Abstract
Purpose :
Visual impairment due to optic neuritis is a major feature of multiple sclerosis (MS). By modulating the polyamine oxidation pathway with MDL72527, an inhibitor of spermine oxidase (SMOX), our prior research revealed a reduction in retinal ganglion cell loss, optic nerve inflammation and improved visual acuity in a mouse model of MS. The present study was undertaken to further elucidate the impact of SMOX inhibition on myelin loss and axonal pathology.
Methods :
We utilized Experimental Autoimmune Encephalomyelitis (EAE) model to induce chronic optic neuritis in female mice (10-12 weeks, C57Bl6J). The SMOX inhibitor MDL 72527 (MDL) was administered at a dose of 20 mg/kg/i.p three times a week in EAE (MDL-EAE) or healthy controls. Saline was used as vehicle in EAE (Veh-EAE) and controls. Motor deficits were evaluated daily and assigned clinical scores on a scale from 0 to 5 for 60 days. Optic nerve sections underwent comprehensive analysis using immunofluorescence and electron microscopy (EM) to evaluate demyelination and axonal loss. Post-imaging quantification and statistical analysis were done using NIH ImageJ and GraphPad Prism.
Results :
The onset of clinical signs were delayed in MDL-EAE group, and the mice showed reduced motor deficit severity compared to Veh-EAE (N=14, p<0.05). EM analysis revealed a significant increase in the axonal g-ratio (showing reduced myelin thickness) in Veh-EAE compared to healthy controls (N=5; p<0.01). However, g-ratio was improved in MDL-EAE (N=6, p<0.01) compared to Veh-EAE. Additionally, Veh-EAE exhibited a reduction in axon count compared to healthy controls (N=5-13; p<0.01), whereas the MDL-EAE showed significantly higher axon count (N=11, p<0.05). Immunostaining of optic nerve sections and quantification of fluorescence intensity revealed reduced expression of myelin basic protein (MBP) in Veh-EAE compared to controls (N=3; p<0.01). In contrast, the MDL-EAE demonstrated higher MBP expression than the Veh-EAE (N=3, P<0.05). Similarly, the marked reduction in the level of neurofilament light chain in Veh-EAE mice was prevented significantly in the MDL–EAE (N=3; p<0.01).
Conclusions :
Our findings provide evidence of a substantial reduction in myelin damage and resistance to axonal loss in EAE mice attributable to SMOX inhibition, emphasizing the potential of SMOX as a therapeutic target for optic neuritis in MS.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.