A Small Molecule TrkB Neurotrophin Receptor Partial Agonist as Possible Treatment for Experimental Nonarteritic Anterior Ischemic Optic Neuropathy

Autor:	Ben Anthony Barres, Chandrani Chakraborty, Mohammad Ali Shariati, Yaping Joyce Liao, Tao Yang, Varun Kumar, Frank M. Longo
Rok vydání:	2018
Předmět:	Retinal Ganglion Cells 0301 basic medicine medicine.medical_specialty Cell Survival Optic Disk Tropomyosin kinase Tropomyosin receptor kinase B Ligands Retinal ganglion Rats Sprague-Dawley Optic neuropathy Mice 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Internal medicine medicine Animals Receptor trkB Optic Neuropathy Ischemic Cells Cultured biology Chemistry medicine.disease Sensory Systems Rats Mice Inbred C57BL Disease Models Animal Ophthalmology Treatment Outcome 030104 developmental biology Endocrinology medicine.anatomical_structure nervous system Retinal ganglion cell Trk receptor Benzamides 030221 ophthalmology & optometry biology.protein Anterior ischemic optic neuropathy sense organs Tomography Optical Coherence Neurotrophin
Zdroj:	Current Eye Research. 43:1489-1499
ISSN:	1460-2202 0271-3683
DOI:	10.1080/02713683.2018.1508726
Popis:	Brain-derived neurotrophic factor (BDNF) and activation of its high affinity receptor tropomyosin kinase (Trk) B promote retinal ganglion cells (RGCs) survival following injury. In this study, we tested the effects of LM22A-4, a small molecule TrkB receptor-specific partial agonist, on RGC survival in vitro and in experimental nonarteritic anterior ischemic optic neuropathy (AION), the most common acute optic neuropathy in those older than 50 years.We assessed drug effects on immunopanned, cultured RGCs and calculated RGC survival and assessed TrkB receptor activation by mitogen-activated protein (MAP) kinase translocation. To assess effects in vivo, we induced murine AION and treated the animals with one intravitreal injection and three-week systemic treatment. We measured drug effects using serial spectral-domain optical coherence tomography (OCT) and quantified retinal Brn3AIn vitro, LM22A-4 significantly increased the survival of cultured RGCs at day 2 (95% CI control: 8.4-13.6; LM22A-4: 23.7-30.3; BDNF: 24.3-29.9; P ≤ 0.0001), similar to the effect of the endogenous TrkB receptor ligand BDNF. There was also significant nuclear and cytoplasmic translocation of MAP kinase (95% CI control: 0.9-6.8; LM22A-4: 38.8-84.4; BDNF: 64.0-93.0; P = 0.0002), a known downstream event of TrkB receptor activation. Following AION, LM22A-4 treatment led to significant preservation of the ganglion cell complex (95% CI: AION-PBS: 66.8-70.7%; AION-LM22A-4: 70.0-73.1; P = 0.03) and total retinal thickness (95% CI: AION-PBS: 185-196%; AION-LM22A-4: 195-203; P = 0.002) as measured by OCT compared with non-treated eyes. There was also significant rescue of the Brn3ATrkB receptor partial agonist LM22A-4 promoted survival of cultured RGCs in vitro by TrkB receptor activation, and treatment in vivo led to increased survival of RGCs after optic nerve ischemia, providing support that LM22A-4 may be effective therapy to treat ischemic optic neuropathy.AION: anterior ischemic optic neuropathy, BDNF: Brain-derived neurotrophic factor, GCC: ganglion cell complex, MAP: mitogen-activated protein, OCT: spectral-domain optical coherence tomography, OD: right eye, ON: optic nerve, ONH: optic nerve head, OS: left eye, RGC: retinal ganglion cell; Trk: tropomyosin kinase.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::528a8bf1f18f5360636731898ad12824 https://doi.org/10.1080/02713683.2018.1508726 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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