A comparative study of oral and intranasal resveratrol nanoparticle administration in a model of multiple sclerosis

Abstract

Purpose : Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system. Immunomodulatory treatments seek to reduce inflammation in MS but have limited effect on neurodegeneration. Resveratrol is a natural polyphenol with antioxidant and anti-inflammatory properties which could be neuroprotective in MS. The purpose of this study is to compare the oral and intranasal administration of resveratrol nanoparticles (RN) in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS with ocular and neurological endpoints.

Methods : RN were formulated using a thin rehydration technique. In the 1^st experiment, 16.9 mg/kg RN (n=6) or equivalent vehicle (n=5) were given orally to EAE mice daily for 30 days. In the 2^nd experiment, 8.44 mg/kg RN (n=6) or vehicle (n=6) were given intranasally to EAE mice daily for 30 days. EAE mice were assessed daily for clinical signs of ascending paralysis and weekly for visual function (optokinetic response). After sacrifice at day 30, retinas were immunostained for brn3a to count retinal ganglion cells (RGC), and spinal cords and optic nerves were stained by H&E and luxol fast blue to assess inflammation and demyelination.

Results : 16.9 mg/kg oral RN treatment reduced RGC loss compared to vehicle (4164±406 vs 2422±401 RGC/1.56 mm², p<0.05). Similarly, 8.44 mg/kg RN given intranasally reduced RGC loss compared to vehicle (3569±241 vs 2280±329 RGC/1.56 mm², p<0.05). Oral and intranasal RN showed similar neuroprotective effects (4164±406 vs 3569±241 RGC/1.56 mm², p>0.05). Although neither route of administration showed a reduction of ascending paralysis compared to vehicle, 16.9 mg/kg RN oral administration reduced the severity of paralysis compared to vehicle and 8.44 mg/kg intranasal RN (survival analysis with median survival 29.5 vs 19.0 and 19.0 days, p<0.05). Likewise, the severity of visual function loss was reduced by the administration of oral 16.9 mg/kg RN compared to vehicle and 8.44 mg/kg intranasal RN (median survival >28.0 vs 28.0 and 21.0 days, p<0.05). Neither oral nor intranasal administration showed a significant reduction of spinal cord or optic nerve inflammation or demyelination compared to vehicle.

Conclusions : RN were able to reduce RGC loss independent of their administration route, but oral administration demonstrated additional neuroprotective effects by reducing paralysis severity.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.