April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
TrkB Neurotrophin Receptor Activation with Pharmacophore as Possible Treatment for Experimental Ischemic Optic Neuropathy
Author Affiliations & Notes
  • M. Ali Shariati
    Ophthalmology, Byers Eye Institute at Stanford, Stanford, CA
  • Jeffrey Ma
    Ophthalmology, Byers Eye Institute at Stanford, Stanford, CA
  • Frank Longo
    Neurology, Stanford School of Medicine, Stanford, CA
  • Tao Yang
    Neurology, Stanford School of Medicine, Stanford, CA
  • Ben Barres
    Neurobiology, Stanford School of Medicine, Stanford, CA
  • Chandrani Chakraborty
    Neurobiology, Stanford School of Medicine, Stanford, CA
  • Yaping Joyce Liao
    Ophthalmology, Byers Eye Institute at Stanford, Stanford, CA
  • Footnotes
    Commercial Relationships M. Ali Shariati, None; Jeffrey Ma, None; Frank Longo, Founder of PharmatrophiX, a company focused on development of neurotrophin small molecule ligands (C); Tao Yang, None; Ben Barres, None; Chandrani Chakraborty, None; Yaping Liao, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 6224. doi:
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      M. Ali Shariati, Jeffrey Ma, Frank Longo, Tao Yang, Ben Barres, Chandrani Chakraborty, Yaping Joyce Liao, ; TrkB Neurotrophin Receptor Activation with Pharmacophore as Possible Treatment for Experimental Ischemic Optic Neuropathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6224.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Anterior ischemic optic neuropathy (AION) is the most common acute optic neuropathy in older adults with no effective treatment. Neurotrophin BDNF (brain-derived neurotrophic factor) binds to TrkB receptors and is retrogradely transported to promote retinal ganglion cells (RGC) survival, leading to the hypothesis that restoration of neurotrophic support may be an effective therapeutic approach. In this study, we tested the effects of LM22A-4, a TrkB receptor small molecule partial agonist with TrkB specificity and nanomolar affinity1-3 on RGC survival.

Methods: To assess in vitro effects, we cultured purified RGCs using immunopanning,4 determined RGC survival, and examined TrkB receptor signalling pathway. To measure in vivo effects, we induced optic nerve head ischemia following rose bengal injection using a frequency doubled Nd: YAG laser (400 μm diameter, 50 mW, 1 second duration, 15 spots).5-6 Animals were treated with one intravitreal injection and 3-week daily intranasal and intraperitoneal treatments immediately following ischemia. We performed spectral-domain optical coherence tomography (OCT) analysis and quantified Brn3A+ RGCs in whole mount preparations at week-3. Data were analysed with custom macro in Image J and Prism.

Results: In vitro, LM22A-4 treatment significantly increased RGC survival (drug: 27.0 ± 1.5%; negative control: 11.0 ± 3.9%; P <0.0001), similar to the effects of BDNF (27.1 ± 1.2%). This improved survival correlated with significant nuclear and cytoplasmic translocation of MAP kinase (P <0.0001), a molecule downstream of TrkB receptor activation. Following AION, OCT circular scan and manual segmentation of the ganglion cell complex (2 µm) and volume scan with automatic segmentation of the total retinal thickness around the optic disc (10 µm) revealed partial preservation of retinal thickness after LM22A-4 administration. LM22A-4 treatment also led to significant rescue of the RGCs (drug: 2087 ± 65 Brn3A+ cells/mm2; saline: 1827 ± 90 Brn3A+ cells/mm2; P = 0.02).

Conclusions: LM22A-4 promoted TrkB receptor activation and RGC survival in culture similar to the effects of endogenous ligand BDNF. Treatment with LM22A-4 after experimental ischemic optic neuropathy led to partial preservation of retinal thinning on OCT analyses and significantly increased the number of surviving Brn3A+ RGCs, suggesting LM22A-4 may be effective treatment for AION.

Keywords: 613 neuro-ophthalmology: optic nerve • 552 imaging methods (CT, FA, ICG, MRI, OCT, RTA, SLO, ultrasound) • 616 neurotransmitters/neurotransmitter systems  
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