Intestinal formation of trans-crocetin from saffron extract (Crocus sativus L.) and in vitro permeation through intestinal and blood brain barrier

Lautenschläger, M; Sendker, Jandirk; Hüwel, Sabine; Galla, Hans‐Joachim; Brandt, Simone; Düfer, Martina; Riehemann, Kristina; Hensel, Andreas

doi:10.1016/j.phymed.2014.10.009

Cited by 115 publications

(92 citation statements)

References 29 publications

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“…The higher crocetin levels measured after oral administration compared to the intravenous administration of the same dose of SFE could be probably attributed to the extended hydrolysis of the main active SFE constituent, crocin, in the gastrointestinal lumen and the intestinal mucosa, to form crocetin which is rapidly absorbed in the blood circulation through the portal vein, as proposed by Asai et al . This suggestion is also supported by the results of Lautenschläger et al . who found in vitro, that crocin is subjected to extensive intestinal hydrolysis to form the deglycosylase trans ‐crocetin which is subsequently absorbed by passive diffusion from the intestinal epithelium to a high extent and rapidly enters the blood circulation.…”

Section: Resultssupporting

confidence: 60%

“…Literature search revealed pharmacokinetic studies after administration of pure crocin or crocetin to animals [13,14] and humans, [21] while in one study [23] saffron extract was administered as tea consumption and only crocetin levels in brain were measured. Furthermore, the intestinal permeation of saffron's crocin and crocetin as well as the crocin's intestinal conversion to crocetin was investigated in vitro by Lautenschl€ ager et al [35] It should be mentioned, however, that the results of the present PK study are in agreement with the previously reported [13,21] and show that oral administration of SFE (60 mg/kg, or 16.7 mg/kg of crocin) led to serum crocetin levels (C max = 2.77 lg/ml, %CV 2.17, Table 3) comparable to those measured in healthy volunteers [21] following oral administration of pure crocetin at doses of 7.5-22.5 mg or 0.11-0.32 mg/kg (C max = 100-280 ng/ml, %CV 24-50), as well as to those measured after oral administration of crocetin 40 nmol or 0.37 mg/kg (C max = 300 nM or 0.098 lg/ ml) and crocin 40 nmol or 1.12 mg/kg (C max = 100 nM or 0.033 lg/ml) to mice, [13] taking into account the different doses administered and the observed variability.…”

Section: Pharmacokinetic Analysismentioning

confidence: 99%

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Preparation, chemical characterization and determination of crocetin's pharmacokinetics after oral and intravenous administration of saffron (Crocus sativus L.) aqueous extract to C57/BL6J mice

Christodoulou

Grafakou

Skaltsa

et al. 2019

Journal of Pharmacy and Pharmacology

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Objectives To prepare a lyophilized saffron aqueous extract (SFE) and determine its chemical profile and serum and tissue pharmacokinetics after intravenous and oral administration to C57/Bl6J mice. Methods Lyophilized SFE was prepared, characterized using semi‐preparative HPLC and NMR analysis, and stability studies at room temperature, and was quantified for crocin content with an HPLC‐PDA method. After intravenous and oral administration of SFE (60 mg/kg, reconstituted with water for injection) to C57/Bl6J mice, crocetin (derived from in vivo crocin hydrolysis) serum and tissue levels (unconjugated and total) were measured with an HPLC‐PDA method and subjected to compartmental and non‐compartmental PK analysis. Key findings Saffron aqueous extract was rich in all‐trans‐crocin (27.8 ± 0.1% w/w) and stable for more than 15 months. One‐compartment PK model described crocetin's (unconjugated) kinetics after intravenous administration of SFE, while a first‐order kinetic parameter described the rate of crocetin biotransformation to crocetin metabolite (conjugated). Α οne‐compartment PK model with first‐order absorption described crocetin and crocetin's metabolite kinetics after SFE oral administration. Relative oral bioavailability was calculated at 1.17 for total crocetin. Tissue NCA PK analysis revealed extensive crocetin distribution to liver and kidneys. Conclusions SFE is a stable lyophilized extract rich in all‐trans‐crocin. The PK study allowed the estimation of basic PK parameters and the bioavailability of SFE’s main bioactive component, crocetin, after peros administration.

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Section: Resultssupporting

confidence: 60%

Section: Pharmacokinetic Analysismentioning

confidence: 99%

Preparation, chemical characterization and determination of crocetin's pharmacokinetics after oral and intravenous administration of saffron (Crocus sativus L.) aqueous extract to C57/BL6J mice

Christodoulou

Grafakou

Skaltsa

et al. 2019

Journal of Pharmacy and Pharmacology

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“…Recent studies have demonstrated that crocetin, a key constituent of saffron, can migrate across in vitro models of the BBB (Lautenschlager et al . ) but these models may not reflect the full complexity of the BBB in situ . Animal studies using HPLC of perfused brain tissue at various time points post‐consumption of saffron might help to resolve some of these issues.…”

Section: Discussionmentioning

confidence: 99%

“…Another avenue for further research is to investigate whether saffron or its constituents cross the BBB and enter the brain, or whether saffron instead stimulates systemic mediators that transduce protective effects to the brain. Recent studies have demonstrated that crocetin, a key constituent of saffron, can migrate across in vitro models of the BBB (Lautenschlager et al 2015) but these models may not reflect the full complexity of the BBB in situ. Animal studies using HPLC of perfused brain tissue at various time points post-consumption of saffron might help to resolve some of these issues.…”

Section: Saffron Modulation Of Candidate Neuroprotective Moleculesmentioning

confidence: 99%

Widespread brain transcriptome alterations underlie the neuroprotective actions of dietary saffron

Skladnev

Ganeshan

Kim

et al. 2016

Journal of Neurochemistry

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Dietary saffron has shown promise as a neuroprotective intervention in clinical trials of retinal degeneration and dementia and in animal models of multiple CNS disorders, including Parkinson's disease. This therapeutic potential makes it important to define the relationship between dose and protection and the mechanisms involved. To explore these two issues, mice were pre-conditioned by providing an aqueous extract of saffron (0.01% w/v) as their drinking water for 2, 5 or 10 days before administration of the parkinsonian neurotoxin MPTP (50 mg/kg). Five days of saffron pre-conditioning provided the greatest benefit against MPTP-induced neuropathology, significantly mitigating both loss of functional dopaminergic cells in the substantia nigra pars compacta (p < 0.01) and abnormal neuronal activity in the caudate-putamen complex (p < 0.0001). RNA microarray analysis of the brain transcriptome of mice pre-conditioned with saffron for 5 days revealed differential expression of 424 genes. Bioinformatics analysis identified enrichment of molecular pathways (e.g. adherens junction, TNFR1 and Fas signaling) and expression changes in candidate genes (Cyr61, Gpx8, Ndufs4, and Nos1ap) with known neuroprotective actions. The apparent biphasic nature of the dose-response relationship between saffron and measures of neuroprotection, together with the stress-inducible nature of many of the up-regulated genes and pathways, lend credence to the idea that saffron, like various other phytochemicals, is a hormetic stimulus, with functions beyond its strong antioxidant capacity. These findings provide impetus for a more comprehensive evaluation of saffron as a neuroprotective intervention.

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“…For example, free CRT but also its sugar esters seem to exert antioxidant action in vivo which is most probably mediated through interaction of the conjugated double bond system with antioxidant enzymes or with signal transduction of free radicals in the cells rather than direct scavenging through H‐atom donation . Data about the bioavailability of CRTSEs after oral administration suggest that sugar esters get enzymatically hydrolyzed in the intestine so that free crocetin or its glucuronide conjugates are finally absorbed in the blood plasma . Thus, the content of a plant extract in total and not in a particular crocetin derivative might be more important for evaluating it as a source of crocetin for pharmaceutical applications.…”

Section: Introductionmentioning

confidence: 99%

Physicochemical Characterization of Crocus serotinus Stigmas Indicates Their Potential as a Source of the Bioactive Apocarotenoid Crocetin

Ordoudi

Pástor‐Férriz

Kyriakoudi

et al. 2019

Euro J Lipid Sci & Tech

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Alternative plant sources to the dried flower stigmas of Crocus sativus L. (saffron) are desirable for the recovery and industrial production of the potentially bioactive apocarotenoid crocetin (CRT). In the present study, the phytochemical profile of the orange‐red stigmas from several wild and cultivated accessions of Crocus serotinus Salisb, a Spanish autumn flowering Crocus plant, is characterized by chromatographic and spectroscopic fingerprinting methods. Saffron but also dried stigmas from two of its closest allies (C. cartwrightianus Herb. and C. thomasii Ten) are used for comparison. Among the studied accessions the cultivated ones present higher coloring strength values, up to fivefold lower than the minimum value of the corresponding ISO 3632 trade specification for saffron. Their polar extracts contain crocetin sugar esters (≈30 mg g−1 dw) with a different pattern than that prevailing in saffron or its closest allies but also simple phenolic and flavonoid constituents. The Fourier Transform Mid‐Infrared (FT‐MIR) spectra of C. serotinus flower stigmas are also assessed and CRT‐related diagnostic bands of potential use in the quality control of the plant material are identified. The results indicate that if successfully breeded, the C. serotinus plant may serve as an alternative source of CRT for food, pharmaceutical, and other applications. Practical Applications: The results of the study show that the red flower stigmas of the fertile C. serotinus plant that is natively grown in the Iberian Peninsula but also cultivated for gardening purposes may be an alternative source of the bioactive compound crocetin. Thus, apart from its morphological and physiological traits that are of interest for plant breeders, the particular natural product may have an added‐value that deserves further exploitation. The physicochemical characterization of stigmas from the non‐sterile Crocus serotinus plant indicates their potential as alternative sources of the bioactive crocetin, a lipophilic apocarotenoid that is primarily obtained from the secondary metabolites of C. sativus plant stigmas, known as saffron.

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Intestinal formation of trans-crocetin from saffron extract (Crocus sativus L.) and in vitro permeation through intestinal and blood brain barrier

Cited by 115 publications

References 29 publications

Preparation, chemical characterization and determination of crocetin's pharmacokinetics after oral and intravenous administration of saffron (Crocus sativus L.) aqueous extract to C57/BL6J mice

Preparation, chemical characterization and determination of crocetin's pharmacokinetics after oral and intravenous administration of saffron (Crocus sativus L.) aqueous extract to C57/BL6J mice

Widespread brain transcriptome alterations underlie the neuroprotective actions of dietary saffron

Physicochemical Characterization of Crocus serotinus Stigmas Indicates Their Potential as a Source of the Bioactive Apocarotenoid Crocetin

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