PMID- 26560713 OWN - NLM STAT- MEDLINE DCOM- 20160616 LR - 20220310 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 10 IP - 11 DP - 2015 TI - Tackling Glaucoma from within the Brain: An Unfortunate Interplay of BDNF and TrkB. PG - e0142067 LID - 10.1371/journal.pone.0142067 [doi] LID - e0142067 AB - 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. FAU - Dekeyster, Eline AU - Dekeyster E AD - Neural Circuit Development and Regeneration Research Group, Department of Biology, KU Leuven, Leuven, Belgium. FAU - Geeraerts, Emiel AU - Geeraerts E AD - Neural Circuit Development and Regeneration Research Group, Department of Biology, KU Leuven, Leuven, Belgium. FAU - Buyens, Tom AU - Buyens T AD - Neural Circuit Development and Regeneration Research Group, Department of Biology, KU Leuven, Leuven, Belgium. FAU - Van den Haute, Chris AU - Van den Haute C AD - Neurobiology and Gene Therapy Research Group, Department of Neurosciences, KU Leuven, Leuven, Belgium. AD - Leuven Viral Vector Core, KU Leuven, Leuven, Belgium. FAU - Baekelandt, Veerle AU - Baekelandt V AD - Neurobiology and Gene Therapy Research Group, Department of Neurosciences, KU Leuven, Leuven, Belgium. FAU - De Groef, Lies AU - De Groef L AD - Neural Circuit Development and Regeneration Research Group, Department of Biology, KU Leuven, Leuven, Belgium. FAU - Salinas-Navarro, Manuel AU - Salinas-Navarro M AD - Neural Circuit Development and Regeneration Research Group, Department of Biology, KU Leuven, Leuven, Belgium. FAU - Moons, Lieve AU - Moons L AD - Neural Circuit Development and Regeneration Research Group, Department of Biology, KU Leuven, Leuven, Belgium. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151111 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Brain-Derived Neurotrophic Factor) RN - EC 2.7.10.1 (Receptor, trkB) SB - IM MH - Animals MH - Brain/drug effects/*metabolism MH - Brain-Derived Neurotrophic Factor/genetics/*metabolism/pharmacology MH - Disease Models, Animal MH - Glaucoma/*metabolism/pathology MH - HEK293 Cells MH - Humans MH - Intraocular Pressure/drug effects MH - Mice MH - Nerve Crush MH - Ocular Hypertension/metabolism/pathology MH - Optic Nerve Injuries/metabolism/pathology MH - Receptor, trkB/genetics/*metabolism MH - Retinal Ganglion Cells/drug effects/metabolism/pathology MH - Up-Regulation PMC - PMC4641732 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2015/11/13 06:00 MHDA- 2016/06/17 06:00 PMCR- 2015/11/11 CRDT- 2015/11/13 06:00 PHST- 2015/07/29 00:00 [received] PHST- 2015/10/17 00:00 [accepted] PHST- 2015/11/13 06:00 [entrez] PHST- 2015/11/13 06:00 [pubmed] PHST- 2016/06/17 06:00 [medline] PHST- 2015/11/11 00:00 [pmc-release] AID - PONE-D-15-33295 [pii] AID - 10.1371/journal.pone.0142067 [doi] PST - epublish SO - PLoS One. 2015 Nov 11;10(11):e0142067. doi: 10.1371/journal.pone.0142067. eCollection 2015.