Tackling Glaucoma from within the Brain: An Unfortunate Interplay of BDNF and TrkB

According to the neurotrophin deprivation hypothesis, diminished retrograde delivery of neurotrophic support during an early stage of glaucoma pathogenesis is one of the main triggers that induce retinal ganglion cell (RGC) degeneration. Therefore, interfering with neurotrophic signaling seems an at...

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Main Authors:	Dekeyster, Eline, Geeraerts, Emiel, Buyens, Tom, Van den Haute, Chris, Baekelandt, Veerle, De Groef, Lies, Salinas-Navarro, Manuel, Moons, Lieve
Format:	Online
Language:	English
Published:	Public Library of Science 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641732/

id	pubmed-4641732
recordtype	oai_dc
spelling	pubmed-46417322015-11-18 Tackling Glaucoma from within the Brain: An Unfortunate Interplay of BDNF and TrkB Dekeyster, Eline Geeraerts, Emiel Buyens, Tom Van den Haute, Chris Baekelandt, Veerle De Groef, Lies Salinas-Navarro, Manuel Moons, Lieve Research Article According to the neurotrophin deprivation hypothesis, diminished retrograde delivery of neurotrophic support during an early stage of glaucoma pathogenesis is one of the main triggers that induce retinal ganglion cell (RGC) degeneration. Therefore, interfering with neurotrophic signaling seems an attractive strategy to achieve neuroprotection. Indeed, exogenous neurotrophin administration to the eye has been shown to reduce loss of RGCs in animal models of glaucoma; however, the neuroprotective effect was mostly insufficient for sustained RGC survival. We hypothesized that treatment at the level of neurotrophin-releasing brain areas might be beneficial, as signaling pathways activated by target-derived neurotrophins are suggested to differ from pathways that are initiated at the soma membrane. In our study, first, the spatiotemporal course of RGC degeneration was characterized in mice subjected to optic nerve crush (ONC) or laser induced ocular hypertension (OHT). Subsequently, the well-known neurotrophin brain-derived neurotrophic factor (BDNF) was chosen as the lead molecule, and the levels of BDNF and its high-affinity receptor, tropomyosin receptor kinase B (TrkB), were examined in the mouse retina and superior colliculus (SC) upon ONC and OHT. Both models differentially influenced BDNF and TrkB levels. Next, we aimed for RGC protection through viral vector-mediated upregulation of collicular BDNF, thought to boost the retrograde neurotrophin delivery. Although the previously reported temporary neuroprotective effect of intravitreally delivered recombinant BDNF was confirmed, viral vector-induced BDNF overexpression in the SC did not result in protection of the RGCs in the glaucoma models used. These findings most likely relate to decreased neurotrophin responsiveness upon vector-mediated BDNF overexpression. Our results highlight important insights concerning the complexity of neurotrophic factor treatments that should surely be considered in future neuroprotective strategies. Public Library of Science 2015-11-11 /pmc/articles/PMC4641732/ /pubmed/26560713 http://dx.doi.org/10.1371/journal.pone.0142067 Text en © 2015 Dekeyster et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Dekeyster, Eline Geeraerts, Emiel Buyens, Tom Van den Haute, Chris Baekelandt, Veerle De Groef, Lies Salinas-Navarro, Manuel Moons, Lieve
spellingShingle	Dekeyster, Eline Geeraerts, Emiel Buyens, Tom Van den Haute, Chris Baekelandt, Veerle De Groef, Lies Salinas-Navarro, Manuel Moons, Lieve Tackling Glaucoma from within the Brain: An Unfortunate Interplay of BDNF and TrkB
author_facet	Dekeyster, Eline Geeraerts, Emiel Buyens, Tom Van den Haute, Chris Baekelandt, Veerle De Groef, Lies Salinas-Navarro, Manuel Moons, Lieve
author_sort	Dekeyster, Eline
title	Tackling Glaucoma from within the Brain: An Unfortunate Interplay of BDNF and TrkB
title_short	Tackling Glaucoma from within the Brain: An Unfortunate Interplay of BDNF and TrkB
title_full	Tackling Glaucoma from within the Brain: An Unfortunate Interplay of BDNF and TrkB
title_fullStr	Tackling Glaucoma from within the Brain: An Unfortunate Interplay of BDNF and TrkB
title_full_unstemmed	Tackling Glaucoma from within the Brain: An Unfortunate Interplay of BDNF and TrkB
title_sort	tackling glaucoma from within the brain: an unfortunate interplay of bdnf and trkb
description	According to the neurotrophin deprivation hypothesis, diminished retrograde delivery of neurotrophic support during an early stage of glaucoma pathogenesis is one of the main triggers that induce retinal ganglion cell (RGC) degeneration. Therefore, interfering with neurotrophic signaling seems an attractive strategy to achieve neuroprotection. Indeed, exogenous neurotrophin administration to the eye has been shown to reduce loss of RGCs in animal models of glaucoma; however, the neuroprotective effect was mostly insufficient for sustained RGC survival. We hypothesized that treatment at the level of neurotrophin-releasing brain areas might be beneficial, as signaling pathways activated by target-derived neurotrophins are suggested to differ from pathways that are initiated at the soma membrane. In our study, first, the spatiotemporal course of RGC degeneration was characterized in mice subjected to optic nerve crush (ONC) or laser induced ocular hypertension (OHT). Subsequently, the well-known neurotrophin brain-derived neurotrophic factor (BDNF) was chosen as the lead molecule, and the levels of BDNF and its high-affinity receptor, tropomyosin receptor kinase B (TrkB), were examined in the mouse retina and superior colliculus (SC) upon ONC and OHT. Both models differentially influenced BDNF and TrkB levels. Next, we aimed for RGC protection through viral vector-mediated upregulation of collicular BDNF, thought to boost the retrograde neurotrophin delivery. Although the previously reported temporary neuroprotective effect of intravitreally delivered recombinant BDNF was confirmed, viral vector-induced BDNF overexpression in the SC did not result in protection of the RGCs in the glaucoma models used. These findings most likely relate to decreased neurotrophin responsiveness upon vector-mediated BDNF overexpression. Our results highlight important insights concerning the complexity of neurotrophic factor treatments that should surely be considered in future neuroprotective strategies.
publisher	Public Library of Science
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641732/
_version_	1613500050558681088

Tackling Glaucoma from within the Brain: An Unfortunate Interplay of BDNF and TrkB

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