Open Access Highly Accessed Research

Activation of microglial cells triggers a release of brain-derived neurotrophic factor (BDNF) inducing their proliferation in an adenosine A2A receptor-dependent manner: A2A receptor blockade prevents BDNF release and proliferation of microglia

Catarina Gomes1*, Raquel Ferreira1, Jimmy George1, Rui Sanches1, Diana I Rodrigues1, Nélio Gonçalves13 and Rodrigo A Cunha12

Author Affiliations

1 Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, Coimbra, 3004-517, Portugal

2 FMUC - Faculty of Medicine, University of Coimbra, Coimbra, 3004-504, Portugal

3 Faculty of Pharmacy, University of Coimbra, Coimbra, 3000-548, Portugal

For all author emails, please log on.

Journal of Neuroinflammation 2013, 10:16  doi:10.1186/1742-2094-10-16

Published: 30 January 2013

Abstract

Background

Brain-derived neurotrophic factor (BDNF) has been shown to control microglial responses in neuropathic pain. Since adenosine A2A receptors (A2ARs) control neuroinflammation, as well as the production and function of BDNF, we tested to see if A2AR controls the microglia-dependent secretion of BDNF and the proliferation of microglial cells, a crucial event in neuroinflammation.

Methods

Murine N9 microglial cells were challenged with lipopolysaccharide (LPS, 100 ng/mL) in the absence or in the presence of the A2AR antagonist, SCH58261 (50 nM), as well as other modulators of A2AR signaling. The BDNF cellular content and secretion were quantified by Western blotting and ELISA, A2AR density was probed by Western blotting and immunocytochemistry and cell proliferation was assessed by BrdU incorporation. Additionally, the A2AR modulation of LPS-driven cell proliferation was also tested in primary cultures of mouse microglia.

Results

LPS induced time-dependent changes of the intra- and extracellular levels of BDNF and increased microglial proliferation. The maximal LPS-induced BDNF release was time-coincident with an LPS-induced increase of the A2AR density. Notably, removing endogenous extracellular adenosine or blocking A2AR prevented the LPS-mediated increase of both BDNF secretion and proliferation, as well as exogenous BDNF-induced proliferation.

Conclusions

We conclude that A2AR activation plays a mandatory role controlling the release of BDNF from activated microglia, as well as the autocrine/paracrine proliferative role of BDNF.

Keywords:
Adenosine A2A receptors; Neuroinflammation; Microglia; BDNF