Treatment with MDL 72527 Ameliorated Clinical Symptoms, Retinal Ganglion Cell Loss, Optic Nerve Inflammation, and Improved Visual Acuity in an Experimental Model of Multiple Sclerosis

Abstract

: Multiple Sclerosis (MS) is a highly disabling neurological disease characterized by inflammation, neuronal damage, and demyelination. Vision impairment is one of the major clinical features of MS. Previous studies from our lab have shown that MDL 72527, a pharmacological inhibitor of spermine oxidase (SMOX), is protective against neurodegeneration and inflammation in the models of diabetic retinopathy and excitotoxicity. In the present study, utilizing the experimental autoimmune encephalomyelitis (EAE) model of MS, we determined the impact of SMOX blockade on retinal neurodegeneration and optic nerve inflammation. The increased expression of SMOX observed in EAE retinas was associated with a significant loss of retinal ganglion cells, degeneration of synaptic contacts, and reduced visual acuity. MDL 72527-treated mice exhibited markedly reduced motor deficits, improved neuronal survival, the preservation of synapses, and improved visual acuity compared to the vehicle-treated group. The EAE-induced increase in macrophage/microglia was markedly reduced by SMOX inhibition. Upregulated acrolein conjugates in the EAE retina were decreased through MDL 72527 treatment. Mechanistically, the EAE-induced ERK-STAT3 signaling was blunted by SMOX inhibition. In conclusion, our studies demonstrate the potential benefits of targeting SMOX to treat MS-mediated neuroinflammation and vision loss.

Triciribine attenuates pathological neovascularization and vascular permeability in a mouse model of proliferative retinopathy

“…For quantification, a minimum of three sections (20 μm apart) per animal were utilized for each antibody. As described in our earlier studies [ 42 , 44 ], images were acquired at 500 μm from the optic nerve head of the retinal sections using a confocal microscope, resulting in a minimum of 6 images per mouse per antibody. Quantification of F4/80 (EGF-like module containing mucin-like hormone receptor-like 1) and Iba-1 positive cells was performed on 20X images using the “point tool” functional module of the ImageJ program.…”

Overview of diet and autoimmune demyelinating optic neuritis: a narrative review

“…The involvement of these cell types in ON and retinal inflammation in EAE animals involves NF-кB [62] , the secretion of IL-6 [83,84] , TNF-α [85] , inducible nitric oxide synthase [85] , reactivation within the CNS of auto-reactive T cells, and suppression of tolerance-promoting Tregs (reviewed in [86] ). Suppression of macrophage/microglia activation on ONs by inhibition of spermine oxidase [87] or genetic ablation of arginase 2 [88] in EAE mice improved visual acuity and reduced macrophage infiltration of ONs. Further, nicotinamide adenine dinucleotide supplementation mitigated microglial and astrocyte numbers on ONs and preserved myelination [89] .…”