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Enhancement of oral bioavailability and anti-Parkinsonian efficacy of resveratrol through a nanocrystal formulation
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 limit...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Shenyang Pharmaceutical University
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486547/ https://www.ncbi.nlm.nih.gov/pubmed/32952674 http://dx.doi.org/10.1016/j.ajps.2019.04.003 |
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author | Xiong, Sha Liu, Wei Zhou, Yile Mo, Yousheng Liu, Yao Chen, Xiaojia Pan, Huafeng Yuan, Dongsheng Wang, Qi Chen, Tongkai |
author_facet | Xiong, Sha Liu, Wei Zhou, Yile Mo, Yousheng Liu, Yao Chen, Xiaojia Pan, Huafeng Yuan, Dongsheng Wang, Qi Chen, Tongkai |
author_sort | Xiong, Sha |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7486547 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Shenyang Pharmaceutical University |
record_format | MEDLINE/PubMed |
spelling | pubmed-74865472020-09-18 Enhancement of oral bioavailability and anti-Parkinsonian efficacy of resveratrol through a nanocrystal formulation Xiong, Sha Liu, Wei Zhou, Yile Mo, Yousheng Liu, Yao Chen, Xiaojia Pan, Huafeng Yuan, Dongsheng Wang, Qi Chen, Tongkai Asian J Pharm Sci Original Research Paper 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. Shenyang Pharmaceutical University 2020-07 2019-05-24 /pmc/articles/PMC7486547/ /pubmed/32952674 http://dx.doi.org/10.1016/j.ajps.2019.04.003 Text en © 2019 Shenyang Pharmaceutical University. Published by Elsevier B.V. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Research Paper Xiong, Sha Liu, Wei Zhou, Yile Mo, Yousheng Liu, Yao Chen, Xiaojia Pan, Huafeng Yuan, Dongsheng Wang, Qi Chen, Tongkai Enhancement of oral bioavailability and anti-Parkinsonian efficacy of resveratrol through a nanocrystal formulation |
title | Enhancement of oral bioavailability and anti-Parkinsonian efficacy of resveratrol through a nanocrystal formulation |
title_full | Enhancement of oral bioavailability and anti-Parkinsonian efficacy of resveratrol through a nanocrystal formulation |
title_fullStr | Enhancement of oral bioavailability and anti-Parkinsonian efficacy of resveratrol through a nanocrystal formulation |
title_full_unstemmed | Enhancement of oral bioavailability and anti-Parkinsonian efficacy of resveratrol through a nanocrystal formulation |
title_short | Enhancement of oral bioavailability and anti-Parkinsonian efficacy of resveratrol through a nanocrystal formulation |
title_sort | enhancement of oral bioavailability and anti-parkinsonian efficacy of resveratrol through a nanocrystal formulation |
topic | Original Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486547/ https://www.ncbi.nlm.nih.gov/pubmed/32952674 http://dx.doi.org/10.1016/j.ajps.2019.04.003 |
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