Targeting Cholesterol Homeostasis Improves Recovery in Experimental Optic Neuritis.
Cheyanne R GodwinJeffrey J AndersLin ChengBenjamin W ElwoodRandy H KardonOliver W GramlichPublished in: Biomolecules (2022)
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<sup>+</sup>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.
Keyphrases
- pet ct
- optic nerve
- multiple sclerosis
- optical coherence tomography
- newly diagnosed
- low density lipoprotein
- single cell
- end stage renal disease
- chronic kidney disease
- high fat diet induced
- drug induced
- ejection fraction
- white matter
- physical activity
- diabetic retinopathy
- endothelial cells
- cell proliferation
- cancer therapy
- binding protein
- cell cycle arrest
- pi k akt
- extracorporeal membrane oxygenation
- mesenchymal stem cells
- metabolic syndrome
- wild type
- signaling pathway
- replacement therapy
- aortic dissection
- acute respiratory distress syndrome