Resveratrol nanoparticles are neuroprotective in a model of Alzheimer's disease

Abstract

AbstractPurpose: Alzheimer's disease (AD) is the major cause of dementia in the world with increasing evidences of the retina being affected. Since no cure exists, there is an urgent unmet need to find new treatments. Resveratrol, a natural polyphenol found in red wine, has been advocated as a potential neuroprotectant in this disease. However, resveratrol has a low solubility and bioavailability limiting its clinical translation. In this study, we assessed a novel formulation of resveratrol in vitro and in vivo in a triple transgenic Alzheimer's disease (3xTg‐AD) mouse model.Methods: Resveratrol nanoparticles (RNs) were formulated using a thin rehydration technique. They were assessed in vitro on R28 cells against glutamate excitotoxicity and cobalt chloride induced hypoxia. Next, 3xTg‐AD mice received intranasally either RNs (n = 7) or an equivalent vehicle (n = 6) 5 days a week for 3 months. After 3 months of treatment, animals were imaged using Detection of Apoptosing Retinal Cells (DARC). DARC count was defined as the number of fluorescent spots counted by a masked investigator. After sacrifice, their brains were harvested and immunostained for amyloid‐beta (Aβ) and phosphorylated tau (pTau). Retinas were immunostained with Brn3a, a retinal ganglion cell (RGC) marker.Results: RN formulation incorporating over 10 mg/ml resveratrol was stable over 90 days. RNs were able to protect R28 cells exposed to glutamate compared to the vehicle (IC50 25.1 ± 0.4 vs. 14.4 ± 1.0 mM, p < 0.0001) but did not show any neuroprotection against cobalt chloride compared to the vehicle (260.3 ± 16.5 vs. 200.7 ± 2 2.3 μM, p > 0.05). In vivo, DARC count was reduced with RN treatment compared to the vehicle (7.7 ± 2.1 vs. 49.1 ± 13.3, p < 0.01). However, these results did not correlate with a higher RGC density compared to the vehicle (1205 ± 203 vs. 1015 ± 100 cells/mm2, p > 0.05). Interestingly, Aβ and pTau depositions in the brain were reduced compared to the vehicle (3.6 ± 0.2 vs. 4.5 ± 0.2 Aβ score, p < 0.01 and 2.1 ± 0.5 vs. 6.6 ± 1.9 pTau score, p < 0.05). No adverse effects were seen in vivo either systemically or in the eye.Conclusions: These promising results show that RN is non‐toxic and neuroprotective in vitro and in vivo when administered intranasally. However, DARC imaging failed to show a correlation with RGC density. Further studies are needed to confirm these results.