Oral Delivery of a Synthetic Sterol Reduces Axonopathy and Inflammation in a Rodent Model of Glaucoma.

Wendi S Lambert,David J Calkins,Rebecca M Sappington,Cathryn R Formichella,Clarence Ahlem,Brian J Carlson

doi:10.3389/fnins.2017.00045

Wendi S Lambert, David J Calkins + Show 4 more

Open Access

https://doi.org/10.3389/fnins.2017.00045

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Abstract

Glaucoma is a group of optic neuropathies associated with aging and sensitivity to intraocular pressure (IOP). The disease is the leading cause of irreversible blindness worldwide. Early progression in glaucoma involves dysfunction of retinal ganglion cell (RGC) axons, which comprise the optic nerve. Deficits in anterograde transport along RGC axons to central visual structures precede outright degeneration, and preventing these deficits is efficacious at abating subsequent progression. HE3286 is a synthetic sterol derivative that has shown therapeutic promise in models of inflammatory disease and neurodegenerative disease. We examined the efficacy of HE3286 oral delivery in preventing loss of anterograde transport in an inducible model of glaucoma (microbead occlusion). Adult rats received HE3286 (20 or 100 mg/kg) or vehicle daily via oral gavage for 4 weeks. Microbead occlusion elevated IOP ~30% in all treatment groups, and elevation was not affected by HE3286 treatment. In the vehicle group, elevated IOP reduced anterograde axonal transport to the superior colliculus, the most distal site in the optic projection, by 43% (p = 0.003); HE3286 (100 mg/kg) prevented this reduction (p = 0.025). HE3286 increased brain-derived neurotrophic factor (BDNF) in the optic nerve head and retina, while decreasing inflammatory and pathogenic proteins associated with elevated IOP compared to vehicle treatment. Treatment with HE3286 also increased nuclear localization of the transcription factor NFκB in collicular and retinal neurons, but decreased NFκB in glial nuclei in the optic nerve head. Thus, HE3286 may have a neuroprotective influence in glaucoma, as well as other chronic neurodegenerations.

Highlights

Glaucoma is the leading cause of irreversible blindness worldwide (Quigley and Broman, 2006)
We found that while HE3286 had no effect on intraocular pressure (IOP), daily oral delivery for 4 weeks prevented deficits in anterograde transport to the superior colliculus (SC), the primary central projection for retinal ganglion cell (RGC) in rodents (Linden and Perry, 1983; Hofbauer and Drager, 1985)
Comparing percent change in weight over the course of treatment for each animal showed that HE3286 decreased weight in both the 20 mg/kg group (p < 0.001, compared to vehicle) and 100 mg/kg group (p < 0.001, compared to vehicle; p = 0.042 compared to 20 mg/kg)

Summary

Introduction

Glaucoma is the leading cause of irreversible blindness worldwide (Quigley and Broman, 2006). Treatment with HE3286 improves outcome measures in models of autoimmune disease, lung inflammation, experimental optic neuritis and Parkinson’s disease, and is currently being tested in clinical trials (Auci et al, 2007, 2010; Ahlem et al, 2009; Offner et al, 2009; Conrad et al, 2010; Lu et al, 2010; Kosiewicz et al, 2011; Nicoletti et al, 2012; Reading et al, 2013a,b; Khan et al, 2014). It is believed HE3286 may act via binding, regulation and/or activation of MAPK or ERK, or through modulation of NFκB (Lu et al, 2010; Ahlem et al, 2011; Nicoletti et al, 2012; Reading et al, 2012)

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