title: Post-injury treatment with 7,8-dihydroxyflavone, a TrkB receptor agonist, protects against experimental traumatic brain injury via PI3K/Akt signaling.
abstract: Tropomyosin-related kinase B (TrkB) signaling is critical for promoting neuronal survival following brain damage. The present study investigated the effects and underlying mechanisms of TrkB activation by the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) on traumatic brain injury (TBI). Mice subjected to controlled cortical impact received intraperitoneal 7,8-DHF or vehicle injection 10 min post-injury and subsequently daily for 3 days. Behavioral studies, histology analysis and brain water content assessment were performed. Levels of TrkB signaling-related molecules and apoptosis-related proteins were analyzed. The protective effect of 7,8-DHF was also investigated in primary neurons subjected to stretch injury. Treatment with 20 mg/kg 7,8-DHF attenuated functional deficits and brain damage up to post-injury day 28. 7,8-DHF also reduced brain edema, neuronal death, and apoptosis at day 4. These changes were accompanied by a significant decrease in cleaved caspase-3 and increase in Bcl-2/Bax ratio. 7,8-DHF enhanced phosphorylation of TrkB, Akt (Ser473/Thr308), and Bad at day 4, but had no effect on Erk 1/2 phosphorylation. Moreover, 7,8-DHF increased brain-derived neurotrophic factor levels and promoted cAMP response element-binding protein (CREB) activation. This beneficial effect was attenuated by inhibition of TrkB or PI3K/Akt. 7,8-DHF also promoted survival and reduced apoptosis in cortical neurons subjected to stretch injury. Remarkably, delayed administration of 7,8-DHF at 3 h post-injury reduced brain tissue damage. Our study demonstrates that activation of TrkB signaling by 7,8-DHF protects against TBI via the PI3K/Akt but not Erk pathway, and this protective effect may be amplified via the PI3K/Akt-CREB cascades.
authors.affiliation: Departments of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan, Republic of China; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.
authors.forename: Chun-Hu
authors.initials: CH
authors.lastname: Wu
authors.affiliation: Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital at Taipei and College of Medicine, Chang Gung University, Taipei, Taiwan, Republic of China.
authors.forename: Tai-Ho
authors.initials: TH
authors.lastname: Hung
authors.affiliation: Department of Physical Medicine and Rehabilitation, Cheng Hsin General Hospital, Taipei, Taiwan, Republic of China.
authors.forename: Chien-Cheng
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Departments of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan, Republic of China; Department of Physical Medicine and Rehabilitation, Cheng Hsin General Hospital, Taipei, Taiwan, Republic of China.
authors.forename: Chia-Hua
authors.initials: CH
authors.lastname: Ke
authors.affiliation: Department of Physical Medicine and Rehabilitation, Cheng Hsin General Hospital, Taipei, Taiwan, Republic of China.
authors.forename: Chun-Yen
authors.initials: CY
authors.lastname: Lee
authors.affiliation: Department of Physical Medicine and Rehabilitation, Cheng Hsin General Hospital, Taipei, Taiwan, Republic of China.
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Wang
authors.affiliation: Departments of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan, Republic of China; Department of Physical Medicine and Rehabilitation, Cheng Hsin General Hospital, Taipei, Taiwan, Republic of China.
authors.forename: Szu-Fu
authors.initials: SF
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001929:Brain Edema / Q000188:drug therapy; D001930:Brain Injuries / Q000473:pathology / Q000517:prevention & control*; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D047309:Flavones / Q000008:administration & dosage* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D007274:Injections, Intraperitoneal; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000494:pharmacology; D020813:Receptor, trkB / Q000037:antagonists & inhibitors*
chemical_list: C485383:6,7-dihydroxyflavone; D047309:Flavones; D018696:Neuroprotective Agents; D020813:Receptor, trkB