Targeting Cholesterol Homeostasis Improves Recovery in Experimental Optic Neuritis

Abstract

Acute optic neuritis (ON) is a common cause of vision loss and is often associated with multiple sclerosis (MS). Cholesterol recycling has been identified as a key limiting factor in recovery after demyelination events. Thus, the purpose of our study was to determine if the augmentation of cholesterol transport by gentisic acid (GA) benefits retinal ganglion cell (RGC) development and myelination in organoid systems and enables the recovery of the ocular phenotype upon systemic GA treatment in a MOG-induced experimental autoimmune encephalomyelitis (EAE) ON model. The retinal organoids treated with GA demonstrate an accelerated maturation when compared to the conventionally derived organoids, which was evidenced by the improved organization of Brn3a-GFP+RGC and increased synaptogenesis. A GA supplementation in brain organoids leads to a 10-fold increase in NG2 and Olig2 expression. Weekly GA injections of EAE mice significantly lessened motor-sensory impairment, protected amplitudes in pattern electroretinogram recordings, and preserved visual acuity over the study period of 56 days. Furthermore, GA-treated EAE mice revealed diminished GCL/IPL complex thinning when compared to the untreated EAE mice. An optic nerve histopathology revealed less severe grades of demyelination in the GA-treated EAE cohort and fewer infiltrating cells were observed. Interventions to improve cholesterol homeostasis may be a viable approach to promoting the rehabilitation of MS patients.

Acriflavine, a HIF-1 inhibitor, preserves vision in an experimental autoimmune encephalomyelitis model of optic neuritis

“…Bilateral visual acuity was measured using the OptoDrum system (Striatech, Tübingen, Germany) as previously described ( 50 ). Awake mice were placed on a platform in a closed chamber with a virtual cylinder projecting stripes of varying spatial frequencies at 99.8% contrast.…”

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

“…Reduced cholesterol biosynthesis may underlie compromised remyelination of the ON because astrocytes provide cholesterol to oligodendrocytes for myelin synthesis and to neurons for building synapses and membranes. Fitting with this, enhancing cholesterol transport using gentisic acid ameliorated ON damage and spared vision and ocular structure in EAE mice [68] .…”

Correlation of visual system biomarkers with motor-sensory deficits in experimental autoimmune encephalomyelitis-optic neuritis

“…Eight-to twelve-week-old female C57BL/6J mice were obtained from Jackson Laboratories (Bar Harbor, ME) and housed in 12h light-dark cycle with ad libitum food and water. After a suitable period of adaptation to the facility, EAE-ON was induced as previously described [34,[43][44][45]. Brie y, 15 mice were injected subcutaneously with 200µg of MOG 35 − 55 (Sigma Aldrich, St Louis, MO, USA) emulsi ed with complete Freund's adjuvant (Sigma Aldrich) containing 2 mg/mL of Mycobacterium tuberculosis H37Ra (BD Difco, Franklin Lakes, NJ, USA) at each of two locations proximal to the shoulder blades.…”

“…OCT imaging was performed as previously described [34,43,45,50]. Mice were anesthetized using 2-4% iso urane (Baxter, Deer eld, IL, USA) supplied via a SomnoSuite system (Kent Scienti c, Torrington, CT, USA).…”

“…Optic nerve histopathology offers an excellent method for discovering structural alterations in the visual system of the EAE model. Speci cally, the ability to detect and quantify demyelination of the axon and immune cell in ltration using readily available lab techniques, such as Luxol fast blue (LFB) and hematoxylin and eosin (H&E) staining [34]. LFB directly stains the myelin sheath, and thus an observation of whitening of the optic nerve directly indicates demyelination [35].…”