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Open Access 01-12-2017 | Original investigation

Advanced glycation end products induce brain-derived neurotrophic factor release from human platelets through the Src-family kinase activation

Authors: Kazuo Furukawa, Ichiro Fuse, Yuriko Iwakura, Hidekazu Sotoyama, Osamu Hanyu, Hiroyuki Nawa, Hirohito Sone, Nobuyuki Takei

Published in: Cardiovascular Diabetology | Issue 1/2017

Abstract

Background

Brain-derived neurotrophic factor (BDNF) exerts beneficial effects not only on diabetic neuropathies but also on cardiovascular injury. There is argument regarding the levels of serum BDNF in patients with diabetes mellitus (DM). Because BDNF in peripheral blood is rich in platelets, this may represent dysregulation of BDNF release from platelets. Here we focused on advanced glycation end products (AGEs), which are elevated in patients with DM and have adverse effects on cardiovascular functions. The aim of this study is to elucidate the role of AGEs in the regulation of BDNF release from human platelets.

Methods

Platelets collected from peripheral blood of healthy volunteers were incubated with various concentrations of AGE (glycated-BSA) at 37 °C for 5 min with or without BAPTA-AM, a cell permeable Ca²⁺ chelator, or PP2, a potent inhibitor of Src family kinases (SFKs). Released and cellular BDNF were measured by ELISA and calculated. Phosphorylation of Src and Syk, a downstream kinase of SFKs, in stimulated platelets was examined by Western blotting and immunoprecipitation.

Results

AGE induced BDNF release from human platelets in a dose-dependent manner, which was dependent on intracellular Ca²⁺ and SFKs. We found that AGE induced phosphorylation of Src and Syk.

Conclusions

AGE induces BDNF release from human platelets through the activation of the Src-Syk-(possibly phospholipase C)-Ca²⁺ pathway. Considering the toxic action of AGEs and the protective roles of BDNF, it can be hypothesized that AGE-induced BDNF release is a biological defense system in the early phase of diabetes. Chronic elevation of AGEs may induce depletion or downregulation of BDNF in platelets during the progression of DM.

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Title: Advanced glycation end products induce brain-derived neurotrophic factor release from human platelets through the Src-family kinase activation
Authors: Kazuo Furukawa
Ichiro Fuse
Yuriko Iwakura
Hidekazu Sotoyama
Osamu Hanyu
Hiroyuki Nawa
Hirohito Sone
Nobuyuki Takei
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Cardiovascular Diabetology / Issue 1/2017
Electronic ISSN: 1475-2840
DOI: https://doi.org/10.1186/s12933-017-0505-y

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Results

Conclusions

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