in immature neurons both in vitro and in vivo. Pretreatment with DHF protected immature neurons from excitotoxicity-mediated death in vitro, and systemic administration of DHF before moderate CCI injury reduced the death of adult-born immature neurons in the hippocampus 24 hours after injury. By contrast, inhibiting BDNF signaling using the TrkB antagonist ANA12 attenuated the neuroprotective effects of DHF. These data indicate that DHF may be a promising chemical compound that promotes immature neuron survival after TBI through activation of the BDNF signaling pathway.