PMID- 30273053
OWN - NLM
STAT- MEDLINE
DCOM- 20191126
LR  - 20231212
IS  - 1460-2202 (Electronic)
IS  - 0271-3683 (Print)
IS  - 0271-3683 (Linking)
VI  - 43
IP  - 12
DP  - 2018 Dec
TI  - A Small Molecule TrkB Neurotrophin Receptor Partial Agonist as Possible Treatment 
      for Experimental Nonarteritic Anterior Ischemic Optic Neuropathy.
PG  - 1489-1499
LID - 10.1080/02713683.2018.1508726 [doi]
AB  - PURPOSE: 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. 
      METHODS: 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 Brn3A(+) RGC density three 
      weeks after ischemia. RESULTS: In 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 Brn3A(+) RGC density on morphometric analysis of whole 
      mount retinae (95% CI control: 2360-2629; AION-PBS: 1647-2008 cells/mm(2); 
      AION-LM22A-4: 1958-2216 cells/mm(2); P = 0.02). CONCLUSIONS: TrkB 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. ABBREVIATIONS: 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.
FAU - Ali Shariati, Mohammad
AU  - Ali Shariati M
AD  - a Departments of Ophthalmology , Stanford University School of Medicine , 
      Stanford , CA , USA.
FAU - Kumar, Varun
AU  - Kumar V
AUID- ORCID: 0000-0001-6867-494X
AD  - a Departments of Ophthalmology , Stanford University School of Medicine , 
      Stanford , CA , USA.
FAU - Yang, Tao
AU  - Yang T
AD  - b Neurobiology , Stanford University School of Medicine , Stanford , CA , USA.
FAU - Chakraborty, Chandrani
AU  - Chakraborty C
AD  - b Neurobiology , Stanford University School of Medicine , Stanford , CA , USA.
FAU - Barres, Ben Anthony
AU  - Barres BA
AD  - b Neurobiology , Stanford University School of Medicine , Stanford , CA , USA.
FAU - Longo, Frank Michael
AU  - Longo FM
AD  - b Neurobiology , Stanford University School of Medicine , Stanford , CA , USA.
FAU - Liao, Yaping Joyce
AU  - Liao YJ
AUID- ORCID: 0000-0001-7958-291X
AD  - a Departments of Ophthalmology , Stanford University School of Medicine , 
      Stanford , CA , USA.
AD  - b Neurobiology , Stanford University School of Medicine , Stanford , CA , USA.
LA  - eng
GR  - P30 EY026877/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20181001
PL  - England
TA  - Curr Eye Res
JT  - Current eye research
JID - 8104312
RN  - 0 (Benzamides)
RN  - 0 (Ligands)
RN  - 0 (N,N',N'-tris(2-hydroxyethyl)-1,3,5-benzenetricarboxamide)
RN  - EC 2.7.10.1 (Receptor, trkB)
SB  - IM
MH  - Animals
MH  - Benzamides/*pharmacology
MH  - Cell Survival
MH  - Cells, Cultured
MH  - Disease Models, Animal
MH  - Ligands
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Optic Disk/drug effects/*pathology
MH  - Optic Neuropathy, Ischemic/diagnosis/*drug therapy
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptor, trkB/*agonists
MH  - Retinal Ganglion Cells/drug effects/*pathology
MH  - Tomography, Optical Coherence/*methods
MH  - Treatment Outcome
PMC - PMC10710940
MID - NIHMS1514543
OTO - NOTNLM
OT  - AION
OT  - BDNF
OT  - OCT
OT  - TrkB
OT  - optic neuropathy
OT  - pharmacophore
OT  - retinal ganglion cell
COIS- Conflict of Interest: Authors declare no conflict of interest.
EDAT- 2018/10/03 06:00
MHDA- 2019/11/27 06:00
PMCR- 2023/12/11
CRDT- 2018/10/02 06:00
PHST- 2018/10/03 06:00 [pubmed]
PHST- 2019/11/27 06:00 [medline]
PHST- 2018/10/02 06:00 [entrez]
PHST- 2023/12/11 00:00 [pmc-release]
AID - 10.1080/02713683.2018.1508726 [doi]
PST - ppublish
SO  - Curr Eye Res. 2018 Dec;43(12):1489-1499. doi: 10.1080/02713683.2018.1508726. Epub 
      2018 Oct 1.