Post-Injury Treatment with 7,8-Dihydroxyflavone, a TrkB Receptor Agonist, Protects against Experimental Traumatic Brain Injury via PI3K/Akt Signaling

PLOS ONE, Dec 2019

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.

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Post-Injury Treatment with 7,8-Dihydroxyflavone, a TrkB Receptor Agonist, Protects against Experimental Traumatic Brain Injury via PI3K/Akt Signaling

November Post-Injury Treatment with 7,8-Dihydroxyflavone, a TrkB Receptor Agonist, Protects against Experimental Traumatic Brain Injury via PI3K/Akt Signaling Chun-Hu Wu 0 1 4 Tai-Ho Hung 2 4 Chien-Cheng Chen 3 4 Chia-Hua Ke 0 3 4 Chun-Yen Lee 3 4 Pei-Yi Wang 3 4 Szu-Fu Chen 0 3 4 0 Departments of Physiology and Biophysics, National Defense Medical Center , Taipei, Taiwan , Republic of China, 1 Graduate Institute of Life Sciences, National Defense Medical Center , Taipei, Taiwan , Republic of China, 2 Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital at Taipei and College of Medicine, Chang Gung University , Taipei, Taiwan , Republic of China, 3 Department of Physical Medicine and Rehabilitation, Cheng Hsin General Hospital , Taipei, Taiwan , Republic of China 4 Editor: Masuo Ohno, Nathan Kline Institute and New York University Langone Medical Center , United States of America 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 Signaling 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. Traumatic brain injury (TBI) triggers a complex cascade of apoptotic events which can contribute to delayed secondary injury processes [1]. Clinically, activation of caspases [2], profiles of Bcl-2 family proteins, and the release of proapoptotic proteins from mitochondria have been linked to TBI outcomes [3]. Experimental studies have also demonstrated that caspase inhibitors [2] or overexpression of Bcl-2, an anti-apoptotic molecule, were protective against TBI [4]. These studies indicate that apoptosis could serve as a therapeutic target following TBI. On the other hand, TBI also activates endogenous protective mechanisms to counteract secondary injury [5]. Tropomyosin-related kinase B (TrkB) signaling has been considered to be an important protective mechanism induced by brain damage and a key regulator of neuronal survival [5, 6]. 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]. PI3K/Akt and Erk signaling pathways are the major TrkBmediated survival pathways that promote neuronal survival and protect against apoptosis [6, 7]. In addition, BDNF/TrkB signaling can promote further BDNF production through cAMP-response element binding protein (CREB), a key transcription factor for BDNF induction via activation of PI3K/Akt or Erk signaling [810], which is emerging as a positive-feedback loop. 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. However, recombinant BDNF has so far yielded disappointing results in clinical trials [13], possibly because of its short plasma half-life and poor blood-brain barrier (BBB) penetration [14]. 7,8-Dihydroxyflavone (7,8-DHF), a flavone derivative, has recently been identified as a specific TrkB agonist which passes the BBB after peripheral administration [15]. 7,8-DHF binds to the extracellular domain of TrkB, inducing its dimerization and autophosphorylation, and activates the downstream PI3K/ Akt and Erk pathways in pri (...truncated)


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Chun-Hu Wu, Tai-Ho Hung, Chien-Cheng Chen, Chia-Hua Ke, Chun-Yen Lee, Pei-Yi Wang, Szu-Fu Chen. Post-Injury Treatment with 7,8-Dihydroxyflavone, a TrkB Receptor Agonist, Protects against Experimental Traumatic Brain Injury via PI3K/Akt Signaling, PLOS ONE, 2014, Volume 9, Issue 11, DOI: 10.1371/journal.pone.0113397