Abstract
Purpose:
Anterior ischemic optic neuropathy (AION) is the most common acute optic neuropathy in older adults, and there is currently no effective treatment. Retrogradely transported neurotrophins like BDNF (brain-derived neurotrophic factor) and its high affinity receptor TrkB are particularly important in the survival of retinal ganglion cells (RGCs) following injury, 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 small molecule pharmacophore that specifically activates the TrkB receptor with nanomolar affinity, on RGC survival and as treatment of experimental AION.
Methods:
We cultured rodent neonatal RGCs using immunopanning. On culture day-2, we calculated RGC survival and assessed TrkB receptor activation by morphometric analysis of MAP kinase translocation. To test in vivo effects, we performed one intravitreal and 3-week daily systemic treatment immediately following murine AION and measured retinal thickness with spectral-domain optical coherence tomography (SD-OCT).
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 effect 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. In vivo treatment for 3-weeks after AION lead to significant preservation of retinal thickness in SD-OCT circular analysis (12 deg) of the ganglion cell complex (N = 15 eyes/condition, P = 0.01) and posterior pole analysis of the optic disc (N = 8-10 eyes/condition, P = 0.02). This in vivo improvement was partial, similar to that of BDNF or antibodies that activate TrkB receptor in other experimental optic neuropathies.
Conclusions:
Pharmacophore LM22A-4 promoted TrkB receptor activation and RGC survival in vitro similar to endogenous ligand BDNF. Treatment for 3-weeks in vivo following murine AION led to partial rescue of retinal thinning on SD-OCT, suggesting LM22A-4 may be effective treatment for AION.
Keywords: 613 neuro-ophthalmology: optic nerve •
615 neuroprotection •
552 imaging methods (CT, FA, ICG, MRI, OCT, RTA, SLO, ultrasound)