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.
Highlights
Traumatic brain injury (TBI) triggers a complex cascade of apoptotic events which can contribute to delayed secondary injury processes [1]
Our study demonstrates that activation of Tropomyosin-related kinase B (TrkB) signaling by 7,8-DHF protects against TBI via the phosphatidylinositol 3-kinase (PI3K)/Akt but not Erk pathway, and this protective effect may be amplified via the PI3K/Akt-cAMP-response element binding protein (CREB) cascades
The TrkB is activated by binding to brain-derived neurotrophic factor (BDNF), which results in activation of downstream phosphatidylinositol 3-kinase (PI3K)/Akt, mitogen-activated protein kinase (MAPK)/Erk, or PLC-c signaling via receptor autophosphorylation and dimerization [6, 7]
Summary
Traumatic brain injury (TBI) triggers a complex cascade of apoptotic events which can contribute to delayed secondary injury processes [1]. TBI induces an acute but transient increase in BDNF and TrkB mRNA, presumably indicating a transient but failed endogenous protective response [11, 12] These data suggest that modulation of TrkB signaling have a therapeutic role in brain damage. As a consequence of activating TrkB signaling, 7,8-DHF promotes survival and enhances neurite growth in cultured neurons [15, 16], and is neuroprotective in rodent models of ischemic stroke [15] and neurodegenerative diseases such as Alzheimer’s disease [17, 18], Parkinson’s disease [15] and Huntington’s disease [19] This evidence indicates that 7,8-DHF, acting as a selective TrkB agonist, can be applied as a tool to investigate the role of BDNF/TrkB signaling. Our aim in the present study is to determine whether activation of TrkB signaling by 7,8-DHF is protective against TBI in a mouse model of TBI and in an in vitro neuronal stretch model and to examine whether 7,8-DHF could promote the TrkB downstream PI3K/Akt or Erk pathways, and increase endogenous BDNF expression
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