Enhancement of oral bioavailability and anti-Parkinsonian efficacy of resveratrol through a nanocrystal formulation

Sha Xiong; Wei Liu; Yile Zhou; Yousheng Mo; Yao Liu; Xiaojia Chen; Huafeng Pan; Dongsheng Yuan; Qi Wang; Tongkai Chen

doi:10.1016/j.ajps.2019.04.003

Enhancement of oral bioavailability and anti-Parkinsonian efficacy of resveratrol through a nanocrystal formulation

Asian J Pharm Sci. 2020 Jul;15(4):518-528. doi: 10.1016/j.ajps.2019.04.003. Epub 2019 May 24.

Authors

Sha Xiong¹, Wei Liu¹, Yile Zhou¹, Yousheng Mo¹, Yao Liu¹, Xiaojia Chen², Huafeng Pan¹, Dongsheng Yuan¹, Qi Wang¹, Tongkai Chen¹

Affiliations

¹ Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
² Institute of Chinese Medical Sciences, University of Macau, Macau, China.

Abstract

Resveratrol (RES), a non-flavonoid polyphenol extracted from a wide variety of plants, exhibits neuroprotective activities against Parkinson's disease (PD). However, undesirable water solubility of RES reduces its oral bioavailability and demonstrates low efficacy in blood and brain, thus limiting its application. In present study, a nanocrystal formulation of RES (RES-NCs) was developed to enhance its oral bioavailability and delivery into brain for PD treatment. RES-NCs were fabricated with hydroxypropyl methylcellulose (HPMC) stabilizer via antisolvent precipitation approach. The obtained RES-NCs displayed the particle size of 222.54 ± 1.66 nm, the PDI of 0.125 ± 0.035, the zeta potential of -9.41 ± 0.37 mV, and a rapid in vitro dissolution rate. Molecular dynamics simulation of RES and HPMC revealed an interaction energy of -68.09 kJ/mol and a binding energy of -30.98 ± 0.388 kJ/mol, indicating that the spontaneous binding between the two molecules is through van der Waals forces. RES-NCs conferred enhanced cellular uptake as well as improved permeability relative to pure RES. In addition, RES-NCs were able to protect neurons against cytotoxicity induced by MPP⁺. Meanwhile, RES-NCs exerted no significant toxic effects on zebrafish embryos and larvae, and did not influence their survival and hatching rates. When orally administered to rats, RES-NCs exhibited more favorable pharmacokinetics than pure RES, with higher plasma and brain concentrations. More importantly, MPTP-induced PD mice showed notable improvements in behavior, attenuated dopamine deficiency, and elevated levels of dopamine and its metabolites after the treatment with RES-NCs. Furthermore, immunoblot analysis revealed that the neuroprotective role of RES-NCs may be at least partially mediated by Akt/Gsk3β signaling pathway. Taken altogether, RES-NCs can serve as a potential treatment modality for PD, offering means of improving RES oral bioavailability and brain accumulation.

Keywords: Anti-Parkinsonian efficacy; Brain permeability; Nanocrystals; Oral absorption; Resveratrol.