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Tropomyosin-related kinase B (TrkB) is a receptorprotein involved in the development and maturation of the centraland peripheral nervous systems. BDNF has a high affinity for TrkBand p75 enhances the interaction between BDNF and TrkB (). Upon ligand-binding, TrkB undergoeshomodimerization, autophosphorylation and activation. It thenrecruits and activates several downstream effectors to regulategene expression and protect neurons. Members of the TrkB downstreamsignaling cascade, including ERK/MAPK and PI3K/PKB, have beenreported to be responsive to BDNF (,).Several studies have hypothesized that BDNF largely activates theERK/MAPK pathway (–). By contrast, other studies havereported that activation of the ERK/MAPK pathway leads to celldeath and PI3K/PKB is the main pathway involved in the protectionof neurons induced by BDNF ().In addition, it has been reported that both pathways are criticalfor neuroprotection induced by BDNF. To the best of our knowledge,no studies to date have addressed which pathway dominates theresponse to TrkB activation (,,).
Metabolic syndrome – Neurotrophic hypothesis - …
One way of looking at the role of BDNF, then, is that it is not levels of BDNF as such that are important, or even that BDNF promotes neurogenesis. According to the network hypothesis, BDNF’s effects on behaviour will depend on in the brain it is active, and which networks it therefore affects.
Apoptosis is a form of programmed cell death that isimportant in multicellular organisms. Apoptosis is regulated bynumerous proteins mainly associated with the canonicalmitochondrial or endoplasmic reticulum signaling pathways. Previousstudies have reported that normal RGCs constitutively express theantiapoptotic molecules, Akt, Cox-2 and Mcl-1, while diabetesinduced the expression of proapoptotic molecules, includingmitochondrial proteins, cytochrome c and AIF (). These observations indicate a markedcorrelation between apoptosis and neuronal survival; however, themechanism of this process remains unclear (–).As apoptosis in diabetic neurons is associated with the lack ofneurotrophic factors, in the present study, we hypothesized thatadding extra neurotrophin may protect diabetic neurons. The resultsconfirmed that BDNF protects retinal neurons from hyperglycemia bydecreasing the rate of apoptosis. As a regulator of apoptosis, theRas-MAPK/ERK pathway was previously reported to be downstream ofTrkB. In the present study, ERK expression was detected in neuronsexposed to hyperglycemia medium or treated with BDNF. The resultsrevealed that hyperglycemia and/or BDNF did not affect theexpression of ERK at the mRNA or protein levels. However, BDNF wasdemonstrated to markedly increase phosphorylation of ERK, whilehyperglycemia treatment had no effect. These observations areconsistent with the findings of a previous study (). These results indicate that theERK/MAPK signaling pathway is downstream of TrkB and BDNF. BDNFactivates the TrkB-ERK/MAPK pathway and inhibits apoptosis, thuspromoting the survival of neurons from hyperglycemia.