HE3286 reduces axonal loss and preserves retinal ganglion cell function in experimental optic neuritis.

PURPOSE

Optic nerve inflammation, demyelination, and axonal loss are all prominent features of optic neuritis. While corticosteroids hasten visual recovery in optic neuritis, no treatment improves final 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 neuroprotective effects as well. HE3286's ability to suppress optic neuritis was examined in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis.

METHODS

Experimental autoimmune encephalomyelitis was induced in C57/BL6 mice. Mice were treated daily with intraperitoneal vehicle or 40 mg/kg HE3286. Visual function was assessed by optokinetic responses (OKR) at baseline and every 10 days until euthanasia at 40 days post immunization. Retinas and optic nerves were isolated. Inflammation (hematoxylin and eosin and Iba1 staining), demyelination (Luxol fast blue staining), and axonal loss (neurofilament staining) were assessed in optic nerve sections. Retinal ganglion cells (RGCs) were immunolabeled with Brn3a antibodies to quantify RGC survival.

RESULTS

Progressive decreases in OKR occurred in vehicle-treated EAE mice, and HE3286 treatment reduced the level of this vision loss. HE3286 also attenuated the degree of inflammation, demyelination, and axonal loss in EAE optic nerves as compared to nerves from vehicle-treated EAE mice. Retinal ganglion cell loss that occurred in both vehicle- and HE3286-treated EAE mice was reduced in the temporal retinal quadrant of HE3286-treated mice.

CONCLUSIONS

HE3286 suppresses inflammation, reduces demyelination and axonal loss, and promotes RGC survival during experimental optic neuritis. Importantly, HE3286 treatment also preserves some RGC function. Results suggest that HE3286 is a potential novel treatment for optic neuritis.