Intranasal delivery of resveratrol nanoparticles reduces retinal ganglion cell loss in a model of multiple sclerosis

Abstract

Purpose : Multiple sclerosis (MS) is a neurodegenerative inflammatory demyelinating disease of the central nervous system with optic neuritis being its most common clinical manifestation. To date, treatments of this condition only reduce inflammation without showing any neuroprotection. Resveratrol is a natural polyphenol with a low solubility in water but with neuroprotective effects which could protect from retinal ganglion cell (RGC) loss in MS. Therefore, a novel resveratrol nanoparticle formulation was developed and assessed in experimental autoimmune encephalomyelitis (EAE), a well-established model for multiple sclerosis and optic neuritis.

Methods : Resveratrol nanoparticles (RNs) were formulated using a thin rehydration technique. C57/BL6 mice were immunized with the myelin oligodendroglial glycoprotein peptide. RNs, equivalent empty nanoparticles (vehicle) or unconjugated resveratrol (unRSV) were administered intranasally in mice from EAE induction for 30 days at the following dosages: 1.27 mg/kg RNs (n=6), 8.44 mg/kg RNs (n=6), 8.44 mg/kg vehicle (n=6) or 8.44 mg/kg unRSV (n=5). EAE mice were scored daily for disease severity and weekly for visual function with the optokinetic response (OKR). At day 30, retinas were immunostained for Brn3a. Inflammation in optic nerves and spinal cords was assessed by hematoxylin and eosin.

Results : RNs containing >10 mg/ml resveratrol were stable over 3 months with an encapsulation efficiency > 70%. Intranasal (IN) administration of RNs did not show any modification of the EAE and OKR scores compared to vehicle. RNs were neuroprotective in EAE mice by reducing RGC loss in a dose-dependent manner. 8.44 mg/kg and 1.27 mg/kg RNs had a higher RGC count than 8.44 mg/kg vehicle (297±8 and 256±12 vs 190±10 cells/standardized field, p<0.0001). Importantly, 8.44 mg/kg unRSV was also neuroprotective compared to 8.44 mg/kg vehicle (256±10 vs 190±10 cells/standardized field, p<0.0001). Inflammation reduction in optic nerves and spinal cords was not significant compared to vehicle.

Conclusions : IN administration of RNs reduces RGC loss in a MS mouse model without reducing inflammation in the optic nerve and spinal cord. Importantly, despite resveratrol’s low solubility in water, IN administration of unRSV is also able to reduce RGC loss suggesting that a specific formulation is not needed via this administration route bypassing liver metabolism.

This is a 2020 ARVO Annual Meeting abstract.