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

• 作者: Dongsheng Yuan Huafeng Pan QiWang Sha Xiong Tongkai Chen Wei Liu Xiaojia Chen Yao Liu Yile Zhou Yousheng Mo
• 来源期刊: 亚洲药物制剂科学(英文)
• 学科: 医学
• 关键词: NANOCRYSTALS RESVERATROL Oral absorption Brain permeability Anti-Parkinsonian efficacy
• 年，卷（期）: 2020,（4）
• 页码范围: 518-528
• 页数: 11页
• 分类号: R28

摘要

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 lowefficacy 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±0.37mV,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-NCsmay be at least partially mediated by Akt/Gsk3βsignaling pathway.Taken altogether,RES-NCs can serve as a potential treatment modality for PD,offering means of improving RES oral bioavailability and brain accumulation.