Are plant N-alkylamide cosmenutriceuticals also active in the central nervous system? Lieselotte Veryser, Evelien Wynendaele, Lien Taevernier, Frederick.

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Are plant N-alkylamide cosmenutriceuticals also active in the central nervous system? Lieselotte Veryser, Evelien Wynendaele, Lien Taevernier, Frederick Verbeke, Tanmayee Joshi, Pratima Tatke and Bart De Spiegeleer* DruQuaR laboratory, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium. *Bart.despiegeleer@ugent.be 11 May 2014 O/Ref. 2014-177c

N-alkylamides E.g. analgesic, antimicrobial, insecticidal, sensory, INTRODUCTION OBJECTIVE METHODS RESULTS CONCLUSIONS N-alkylamides Plant secundary metabolites Occurance > 25 plant families Wide structural diversity: central peptide bond Functionalities E.g. analgesic, antimicrobial, insecticidal, sensory, anti-inflammatory, immune-modulating … Traditional use Potential lead compounds for functional food, cosmetics and medicines

Alkamid®: online N-alkylamide database http://alkamid.ugent.be/ INTRODUCTION OBJECTIVE METHODS RESULTS CONCLUSIONS Alkamid®: online N-alkylamide database Name Botanical occurance Chemistry Physico-chemical properties Functionality Traditional use

spilanthol pellitorine INTRODUCTION OBJECTIVE METHODS RESULTS CONCLUSIONS Spilanthes Acmella Anacyclus Pyrethrum spilanthol deca-2E,6Z,8E-trienoic acid isobutylamide (a triene NAA) pellitorine deca-2E,4E-dienoic acid isobutylamide (a diene NAA)

INTRODUCTION OBJECTIVE METHODS RESULTS CONCLUSIONS

Gut (Caco-2 cell monolayer) Blood-brain barrier (BBB) INTRODUCTION OBJECTIVE METHODS RESULTS CONCLUSIONS To investigate the permeability of spilanthol and pellitorine through several biological barriers: Skin Oral mucosa Gut (Caco-2 cell monolayer) Blood-brain barrier (BBB) NAA NAA Gravensteen, Ghent, Belgium

In vitro skin permeability study: Franz Diffusion cell INTRODUCTION OBJECTIVE METHODS RESULTS CONCLUSIONS In vitro skin permeability study: Franz Diffusion cell Dermatomed human skin (± 400 µm thick) (32°C) or pig oral mucosa Dose formulation containing pellitorine and spilanthol Sampling at regular time intervals Quantification using validated high-throughput HPLC-UV Ref figure: http://www.permegear.com/franz.htm

In vitro gut permeation study in Caco-2 monolayers INTRODUCTION OBJECTIVE METHODS RESULTS CONCLUSIONS In vitro gut permeation study in Caco-2 monolayers Caco-2 cell intestinal model Caco-2 cells grown to a monolayer on 0.4 µm polycarbonate membrane Transport: apical-to-basolateral + basolateral-to-apical Final sample volumes of 0.4 ml apically and 1.2 ml basolaterally for 12-mm filter supports Sampling at 15, 30, 60, 90 and 120 min from the acceptor solution Ref figure http://www.admedata.com/caco-2/

MTR: INFLUX (blood to brain) EFFLUX (brain to blood) INTRODUCTION OBJECTIVE METHODS RESULTS CONCLUSIONS INFLUX (blood to brain) MTR: IV injection isolation of serum and brain at specified time points EFFLUX (brain to blood) intraventricular injection isolation of serum and brain at specified time points Analytics by UPLC-MS In vivo blood-brain barrier (BBB) experiment

A. Vogel® Spilanthes acmella commercial extract Skin permeability of spilanthol INTRODUCTION OBJECTIVE METHODS RESULTS CONCLUSIONS Transmucosal data Formulation Receptor fluid Kp (x 10-3 cm/h) Indolphar® PBS + HPbCD 19.5 Buccaldol® 47.5 Ethanolic extract 5.27 10% PG 10.9 30% PG 11.7 Transdermal data Kp (x 10-4 cm/h) 65% EtOH PBS 4.38 EtOH/H2O 0.70 15.3 16.6 5.46 A. Vogel® Spilanthes acmella commercial extract 3.56 4.95 0.64 10% EtOH 37.9 30% EtOH 53.3 6.59 31.5 22.7 65% PG 2.94

Skin permeability PELLITORINE Transdermal effect of pellitorine (n=4) INTRODUCTION OBJECTIVE METHODS RESULTS CONCLUSIONS Skin permeability PELLITORINE Transdermal effect of pellitorine (n=4)

Caco-2 cell monolayer permeability INTRODUCTION OBJECTIVE METHODS RESULTS CONCLUSIONS Caco-2 cell monolayer permeability SPILANTHOL Apical-basolateral transport (n=2) Basolateral-apical transport (n=2)

Caco-2 cell monolayer permeability INTRODUCTION OBJECTIVE METHODS RESULTS CONCLUSIONS Caco-2 cell monolayer permeability PELLITORINE Apical-basolateral transport (n=2) Basolateral-apical transport (n=2)

Blood-brain barrier transport of spilanthol INTRODUCTION OBJECTIVE METHODS RESULTS CONCLUSIONS Blood-brain barrier transport of spilanthol MTR EFFLUX

→ N-alkylamides: cosmenutriceuticals INTRODUCTION OBJECTIVE METHODS RESULTS CONCLUSIONS Spilanthol/pellitorine passes skin oral mucosa gut (Caco-2 cell monolayer) blood-brain barrier → N-alkylamides: cosmenutriceuticals

C. U. Shah College of Pharmacy DruQuaR laboratory Ghent University Ghent, Belgium Lieselotte Veryser Evelien Wynendaele Lien Taevernier Frederick Verbeke Prof. Bart De Spiegeleer C. U. Shah College of Pharmacy S.N.D.T. Women's University Santacruz Mumbai, India Tanmayee Joshi Prof. Pratima Tatke ACKNOWLEDGEMENT Financial support of this study: IWT and BOF Financial support of this symposium: FWO + FCWO The graslei, Ghent, Belgium