Flavonoid metabolites transport across a human BBB model

Faria, Ana; Meireles, Manuela; Fernandes, Iva; Santos‐Buelga, Celestino; González‐Manzano, Susana; Dueñas, Montserrat; Freitas, Víctor de; Mateus, Nuno; Calhau, Conceição

doi:10.1016/j.foodchem.2013.10.095

Cited by 115 publications

(75 citation statements)

References 30 publications

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“…The exact mechanism by which BCRP regulation is precisely controlled therefore warrants further study, particularly considering there is evidence to suggest that flavonoids are capable of permeating the BBB and/or the BCSFB, for example quercetin (119,143); catechin and epicatechin (144); hesperetin, naringenin, epicatechin and their glucuronides (118) and kaempferol and isorhamnetin (120) are capable of permeating the BBB and/or the BCSFB and therefore have the potential to interact with any of these regulatory elements.…”

Section: Discussionmentioning

confidence: 99%

Phytoestrogens Modulate Breast Cancer Resistance Protein Expression and Function at the Blood-Cerebrospinal Fluid Barrier

Kaur

Badhan

2015

J Pharm Pharm Sci

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-PURPOSE: Breast cancer resistance protein (BCRP/ABCG2) is a drug efflux transporter expressed at the blood cerebrospinal fluid barrier (BCSFB), and influences distribution of drugs into the central nervous systems (CNS). Current inhibitors have failed clinically due to neurotoxicity. Novel approaches are needed to identify new modulators to enhance CNS delivery. This study examines 18 compounds (mainly phytoestrogens) as modulators of the expression/function of BCRP in an in vitro rat choroid plexus BCSFB model. METHODS: Modulators were initially subject to cytotoxicity (MTT) assessment to determine optimal non-toxic concentrations. Reverse-transcriptase PCR and confocal microscopy were used to identify the presence of BCRP in Z310 cells. Thereafter modulation of the intracellular accumulation of the fluorescent BCRP probe substrate Hoechst 33342 (H33342), changes in protein expression of BCRP (western blotting) and the functional activity of BCRP (membrane insert model) were assessed under modulator exposure. RESULTS: A 24 hour cytotoxicity assay (0.001 µM-1000 µM) demonstrated the majority of modulators possessed a cellular viability IC50 > 148 µM. Intracellular accumulation of H33342 was significantly increased in the presence of the known BCRP inhibitor Ko143 and, following a 24 hour pre-incubation, all modulators demonstrated statistically significant increases in H33342 accumulation (P < 0.001), when compared to control and Ko143. After a 24 hour pre-incubation with modulators alone, a 0.16-2.5 -fold change in BCRP expression was observed for test compounds. The functional consequences of this were confirmed in a permeable insert model of the BCSFB which demonstrated that 17-β-estradiol, naringin and silymarin (down-regulators) and baicalin (up-regulator) can modulate BCRP-mediated transport function at the BCSFB. CONCLUSION: We have successfully confirmed the gene and protein expression of BCRP in Z310 cells and demonstrated the potential for phytoestrogen modulators to influence the functionality of BCRP at the BCSFB and thereby potentially allowing manipulation of CNS drug disposition.

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Section: Discussionmentioning

confidence: 99%

Phytoestrogens Modulate Breast Cancer Resistance Protein Expression and Function at the Blood-Cerebrospinal Fluid Barrier

Kaur

Badhan

2015

J Pharm Pharm Sci

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“…Several studies have shown that flavanols are metabolized by the body after administration (de Boer et al, 2005;Faria et al, 2014). For this reason, it is important to evaluate the biodistribution of flavanols and its metabolites in both dams and offspring.…”

Section: Discussionmentioning

confidence: 99%

“…In order to be able to influence brain health directly, flavonoids or their metabolites must pass the blood-brain barrier (BBB). The ability of structures to cross the BBB depends on their systemic availability and lipophilicity (Faria et al, 2014;Rendeiro et al, 2012). As a result, theoretically the O-methylated metabolites would be more potent to pass the BBB than sulphates and glucuronides, which has been shown in in vitro studies (Rendeiro et al, 2012;Vauzour, 2012;Youdim et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Effect of perinatally supplemented flavonoids on brain structure, circulation, cognition, and metabolism in C57BL/6J mice

Janssen

Zerbi

Mutsaers

et al. 2015

Neurochemistry International

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“…TBI occurs as a result of direct mechanical insult to the brain followed by secondary events resulting in cell degeneration and death. Secondary insults include excitotoxic damage, blood brain barrier disruption, free radical production, calcium-mediated damage, neuro-inflammation, and hypoxia due to circulatory disturbance [2][3][4]. Since the primary insult is not preventable, investigations are mainly focused on reversing the secondary insults [5,6].…”

Section: Introductionmentioning

confidence: 99%

Impact of Acute Phase Epigallocatechin-3-gallate Supplementation on Consciousness and S100B Serum Levels in TBI Patients: A Double Blind Randomized Clinical Trial

Zareian

Azarhomayoun

Alimohamadi

et al. 2017

IrJNS

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Background and Aim: Traumatic brain injury is one of the leading causes of mortality and disability in young adults. Epigallocatechin-3-gallate, the antioxidant compound of green tea, has been proposed to have antioxidant and anti-inflammatory properties. This study evaluates the potential effects of epigallocatechin-3-gallate on the early clinical outcome and serum S100B levels (biomarker for brain tissue damage severity) in patients with moderate to severe traumatic brain injury. Methods and Materials/Patients:Thirty patients with moderate to severe traumatic brain injury admitted to the intensive care unit were enrolled. The patients were randomly allocated to treatment with either a daily oral dose of 400 mg epigallocatechin-3-gallate or placebo (distilled water) for seven days. The main outcome measures were duration of mechanical ventilation and ICU stay, Glasgow Coma Scale, and S100B protein level. Results:The results revealed a significant improvement in consciousness level after seven days in the epigallocatechin-3-gallate group (2.93±3.9 unit improvement in GCS versus 0.14±3.05 reduction in GCS, p-value:0.033). There was also a significantly shorter duration of mechanical ventilation in the epigallocatechin-3-gallate compared to the control group (5.1 days versus 9.8 days, p-value:0.02). Reduction of the serum S100B level was slightly higher in the epigallocatechin-3-gallate group (23.96 versus 18.6 pg/ml) but the difference was not statistically significant. Conclusion:Epigallocatechin-3-gallate supplementation had beneficial effects on consciousness level of the patients with moderate to severe traumatic brain injury in the acute phase.

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Flavonoid metabolites transport across a human BBB model

Cited by 115 publications

References 30 publications

Phytoestrogens Modulate Breast Cancer Resistance Protein Expression and Function at the Blood-Cerebrospinal Fluid Barrier

Phytoestrogens Modulate Breast Cancer Resistance Protein Expression and Function at the Blood-Cerebrospinal Fluid Barrier

Effect of perinatally supplemented flavonoids on brain structure, circulation, cognition, and metabolism in C57BL/6J mice

Impact of Acute Phase Epigallocatechin-3-gallate Supplementation on Consciousness and S100B Serum Levels in TBI Patients: A Double Blind Randomized Clinical Trial

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