Curry-Odorants and Their Metabolites Transfer into Human Milk and Urine.

SCOPE: The excretion of dietary odorants into urine and milk is evaluated and the impact of possible influencing factors determined. Furthermore, the metabolic relevance of conjugates for the excretion into milk is investigated. METHODS AND RESULTS: Lactating mothers (n = 20) are given a standardized curry dish and donated one milk and urine sample each before and 1, 2, 3, 4.5, 6, and 8 h after the intervention. The concentrations of nine target odorants in these samples are determined. A significant transition is observed for linalool into milk, as well as for linalool, cuminaldehyde, cinnamaldehyde, and eugenol into urine. Maximum concentrations are reached within 1 h after the intervention in the case of milk and within 2-3 h in the case of urine. In addition, the impact of glucuronidase treatment on odorant concentrations is evaluated in a sample subset of twelve mothers. Linalool, eugenol, and vanillin concentrations increased 3-77-fold in milk samples after treatment with ß-glucuronidase. CONCLUSION: The transfer profiles of odorants into milk and urine differ qualitatively, quantitatively, and in temporal aspects. More substances are transferred into urine and the transfer needs a longer period compared with milk. Phase II metabolites are transferred into urine and milk.

Commentary of the SKLM to the EFSA opinion on risk assessment of N-nitrosamines in food.

Dietary exposure to N-nitrosamines has recently been assessed by the European Food Safety Authority (EFSA) to result in margins of exposure that are conceived to indicate concern with respect to human health risk. However, evidence from more than half a century of international research shows that N-nitroso compounds (NOC) can also be formed endogenously. In this commentary of the Senate Commission on Food Safety (SKLM) of the German Research Foundation (DFG), the complex metabolic and physiological biokinetics network of nitrate, nitrite and reactive nitrogen species is discussed with emphasis on its influence on endogenous NOC formation. Pioneering approaches to monitor endogenous NOC have been based on steady-state levels of N-nitrosodimethylamine (NDMA) in human blood and on DNA adduct levels in blood cells. Further NOC have not been considered yet to a comparable extent, although their generation from endogenous or exogenous precursors is to be expected. The evidence available to date indicates that endogenous NDMA exposure could exceed dietary exposure by about 2-3 orders of magnitude. These findings require consolidation by refined toxicokinetics and DNA adduct monitoring data to achieve a credible and comprehensive human health risk assessment.

Linalool, 1,8-Cineole, and Eugenol Transfer from a Curry Dish into Human Urine.

SCOPE: For most substances, there are several routes of excretion from the human body. This study focuses on urinary excretion of dietary odorants and compares the results with previously obtained results on excretion into milk. METHODS AND RESULTS: Lactating mothers (n = 18) are given a standardized curry dish and donate urine samples before and after the intervention. The odorants 1,8-cineole, linalool, cuminaldehyde, cinnamaldehyde, 4-hydroxy-2,5-dimethyl-3(2H)-furanone, sotolone, eugenol, vanillin, and γ-nonalactone are quantitatively analyzed. A significant transition of up to 6 µg g-1 creatinine into urine is observed for linalool, 1,8-cineole, and eugenol. Maximum concentrations are reached 1.5 h after the intervention for 1,8-cineole and eugenol as well as 2.5 h after the intervention for linalool. Comparison with previous results reveals that the excretion pattern of odorants into urine is divergent from the one into milk. In a second intervention study (n = 6), excretion of phase II metabolites into urine is studied using ß-glucuronidase treatment. Linalool and eugenol concentrations are 23 and 77 times higher after treatment than before treatment with ß-glucuronidase, respectively. CONCLUSION: The study demonstrates transition of linalool, 1,8-cineole, and eugenol from the diet into urine and excretion of glucuronides in the case of linalool, eugenol, and vanillin.

Quantification of odorous and potentially harmful substances in acrylic paint.

Within this study sixteen odour active substances (1-butanol, butyl acetate, 3-methyl-4-heptanone, butyl acrylate, styrene, ethylbenzene, propylbenzene, cumene, sec-butylbenzene, benzaldehyde, 2-ethylhexyl acrylate, naphthalene, 1-methylnaphthalene, 2-methylnaphthalene, 1,2-dimethylnaphthalene, 1,7-dimethylnaphthalene), that have previously been identified in acryl paints were quantified in ten black acrylic paint samples using GC-GC-MS (heart-cut two-dimensional gas chromatography-mass spectrometry) after prior extraction and purification via solvent assisted flavour evaporation. In this case, the preceding analysis of the most abundant odour active volatiles via GC-O (gas chromatography-olfactometry) provided indications on which smell properties might be linked with elevated and concerning levels of possibly harmful substances. Based on that work, four samples raised attention due to their mainly repelling or unpleasant odour with mainly aromatic, solvent-like, mothball-like or geranium-like smell impressions. The remaining samples either showed fruity/fermented, fruity/apple juice-like, mushroom-like or cocoa-like/earthy odour qualities. The repelling and unpleasant odour was generally linked to naphthalene or benzene derivatives that are of concern with regard to being potential carcinogens. With concentrations ranging as high as from 3.75 mg/kg to 143.41 mg/kg, n-butanol was found to be the odour active substance with the highest concentrations in all but one paint sample. The results showed that all paints contain different and specific patterns of the analysed odour active substances and volatiles. Whereas only two samples revealed no elevated concentration of any of the quantified substances, two samples (A9 and A10) showed elevated levels for all or nearly all substances. The concentrations for single substances were generally lower than the recommended exposure limit and therefore unlikely to cause any adverse effects with regards to toxicity and irritation as single constituents. However, as a group of substances these might exert adverse health effects due to combined or synergistic effects. Based on these observations, the occurrence of combinations of potentially carcinogenic substances in products which are occupationally used on a daily basis or are in direct skin contact should thus be regarded with care in the future.

Comparative Evaluation of Wild and Farmed Rainbow Trout Fish Based on Representative Chemosensory and Microbial Indicators of Their Habitats.

Wild and farmed rainbow trout were compared with chemical profiling, chemosensory properties, carbon concentration and isotope analyses, 1- and 2-GC/O-MS, GC-FID, and aroma profile analyses. Results were linked with the prokaryotic and eukaryotic microbiological profile of the fish sources using multivariate statistical analysis. Fish from natural environments proved to have better sensory properties in terms of fruity, sweet, and citrusy attributes, compared to farmed fish. However, the farmed fish were found to have higher nutritional value based on their lipid contents. These differences might relate to the introduction of feed extrudates, which could influence the overall quality of fish products. Thereby, malodor episodes linked to musty/earthy off-odor notes related to odorants including geosmin, ß-caryophyllene, (E,Z)-2,4-nonadienal, and (E,E)-2,4-nonadienal. These compounds, in turn, correlated with Asticcacaulis benevestitus, Curvibacter sp., Albidiferax sp., Aquabacterium commune, and Aquabacterium citratiphilum abundance and were further affected by oxygen levels in the water column.

Aroma-active volatiles and rheological characteristics of the plastic mass during conching of dark chocolate.

Chocolate conching is a highly complex, thermomechanical process that transforms the aroma and flow properties of a dry starting material. Different conched plastic masses of dark chocolate were characterized. Rheological characterization of plastic masses was performed for the first time using a closed cavity rheometer (CCR1). In free cocoa butter derived from the plastic masses, acetic acid, benzaldehyde, (R,S)-(±)-linalool, 2,3,5,6-tetramethylpyrazine, and 2-phenylethanol were quantified by stable isotope dilution analysis (SIDA2) and gas chromatography-mass spectrometry. During the conching process, the amount of free cocoa butter increased possibly due to de-agglomeration. The complex viscosity of the plastic mass decreased as a function of conching time. Regarding aroma refinement, the concentrations of all five aroma-active volatiles decreased with increasing conching duration, albeit to varying degrees. The level of acetic acid showed the most pronounced decrease of about 60%, whereas linalool exhibited the lowest decrease in concentration, up to 26%. Overall, a lower polarity or boiling point of the aroma-active volatiles was linked to a stronger decrease in concentration during conching. These data illustrate the influence of conching on texture and the respective aroma changes, which deepens understanding of the conching effect on the sensory quality of dark chocolate.

Influence of elongation and desaturation on chemosensory properties in acrylates and their corresponding 1-alken-3-ones.

Acrylates as well as 1-alken-3-ones are both known to be odour active substances but are generally identified in different materials. Nonetheless, butyl acrylate and 1-octen-3-one were both found to elicit a similar mushroom-like odour in previous studies. This led to the question of whether acrylates and enones with the same overall chain length generally elicited similar odours and whether they had similar odour thresholds. Overall, most of the investigated substances showed a mushroom-like, geranium-like or fruity odour. In contrast, short chained substances elicited garlic-like, lighter gas-like or glue-like, odour qualities, suggesting a correlation between the odour quality and the overall chain length. The results showed that only between the analogue structures butyl acrylate and 1-octen-3-one as well as hexyl acrylate and 1-decen-3-one could similar odour qualities be observed. All investigated substances showed low odour threshold values in air between 0.0032 ng/lair (1-hexen-3-one) and 55 ng/lair (1-dodecen-3-one). Overall, 1-alken-3-ones revealed a higher dependency on the chain length when compared to their respective acrylates. The introduction of a second terminal double bond led to a decrease of OT values in case of the acrylates and to an increase in case of the ketones that neither contained a second terminal double bond nor a double bond located close to the carbonyl group. Despite their structural similarities, the results suggest that both substance classes are perceived in a different manner and are therefore likely to be recognized by different types of receptors or are related to different activation patterns in multi-receptor stimulation processes.

Smells like new car or rather like an old carriage? - Resolution of the decay behavior of odorants in vehicle cabins during usage.

The typical new car smell is not only perceived directly after vehicle delivery. Vehicle interiors maintain their characteristic odors for a period of time during use even though the gas composition of the vehicle interior changes due to external influences. To obtain deeper insights into the odorant composition of a passenger cabin, this study aimed at characterizing the gas phase of two vehicle interiors at defined time intervals after vehicle delivery, and use by a customer in a controlled environment using a targeted odorant analysis. Thereby, the decrease in the general emissions in the cars did not coincide with the decay behavior of the odorants due to the chemical characteristics such as polarity of the odorants. Identification of the odorants in the vehicle interior during use revealed three groups of odor contributors exhibiting different decay behaviors: (i) odorants vaporizing rapidly via elevated temperature; (ii) odorants released by continued diffusion from materials; and (iii) fragrance chemicals of the customer. After 23 weeks of vehicle use, octanal, p-chloro-m-cresol, nonanal, p-tert-butylphenol, γ-nonalactone, and unsaturated aldehydes and ketones represented the most important odorants in the vehicle interior constituting the investigated car odor. The results of a descriptive sensory analysis corresponded with the identified odorants.

Odor-Reduced HDPE-Lignin Blends by Use of Processing Additives.

The comprehensive use of natural polymers, such as lignin, can accelerate the replacement of mineral oil-based commodities. Promoting the material recovery of the still underutilized technical lignin, polyolefin-lignin blends are a highly promising approach towards sustainable polymeric materials. However, a limiting factor for high-quality applications is the unpleasant odor of technical lignin and resulting blends. The latter, especially, are a target for potential odor reduction, since heat- and shear-force intense processing can intensify the smell. In the present study, the odor optimization of kraft and soda HDPE-lignin blends was implemented by the in-process application of two different processing additives-5% of activated carbon and 0.7% of a stripping agent. Both additives were added directly within the compounding process executed with a twin screw extruder. The odor properties of the produced blends were assessed systematically by a trained human panel performing sensory evaluations of the odor characteristics. Subsequently, causative odor-active molecules were elucidated by means of GC-O and 2D-GC-MS/O while OEDA gave insights into relative odor potencies of single odorants. Out of 70 different odorants detected in the entirety of the sample material, more than 30 sulfur-containing odorants were present in the kraft HDPE-lignin blend, most of them neo-formed due to high melt temperatures during extrusion, leading to strong burnt and sulfurous smells. The addition of activated carbon significantly decreased especially these sulfurous compounds, resulting in 48% of overall odor reduction of the kraft blend (mean intensity ratings of 5.2) in comparison to the untreated blend (10.0). The applied stripping agent, an aqueous solution of polymeric, surface-active substances adsorbed onto a PP carrier, was less powerful in reducing neo-formed sulfur odorants, but led to a decrease in odor of 26% in the case of the soda HDPE-lignin blend (7.4). The identification of single odorants on a molecular level further enabled the elucidation of odor reduction trends within single compound classes. The obtained odor reduction strategies not only promote the deodorization of HDPE-lignin blends, but might be additionally helpful for the odor optimization of other natural-fiber based materials.

Odorant Metabolism in Humans.

Odorants are relatively small molecules which are easily taken up and distributed in the human body. Despite their relevance in everyday life, however, only a limited amount of evidence about their metabolism, pathways, and bioactivities in the human body exists. With this Review, we aim to encourage future interdisciplinary research on the function and mechanisms of the biotransformation of odorants, involving different disciplines such as nutrition, medicine, biochemistry, chemistry, and sensory sciences. Starting with a general overview of the different ways of odorant uptake and enzymes involved in the metabolism of odorants, a more precise description of biotransformation processes and their function in the oral cavity, the nose, the lower respiratory tract (LRT), and the gastrointestinal tract (GIT) is given together with an overview of the different routes of odorant excretion. Finally, perspectives for future research are discussed.

Follow your nose - Traveling the world of odorants in new cars.

Volatile organic compounds of the vehicle interior are well investigated, but only limited information is available on the odorants of the passenger cabin. To close this gap, we aimed at specifically elucidating the odor, as a general proof of principle, of two new cars with different seat upholstery in a controlled environment using a targeted odorant analysis. In a first step, odor profiles were evaluated by a descriptive sensory analysis. Then, potent odorants of the passenger cabins were characterized by gas chromatography-olfactometry and ranked according to their odor potency via odor extract dilution analysis. Using this approach, 41 potent odorants were detected, and 39 odorants were successfully identified by two-dimensional gas chromatography-mass spectrometry/olfactometry. In a third step, important odorants of the vehicle interior were quantified by means of internal standard addition. The most dominant odorants could be assigned to several specific substance classes comprising esters, saturated and unsaturated aldehydes, unsaturated ketones, rose ketones, phenolic and benzene derivatives, and pyrazines, occurring in a concentration range between 0.05 and 219 ng/L in air. Of these potent odorants, the aldehydes 2-butylhept-2-enal, 2-propyloct-2-enal, and (Z)-2-butyloct-2-enal are reported here for the first time as odorants in the environment of a passenger cabin.

Odor and Constituent Odorants of HDPE-Lignin Blends of Different Lignin Origin.

The still-rising global demand for plastics warrants the substitution of non-renewable mineral oil-based resources with natural products as a decisive step towards sustainability. Lignin is one of the most abundant natural polymers and represents an ideal but hitherto highly underutilized raw material to replace petroleum-based resources. In particular, the use of lignin composites, especially polyolefin-lignin blends, is currently on the rise. In addition to specific mechanical property requirements, a challenge of implementing these alternative polymers is their heavy odor load. This is especially relevant for lignin, which exhibits an intrinsic odor that limits its use as an ingredient in blends intended for high quality applications. The present study addressed this issue by undertaking a systematic evaluation of the odor properties and constituent odorants of commercially available lignins and related high-density polyethylene (HDPE) blends. The potent odors of the investigated samples could be attributed to the presence of 71 individual odorous constituents that originated primarily from the structurally complex lignin. The majority of them was assignable to six main substance classes: carboxylic acids, aldehydes, phenols, furan compounds, alkylated 2-cyclopenten-1-ones, and sulfur compounds. The odors were strongly related to both the lignin raw materials and the different processes of their extraction, while the production of the blends had a lower but also significant influence. Especially the investigated soda lignin with hay- and honey-like odors was highly different in its odorant composition compared to lignins resulting from the sulfurous kraft process predominantly characterized by smoky and burnt odors. These observations highlight the importance of sufficient purification of the lignin raw material and the need for odor abatement procedures during the compounding process. The molecular elucidation of the odorants causing the strong odor represents an important procedure to develop odor reduction strategies.

Deodorization of post-consumer plastic waste fractions: A comparison of different washing media.

An important impediment to the acceptance of recyclates into a broader market is their unwanted odor after reprocessing. Different types of washing procedures are already in place, but fundamental insights into the deodorization efficiencies of different washing media are still relatively scarce. Therefore, in this study, the deodorization efficiencies of different types of plastics after washing with different media were determined via gas chromatography and mass spectrometry analysis. A total of 169 compounds subdivided into various chemical classes, such as alkanes, terpenes, and oxygenated compounds, were detected across all packaging types. Around 60 compounds were detected on plastic bottles, and around 40 were detected on trays and films. Owing to the differences in physicochemical properties of odor compounds, different deodorization efficiencies were obtained with different washing media. Water and caustic soda were significantly more efficient for poly(ethylene terephthalate) bottles with deodorization efficiencies up to 80%, whereas for polyethylene (PE) and polypropylene bottles, the washing media were relatively inefficient (around 30-40%). Adding a detergent or an organic solvent could increase deodorization efficiencies by up to 70-90% for these packaging types. A similar trend was observed for PE films having deodorization efficiencies in the range of 40-50% when washing with water or caustic soda and around 70-80% when a detergent was added. Polystyrene trays were most effectively deodorized with a detergent, achieving efficiencies up to 67%. Hence, this study shows that optimal washing processes should be tailored to specific packaging types to further improve deodorization and to eventually be able to meet ambitious European recycling targets.

Chemo-sensory characterization of aroma active compounds of native oak wood in relation to their geographical origins.

Oak wood contains aroma-active compounds that contribute significantly to the chemical structure, olfactory and gustatory qualities of alcoholic beverages and vinegars as by-products that have been either fermented and/or aged in oak barrels. The chemical composition of cooperage oak is highly variable, depending on the degree of toasting and natural seasoning. However, it is unclear whether the odor of oak varies according to different geographical regions and pedoclimatic conditions. Especially in view of the actual challenges in forestry in relation to climate change, the present study aimed at elucidating the odorous constituents of nine natural oak samples from Germany, Austria and Hungary with respect to these influencing parameters. The odor profiles of the oaks were compared, the potent odorants were determined, and selected odorants were quantified using stable isotope dilution assays (SIDA). The majority of the identified odorants in all samples were fatty acid degradation products, followed by a series of odorants with terpenoic structure and others resulting from the degradation of lignin. Several different odorants including 2-propenoic acid and cinnamaldehyde are reported here for the first time in oaks from different growth regions. Odor activity values (OAVs), calculated based on odor thresholds (OTs) in water, revealed hexanal, (E)-2-nonenal, (Z)-3-hexenal, eugenol, vanillin, and whiskey lactone as potent odorants for the oak odor. Principal component analysis of the data obtained from sensory evaluation, comparative aroma extract dilution analysis (cAEDA) and their corresponding quantified odorants showed that the highest separation rate was obtained for Hungarian oak, whereas Austrian and Bavarian oak samples were more similar. Recombination experiments by mixing the dominant odorants in their naturally occurring concentrations revealed a good agreement of the smell properties of the model mixture with the smell of the respective original sample. These findings aimat evaluating and establishing a better understanding of the distinctive smell of oak wood and demonstrated the prospects of new oak sources.

Dietary Linalool is Transferred into the Milk of Nursing Mothers.

SCOPE: Breast milk is repeatedly postulated to shape the first aroma and taste impressions of infants and thus impact their flavor learning. The objective of this study is to assess the transition of aroma compounds from a customary curry dish into milk. METHODS AND RESULTS: The article prepares a standardized curry dish and administers the dish to nursing mothers (n = 18) in an intervention study. The participants donate one milk sample before and three samples after the intervention. Due to their olfactory or quantitative relevance in the curry dish, 1,8-cineole, linalool, cuminaldehyde, cinnamaldehyde, 4-hydroxy-2,5-dimethyl-3(2H)-furanone, sotolone, eugenol, vanillin, and γ-nonalactone are defined as target compounds, and their transition into milk is quantified by gas chromatography-mass spectrometry. A significant transition into the milk is observed for linalool, and its olfactory relevance in this respect is supported by calculated odor activity values. In contrast, no relevant levels are detected for the other eight target compounds. CONCLUSION: Ingestion of a customary curry dish can lead to an alteration of the milk aroma, which might be perceived by the infant during breastfeeding. The current study also demonstrates that the extent of aroma transfer differs between both substances and individuals.

Dietary Piperine is Transferred into the Milk of Nursing Mothers.

INTRODUCTION: The diet of breastfeeding mothers could bring nurslings into contact with flavor compounds putatively contributing to early sensory programming of the infant. The study investigates whether tastants from a customary curry dish consumed by mothers are detectable in their milk afterwards and can be perceived by the infant. METHODS AND RESULTS: Sensory evaluation identifies pungency as the dominating taste impression of the curry dish. Its ingredients of chili, pepper, and ginger suggest the flavor compounds capsaicin, piperine, and 6-gingerol as analytical targets. Breastfeeding mothers are recruited for an intervention trial involving the consumption of the curry dish and subsequent collection of milk samples for flavor compound analysis. Targeted and untargeted mass spectrometric (MS)- investigations identify exclusively piperine as an intervention-derived compound in human milk. However, concentrations are below the human taste threshold. CONCLUSION: Piperine from pepper-containing foods transfers into the mother's milk within 1 h and is delivered to the nursling. Concentrations of 50 and 200 nM of piperine are 70-350 times below the human taste threshold, but TRPV1 (Transient Receptor Potential Vanilloid-1 ion channel) desensitization through frequent exposure to sub-taste-threshold concentrations could contribute to an increased tolerance at a later age.

Antibacterial and antioxidant activity of cinnamon essential oil-laden 45S5 bioactive glass/soy protein composite scaffolds for the treatment of bone infections and oxidative stress.

This study aimed to fabricate cinnamon essential oil (CO)-laden 45S5 bioactive glass (BG)/soy protein (SP) scaffolds exhibiting antioxidant and antibacterial activity. In this regard, 45S5 BG-based scaffolds were produced by the foam replica method, and subsequently the scaffolds were coated with various concentrations of CO (2.5, 5 and 7 (v/v) %) incorporated SP solution. Scanning electron microscopy images revealed that the CO-laden SP effectively attached to the 45S5 BG scaffold struts. The presence of 45S5 BG, SP and CO was confirmed using Fourier transform infrared spectroscopy. Compressive strength results indicated that SP based coatings improved the scaffolds' mechanical properties compared to uncoated BG scaffolds. The loading efficiency and releasing behaviour of the different CO concentrations were tested by gas chromatography-mass spectroscopy and UV-Vis spectroscopy. The results showed that CO incorporated scaffolds have controlled releasing behaviour over seven days. Furthermore, the coating on the scaffold surfaces slightly retarded, but it did not inhibit, the in vitro bioactivity of the scaffolds. Moreover, the antioxidant and antibacterial activity of CO was studied. The free radical scavenging activity measured by DPPH was 5 ± 1, 41 ± 3, 44 ± 1 and 43 ± 1 % for BGSP, CO2.5, CO5 and CO7, respectively. The antioxidant activity was thus enhanced by incorporating CO. Agar diffusion and colony counting results indicated that the incorporation of CO increased the antibacterial activity of scaffolds against S. aureus and E. coli. In addition, cytotoxicity of the scaffolds was investigated using MG-63 osteoblast-like cells. The results showed that the BG-SP scaffold was non-toxic under the investigated conditions, whereas dose-dependent toxicity was observed in CO-laden scaffolds. Considered together, the developed phytotherapeutic agent laden 45S5 BG-based scaffolds are promising for bone tissue engineering exhibiting capability to combat bone infections and to protect against oxidative stress damage.

Contribution of S. xylosus and L. sakei ssp. carnosus Fermentation to the Aroma of Lupin Protein Isolates.

Aroma-active compounds of lupin protein isolate and lupin protein isolate fermented with Staphylococcus xylosus and Lactobacillus sakei ssp. carnosus were investigated. The changes in aroma-active compounds were determined by application of aroma extract dilution analysis in combination with gas chromatography-mass spectrometry/olfactometry for identification, and by stable isotope dilution assays for quantification. A total of 30 aroma-active compounds for non-fermented and fermented samples were identified. The aroma profile of LPI fermented with Lactobacillus sakei ssp. carnosus was characterized as roasty and popcorn-like. Staphylococcus xylosus generated cheesy impressions, being in line with the fact that the main aroma compounds acetic acid, butanoic acid, and 2/3-methylbutanoic acid could be identified. Quantification of butanoic acid further confirmed these findings with the highest concentration of 140 mg/kg for LPI fermented with Staphylococcus xylosus. Our study provides insights into how fermentation utilizing different fermentative microbial strains, namely Staphylococcus xylosus and Lactobacillus sakei ssp. carnosus alters the aroma profile of lupin protein isolates. This demonstrates the potential of shaping fermented protein-based foods via targeted microbiological refinement.

Sesquiterpenes and sesquiterpenoids harbor modulatory allosteric potential and affect inhibitory GABAA receptor function in vitro.

Naturally occurring compounds such as sesquiterpenes and sesquiterpenoids (SQTs) have been shown to modulate GABAA receptors (GABAA Rs). In this study, the modulatory potential of 11 SQTs at GABAA Rs was analyzed to characterize their potential neurotropic activity. Transfected HEK293 cells and primary hippocampal neurons were functionally investigated using electrophysiological whole-cell recordings. Significantly different effects of ß-caryophyllene and α-humulene, as well as their respective derivatives ß-caryolanol and humulol, were observed in the HEK293 cell system. In neurons, the concomitant presence of phasic and tonic GABAA R configurations accounts for differences in receptor modulation by SQTs. The in vivo presence of the γ2 and δ subunits is important for SQT modulation. While phasic GABAA receptors in hippocampal neurons exhibited significantly altered GABA-evoked current amplitudes in the presence of humulol and guaiol, negative allosteric potential at recombinantly expressed α1 ß2 γ2 receptors was only verified for humolol. Modeling and docking studies provided support for the binding of SQTs to the neurosteroid-binding site of the GABAA R localized between transmembrane segments 1 and 3 at the (+ α)-(- α) interface. In sum, differences in the modulation of GABAA R isoforms between SQTs were identified. Another finding is that our results provide an indication that nutritional digestion affects the neurotropic potential of natural compounds.