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Reas Sulaimankutty, Kimberly Dine, Esteban Luna, Clarence Ahlem, Kenneth S Shindler; HE3286 Reduces Axonal Loss and Preserves Retinal Ganglion Cell Function in Experimental Optic Neuritis. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5771.
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© ARVO (1962-2015); The Authors (2016-present)
Optic nerve inflammation, demyelination and axonal loss are all prominent features of optic neuritis. While corticosteroids can hasten visual recovery in optic neuritis, no treatment is available to improve visual outcomes. HE3286 (17α-ethynyl-5-androstene-3β, 7β, 17β-triol), a synthetic derivative of a natural steroid, β-AET (5-androstene-3β, 7β, 17β-triol), exerts anti-inflammatory effects in several disease models, and has purported direct neuroprotective effects as well. The ability of HE3286 to suppress optic neuritis in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis was examined.
EAE was induced in C57/Bl6 mice by immunization with myelin oligodendroglial glycoprotein peptide. Mice were treated daily with vehicle or 40 mg/kg HE3286 i.p. Visual function was assessed by optokinetic responses (OKR) at baseline and every 10 days until sacrifice 6 weeks post-immunization. Retinas and optic nerves were isolated. Inflammation was assessed by H&E staining, demyelination was assessed by luxol fast blue staining and axonal loss was assessed by neurofilament staining of optic nerve sections. Retinal ganglion cells (RGCs) were immunolabeled with Brn3a antibodies to quantify RGC survival.
Progressive decreases in OKR occurred in vehicle-treated EAE mice, and HE3286 treatment significantly reduced the level of this vision loss. HE3286 also significantly attenuated the degree of inflammation, demyelination and axonal loss in EAE optic nerves as compared to nerves from vehicle-treated EAE mice. RGC loss was observed in eyes from both vehicle- and HE3286-treated EAE mice, with a trend toward increased RGC survival in the HE3286-treated mice.
HE3286 suppresses inflammation and reduces demyelination and axonal loss during experimental optic neuritis. Importantly, HE3286 treatment also preserves some RGC function. Results suggest HE3286 is a potential novel treatment for optic neuritis and MS that warrants further study.
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