Treatment with spermine oxidase inhibitor ameliorates retinal neuronal and optic nerve degeneration in a mouse model of Multiple Sclerosis

Abstract

Purpose : Visual impairment due to optic neuritis (ON) is a major feature of multiple sclerosis (MS) and can lead to temporary or permanent vision loss. ON is characterized by retinal ganglion cell (RGC) loss, optic nerve degeneration, and inflammation of the retina and optic nerve. The current study was undertaken to investigate the role of spermine oxidase (SMOX, an inducible enzyme in polyamine oxidation pathway) in MS-induced retinal neuronal damage and the optic nerve degeneration.

Methods : These studies used the experimental autoimmune encephalomyelitis (EAE) model of MS. Chronic EAE was induced in female mice (10-12 weeks old, C57Bl6J). The SMOX inhibitor MDL 72527 was administered intraperitoneally (immediately following EAE induction) at a dose of 20 mg/kg in saline, three times a week. Studies were performed to analyze EAE-induced motor deficits, neuronal cell loss, optic nerve degeneration, loss of synapses, demyelination, activation of microglia/macrophages, and accumulation of protein-conjugated acrolein as a marker of SMOX-mediated damage.

Results : Clinical signs of paralysis were evident at 9 days post-induction in the EAE mice and worsened over time. Treatment with MDL 72527 delayed the onset of the clinical signs of EAE and significantly lowered the motor deficits. Retinas of EAE mice had significant increases in SMOX as compared with the non-EAE controls (p<0.01, N=6). Quantification of RGCs (studied by Brn3a and NeuN positive cells in the GCL) showed a 50% decrease in EAE retinas as compared to controls. However, MDL 72527 treatment significantly improved RGC survival (p<0.05, N= 6). EAE also induced decreases in synaptophysin (presynaptic marker) and Tuj1 (axonal marker) levels in the retina, and both were improved by MDL 72527 treatment. Immunostaining using F4/80 and Iba1 showed increases in microglial/macrophage activation in the retina and optic nerve of EAE mice, this was reduced by MDL 72527 treatment. Analysis using FlouroMyelin indicated that EAE-induced demyelination of optic nerve was significantly prevented in response to MDL 72527 (p<0.01; N=5). Our studies further showed an upregulation in protein conjugated acrolein in the EAE retina, which was suppressed in response to MDL 72527 treatment.

Conclusions : Our results suggest that the SMOX blockade offers a potential treatment strategy for reducing vision loss in MS patients.

This is a 2020 ARVO Annual Meeting abstract.