N-alkylamides: from plant to brain

Abstract

Background: Plant N-alkylamides (NAAs) are bio-active compounds with a broad functional spectrum. In order to reach their pharmacodynamic targets, they have to overcome several barriers of the body in the absorption phase. The permeability kinetics of spilanthol (a diene NAA) and pellitorine (a triene NAA) across these barriers (i.e. skin, oral/gut mucosa, blood-brain barrier) were investigated.Methods: The skin and oral mucosa permeability were investigated using human skin and pig mucosa in an ex vivo in vitro Franz diffusion cell set-up. The gut absorption characteristics were examined using the in vitro Caco-2 cell monolayer test system. The initial blood-brain barrier transport kinetics were investigated in an in vivo mice model using multiple time regression and efflux experiments. Quantification of both NAAs was conducted using HPLC-UV and bio-analytical UPLC-MS methods.Results: We demonstrated that spilanthol and pellitorine are able to penetrate the skin after topical administration. It is likely that spilanthol and pellitorine can pass the endothelial gut as they easily pass the Caco-2 cells in the monolayer model. It has been shown that spilanthol also crosses the oral mucosa as well as the blood-brain barrier. Conclusion: It was demonstrated that NAAs pass various physiological barriers i.e. the skin, oral and gut mucosa, and after having reached the systemic circulation, also the blood-brain barrier. As such, NAAs are cosmenutriceuticals which can be active in the brain.Key words: Plant N-alkylamides, pharmacokinetics, mucosa/skin, blood-brain barrier (BBB), cosmenutriceuticals

Chemistry and Pharmacology of Alkylamides from Natural Origin

“…The permeability kinetics of spilanthol and pellitorine across the skin, oral/gut mucosa, and blood-brain barrier showed that the alkylamides can penetrate the skin after topical administration and that they may likely pass the endothelial gut as they easily pass the Caco-2 cells in the monolayer model. The study also revealed spilanthol crosses the oral mucosa as well as the blood-brain barrier (Veryser et al 2014 ). Transdermal and pharmacokinetic properties of spilanthol and pellitorine have been studied (Veryser 2016 ).…”

“…Another HPLC-MS/MS method was developed and validated for the detection and quantification of undeca-2-ene-8,10-diynoic acid isobutylamide in human plasma (Goey et al 2011 ) and used for the analysis of dodeca-2 E ,4 E ,8 Z ,10 E / Z -tetraenoic acid isobutylamides (Goey et al 2012 ). Quantification of spilanthol and pellitorine across the skin, oral/gut mucosa, and the blood-brain barrier was carried out using HPLC-UV and bio-analytical UPLC-MS methods (Veryser et al 2014 ). A rapid, sensitive, and accurate UHPLC–MS/MS method was developed for the determination of hydroxy-α-sanshool, hydroxy-β-sanshool, and hydroxy-γ-sanshool isolated from Zanthoxylum bungeanum Maxim., Rutaceae, in rat plasma (Rong et al 2016 ).…”

Affinin (Spilanthol), Isolated from Heliopsis longipes, Induces Vasodilation via Activation of Gasotransmitters and Prostacyclin Signaling Pathways

“…An in vitro permeability test showed that this alkamide (10 µg/mL) permeates through CaCo-2 cell monolayer cultures via passive diffusion. Whereas in vivo assays demonstrated that it is able to permeate skin and oral mucosa, and subsequently reach blood circulation, and cross the blood-brain barrier in high amounts (~98%) [ 23 , 32 ]. Therefore, this compound might be considered a valuable potential drug candidate [ 13 , 18 , 23 , 33 ].…”

The prospects for pharmaceutical use of herbal raw material containing alkylamides

“…Основной алкила-мид спилантеса -спилантол (аффинин) -содер-жится в листьях и цветках, обладает антибакте-риальным, противогрибковым, диуретическим, противовоспалительным и анальгетическим дей-ствием [19][20][21][22][23]. Кроме того, спилантол может вы-ступать в роли иммуностимулятора и способен снижать степень выраженности противовоспали-тельных реакций [24].…”