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Planta Med 2018; 84(11): 820-828
DOI: 10.1055/s-0043-125337
Formulation and Delivery Systems of Natural Products
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

A Self-Microemulsifying Formulation of Oxyresveratrol Prevents Amyloid Beta Protein-Induced Neurodegeneration in Mice

Yaowaporn Sangsen
1   Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, Songkhla, Thailand
2   Phytomedicine and Pharmaceutical Biotechnology Excellence Research Center, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, Songkhla, Thailand
,
Thongchai Sooksawate
3   Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
,
Kittisak Likhitwitayawuid
4   Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
,
Boonchoo Sritularak
4   Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
,
Ruedeekorn Wiwattanapatapee
1   Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, Songkhla, Thailand
2   Phytomedicine and Pharmaceutical Biotechnology Excellence Research Center, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, Songkhla, Thailand
› Author Affiliations
Further Information

Publication History

received 01 October 2017
revised 29 November 2017

accepted 18 December 2017

Publication Date:
04 January 2018 (online)

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Abstract

The polyphenol compound, oxyresveratrol (OXY) possesses potent antioxidant and neuroprotective properties of potential utility in the treatment of Alzheimerʼs disease. However, the low oral bioavailability limits its neuroprotective effect and clinical application. The neuroprotective effect of orally administered OXY-loaded self-microemulsifying drug delivery system (OXY-SMEDDS) was compared with free OXY in vivo. Mice were orally administered either free OXY or OXY-SMEDDS once daily at a dose of 90, 180, or 360 mg/kg for 14 d. Mice received a single intracerebroventricular injection of the neurotoxic amyloid β (Aβ)25 – 35 peptide at day 8 during oral treatment. The OXY-SMEDDS formulation resulted in four-times reduction of the free OXY dose required for prevention of neurotoxicity effects due to Aβ 25 – 35 peptide as demonstrated by a significant decline in behavior impairments, lipid oxidation levels, and neuronal cell loss in all hippocampal subfields (p < 0.0001). These results indicate the potential of OXY-SMEDDS by oral delivery to improve the efficacy of this compound in the treatment of Alzheimerʼs disease.

Key words

Alzheimerʼs disease - neuroprotection - oxyresveratrol - oral delivery - self-microemulsifying drug delivery systems - bioavailability - Artocarpus lacucha - Moraceae
 

  • References

  • 1 Selkoe DJ. Translating cell biology into therapeutic advances in Alzheimerʼs disease. Nature 1999; 399: A23-A31
    CrossrefPubMedGoogle Scholar
  • 2 Pike CJ, Walencewicz-Wasserman AJ, Kosmoski J, Cribbs DH, Glabe CG, Cotman CW. Structure-activity analyses of β‐amyloid peptides: contributions of the β25–35 region to aggregation and neurotoxicity. J Neurochem 1995; 64: 253-265
    PubMedGoogle Scholar
  • 3 Watson D, Castaño E, Kokjohn TA, Kuo YM, Lyubchenko Y, Pinsky D, Connolly jr. ES, Esh C, Luehrs DC, Stine WB, Rowse LM, Emmerling MR, Roher AE. Physicochemical characteristics of soluble oligomeric Aβ and their pathologic role in Alzheimerʼs disease. Neurol Res 2005; 27: 869-881
    CrossrefPubMedGoogle Scholar
  • 4 Frozza RL, Bernardi A, Hoppe JB, Meneghetti AB, Matté A, Battastini AM, Pohlmann AR, Guterres SS, Salbego C. Neuroprotective effects of resveratrol against Aβ administration in rats are improved by lipid-core nanocapsules. Mol Neurobiol 2013; 47: 1066-1080
    CrossrefPubMedGoogle Scholar
  • 5 Alzheimerʼs Association. 2016 Alzheimerʼs Disease Facts and Figures. Alzheimerʼs & Dementia. Available at. https://www.alz.org/documents_custom/2016-facts-and-figures.pdf Accessed November 01, 2016
    PubMedGoogle Scholar
  • 6 Sasivimolphan P, Lipipun V, Ritthidej G, Chitphet K, Yoshida Y, Daikoku T, Sritularak B, Likhitwitayawuid K, Pramyothin P, Hattori M, Shiraki K. Microemulsion-based oxyresveratrol for topical treatment of herpes simplex virus (HSV) infection: physicochemical properties and efficacy in cutaneous HSV-1 infection in mice. AAPS PharmSciTech 2012; 13: 1266-1275
    CrossrefPubMedGoogle Scholar
  • 7 Kim YM, Yun J, Lee CK, Lee H, Min KR, Kim Y. Oxyresveratrol and hydroxystilbene compounds. J Biol Chem 2002; 277: 16340-16344
    CrossrefPubMedGoogle Scholar
  • 8 Joung DK, Mun SH, Choi SH, Kang OH, Kim SB, Lee YS, Zhou T, Kong R, Choi JG, Shin DW, Kim YC, Lee DS, Kwon DY. Antibacterial activity of oxyresveratrol against methicillin-resistant Staphylococcus aureus and its mechanism. Exp Ther Med 2016; 12: 1579-1584
    CrossrefPubMedGoogle Scholar
  • 9 Chung KO, Kim BY, Lee MH, Kim YR, Chung HY, Park JH, Moon JO. In-vitro and in-vivo anti-inflammatory effect of oxyresveratrol from Morus alba L. J Pharm Pharmacol 2003; 55: 1695-1700
    CrossrefPubMedGoogle Scholar
  • 10 Andrabi SA, Spina MG, Lorenz P, Ebmeyer U, Wolf G, Horn TFW. Oxyresveratrol (trans-2,3′,4,5′-tetrahydroxystilbene) is neuroprotective and inhibits the apoptotic cell death in transient cerebral ischemia. Brain Res 2004; 1017: 98-107
    CrossrefPubMedGoogle Scholar
  • 11 Weber JT, Lamont M, Chibrikova L, Fekkes D, Vlug AS, Lorenz P, Kreutzmann P, Slemmer JE. Potential neuroprotective effects of oxyresveratrol against traumatic injury. Eur J Pharmacol 2012; 680: 55-62
    CrossrefPubMedGoogle Scholar
  • 12 Ban JY, Jeon SY, Nguyen T, Bae K, Song KS, Seong YH. Neuroprotective effect of oxyresveratrol from smilacischinae rhizome on amyloid beta protein (25–35)-induced neurotoxicity in cultured rat cortical neurons. Biol Pharm Bull 2006; 29: 2419-2424
    CrossrefPubMedGoogle Scholar
  • 13 Karuppagounder SS, Pinto JT, Xu H, Chen HL, Beal MF, Gibson GE. Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimerʼs disease. Neurochem Int 2009; 54: 111-118
    CrossrefPubMedGoogle Scholar
  • 14 Mei M, Ruan JQ, Wu WJ, Zhou RN, Lei JPC, Zhao HY. In vitro pharmacokinetic characterization of Mulberroside A, the main polyhydroxylated stilbene in mulberry (Morus alba L.), and its bacterial metabolite oxyresveratrol in traditional oral use. J Agric Food Chem 2012; 60: 2299-2308
    CrossrefPubMedGoogle Scholar
  • 15 Hu N, Mei M, Ruan J, Wu W, Wang Y, Yan R. Regioselective glucuronidation of oxyresveratrol, a natural hydroxystilbene, by human liver and intestinal microsomes and recombinant UGTs. Drug Metab Pharmacokinet 2014; 29: 229-236
    CrossrefPubMedGoogle Scholar
  • 16 Huang H, Zhang J, Chen G, Lu Z, Wang X, Sha N, Shao B, Li P, Guo DA. High performance liquid chromatographic method for the determination and pharmacokinetic studies of oxyresveratrol and resveratrol in rat plasma after oral administration of Smilax china extract. Biomed Chromatogr 2008; 22: 421-427
    CrossrefPubMedGoogle Scholar
  • 17 Huang H, Chena G, Lua Z, Zhang J, Guoa DA. Identification of seven metabolites of oxyresveratrol in rat urine and bile using liquid, chromatography/tandem mass spectrometry. Biomed Chromatogr 2010; 24: 426-432
    PubMedGoogle Scholar
  • 18 Pardridge WM. The blood-brain barrier: bottleneck in brain drug development. NeuroRx 2005; 2: 3-14
    CrossrefPubMedGoogle Scholar
  • 19 Masserini M. Nanoparticles for brain drug delivery. ISRN Biochem 2013; 2013: 1-18
    PubMedGoogle Scholar
  • 20 Lalatsa A, Garrett NL, Ferrarelli T, Moger J, Schätlein AG, Uchegbu IF. Delivery of peptides to the blood and brain after oral uptake of quaternary ammonium palmitoyl glycol chitosan nanoparticles. Mol Pharmaceutics 2012; 9: 1764-1774
    CrossrefPubMedGoogle Scholar
  • 21 Gursoy RN, Benita S. Self-emulsifying drug delivery systems (SEDDS) for improved oral bioavailability of lipophilic drugs. Biomed Pharmacother 2004; 58: 173-182
    CrossrefPubMedGoogle Scholar
  • 22 Sangsen Y, Wiwattanawongsa K, Likhitwitayawuid K, Sritularak B, Graidist P, Wiwattanapatapee R. Influence of surfactants in self-microemulsifying formulations on enhancing oral bioavailability of oxyresveratrol: studies in Caco-2 cells and in vivo . Int J Pharm 2016; 498: 294-303
    CrossrefPubMedGoogle Scholar
  • 23 Janga KY, Jukanti R, Bandari S, Kandadi P, Veerareddy PR. Pharmacokinetics and Brain Distribution Studies of Zaleplon loaded solid self-emulsifying Drug Delivery Systems. Washington DC: American Association of Pharmaceutical Scientists; 2011
    Google Scholar
  • 24 Lin Y, Shen Q, Katsumi H, Okada N, Fujita T, Jiang X, Yamamoto A. Effects of labrasol and other pharmaceutical excipients on the intestinal transport and absorption of rhodamine123, a P-glycoprotein substrate, in rats. Biol Pharm Bull 2007; 30: 1301-1307
    CrossrefPubMedGoogle Scholar
  • 25 Kogan A, Kesselman E, Danino D, Aserin A, Garti N. Viability and permeability across Caco-2 cells of CBZ solubilized in fully dilutable microemulsions. Colloids Surf B 2008; 66: 1-12
    CrossrefPubMedGoogle Scholar
  • 26 Ujhelyi Z, Fenyvesi F, Váradi J, Fehér P, Kiss T, Veszelka S, Deli M, Vecsernyés M, Bácskay I. Evaluation of cytotoxicity of surfactants used in self-micro emulsifying drug delivery systems and their effects on paracellular transport in Caco-2 cell monolayer. Eur J Pharm Sci 2012; 47: 564-573
    CrossrefPubMedGoogle Scholar
  • 27 Seeballuck F, Lawless E, Ashford MB, OʼDriscoll CM. Stimulation of triglyceride-rich lipoprotein secretion by polysorbate 80: in vitro and in vivo correlation using Caco-2 cells and a cannulated rat intestinal lymphatic model. Pharm Res 2004; 21: 2320-2326
    CrossrefPubMedGoogle Scholar
  • 28 Zussy C, Brureau A, Delair B, Marchal S, Keller E, Ixart G, Naert G, Meunier J, Chevallier N, Maurice T, Givalois L. Time-course and regional analyses of the physiopathological changes induced after cerebral injection of an amyloid β fragment in rats. Am J Pathol 2011; 179: 315-334
    CrossrefPubMedGoogle Scholar
  • 29 Breuer C, Wolf G, Andrabi SA, Lorenz P, Horn TFW. Blood-brain barrier permeability to the neuroprotectant oxyresveratrol. Neurosci Lett 2006; 393: 113-118
    CrossrefPubMedGoogle Scholar
  • 30 Laursen SE, Belknap J. Intracerebroventricular injections in mice: some methodological refinements. J Pharmacol Methods 1986; 16: 355-357
    CrossrefPubMedGoogle Scholar
  • 31 Franklin KBJ, Paxinos G. The Mouse Brain in stereotaxic Coordinates. 3rd ed.. ed. New York: Academic Press; 2008
    Google Scholar
  • 32 Maurice T, Lockhart BP, Privat A. Amnesia induced in mice by centrally administered β-amyloid peptides involves cholinergic dysfunction. Brain Res 1996; 706: 181-193
    CrossrefPubMedGoogle Scholar
  • 33 Delobette S, Privat A, Maurice T. In vitro aggregation facilitates β-amyloid peptide-(25–35)-induced amnesia in the rat. Eur J Pharmacol 1997; 319: 1-4
    CrossrefPubMedGoogle Scholar
  • 34 Hermes-Lima M, Willmore WG, Storey KB. Quantification of lipid peroxidation in tissue extracts based on Fe (III) xylenol orange complex formation. Free Radic Biol Med 1995; 19: 271-280
    CrossrefPubMedGoogle Scholar
  • 35 Meunier J, Ieni J, Maurice T. The anti‐amnesic and neuroprotective effects of donepezil against amyloid β 25–35 peptide-induced toxicity in mice involve an interaction with the σ1 receptor. Br J Pharmacol 2006; 149: 998-1012
    CrossrefPubMedGoogle Scholar
  • 36 Wanakhachornkrai O. Effects of N-(2-propylpentanoyl) Urea on Impairment of learning Memory and neuronal Cell Death after bilateral common carotic Arteries Occlusion in Mice [Masterʼs Degree Thesis]. Bangkok: Chulalongkorn University; 2006
    PubMedGoogle Scholar