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Review
, 12 (1), 7-12

Therapeutic Potential of Brain-Derived Neurotrophic Factor (BDNF) and a Small Molecular Mimics of BDNF for Traumatic Brain Injury

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Review

Therapeutic Potential of Brain-Derived Neurotrophic Factor (BDNF) and a Small Molecular Mimics of BDNF for Traumatic Brain Injury

Mary Wurzelmann et al. Neural Regen Res.

Abstract

Traumatic brain injury (TBI) is a major health problem worldwide. Following primary mechanical insults, a cascade of secondary injuries often leads to further neural tissue loss. Thus far there is no cure to rescue the damaged neural tissue. Current therapeutic strategies primarily target the secondary injuries focusing on neuroprotection and neuroregeneration. The neurotrophin brain-derived neurotrophic factor (BDNF) has significant effect in both aspects, promoting neuronal survival, synaptic plasticity and neurogenesis. Recently, the flavonoid 7,8-dihydroxyflavone (7,8-DHF), a small TrkB agonist that mimics BDNF function, has shown similar effects as BDNF in promoting neuronal survival and regeneration following TBI. Compared to BDNF, 7,8-DHF has a longer half-life and much smaller molecular size, capable of penetrating the blood-brain barrier, which makes it possible for non-invasive clinical application. In this review, we summarize functions of the BDNF/TrkB signaling pathway and studies examining the potential of BDNF and 7,8-DHF as a therapy for TBI.

Keywords: 7,8-dihydroxyflavone; brain-derived neurotrophic factor; neuroprotection; neuroregeneration; traumatic brain injury; tropomyosin related kinase B (TrkB) receptor.

Conflict of interest statement

Conflicts of interest: None declared.

Figures

Figure 1
Figure 1
The activation pathways of the TrkB receptor. The binding of BDNF or 7,8-DHF leads to auto-phosphorylation of the intracellular domain of the receptor and activation of the downstream pathways. 1) The MAPK pathway. Activation of this pathway stimulates anti-apoptotic proteins, including Bcl2 and cAMP response-element binding protein (CREB). CREB is required by neurotrophin mediated neuronal survival. Activation of the MAPK pathway also stimulates extracellular signal related kinase (ERK), which induces phosphorylation of Synapsin I mediating the clustering and release of synaptic vesicles. 2) Activation of the PI3K pathway, which activates Akt. Akt inhibits apopotosis by inhibiting activation of antiapoptotic proteins including Bad, Pro-caspase 9 and Forkhead. PI3K = phosphatidylinositol 3 kinase; Akt = Protein Kinase B, PKB; Bad = Bcl2 associated death promoter. 3) The Phospholipase C-gamma (PLCγ) pathway. PLC-γ can lead to an increase in intracellular calcium levels, which activates the calcium/calmodulin pathway leading to CREB activation. 7,8-DHF: 7,8-Dihydroxyflavone; BDNF: brain-derived neurotrophic factor; MAPK: mitogen-activated protein kinase; TrkB: tropomyosin related kinase B.

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