Transport of ginkgolides with different lipophilicities based on an hCMEC/D3 cell monolayer as a blood–brain barrier cell model

Ma, Shuwei; Liu, Xingyan; Xu, Qingrun; Zhang, Xiantao

doi:10.1016/j.lfs.2014.08.006

Cited by 25 publications

(10 citation statements)

References 31 publications

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“…This parameter completely determines the interaction between the drugs and ABC transporter function (Food and drug administration, 2012;Hubatsch et al, 2007;Kikuchi et al, 2013). To date, only few studies on human BBB cell lines have evaluated this parameter (Eigenmann et al, 2016a;Jähne et al, 2016;Ma et al, 2014). In our model, ER parameter was higher in HBEC-5i with the HA conditioned medium than HBEC-5i alone.…”

Section: Discussionmentioning

confidence: 83%

Assessment of HBEC-5i endothelial cell line cultivated in astrocyte conditioned medium as a human blood-brain barrier model for ABC drug transport studies

Puech

Hodin

Forest

et al. 2018

International Journal of Pharmaceutics

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Endothelial cells are main components of the Blood-Brain Barrier (BBB) and form a tight monolayer that regulates the passage of molecules, with the ATP-Binding Cassette (ABC) transporters efflux pumps. We have developed a human in vitro model of HBEC-5i endothelial cells cultivated alone or with human astrocytes conditioned medium on insert. HBEC-5i cells showed a tight monolayer within 14 days, expressing ZO-1 and claudin 5, a low apparent permeability to small molecules, with a TEER stability during five days. The P-gp, BCRP, MRPs transporters were well expressed and functional. Accumulation and efflux ratio measurement with different ABC transporters substrates (Rhodamine 123, BCECF AM, Hoechst 33342) and inhibitors (verapamil, Ko143, probenecid and cyclosporin A) were conducted. At barrier level, the functionality of ABC transporters was three-fold enhanced in astrocyte conditioned medium. We validated our model by the transport of pharmacological substrates: caffeine, rivaroxaban, and methotrexate. The rivaroxaban and methotrexate were released with an efflux ratio>3 and were decreased by more than half with inhibitors. HBEC-5i model could be used as relevant tool in preclinical studies for assessing the permeability of therapeutic molecules to cross human BBB.

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Section: Discussionmentioning

confidence: 83%

Assessment of HBEC-5i endothelial cell line cultivated in astrocyte conditioned medium as a human blood-brain barrier model for ABC drug transport studies

Puech

Hodin

Forest

et al. 2018

International Journal of Pharmaceutics

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“…The hCMEC/D3 cell line has been developed as a model for the human BBB and has been used to test the permeability of several drugs (Al‐Shehri et al ., ; Ma et al ., ). Here, the results indicated that 62‐71‐3 ScFv was able to pass across the hCMEC/D3 cells whilst the 62‐71‐3 IgG was not.…”

Section: Discussionmentioning

confidence: 97%

Enhanced transport of plant‐produced rabies single‐chain antibody‐RVG peptide fusion protein across an in cellulo blood–brain barrier device

Phoolcharoen

Préhaud

Dolleweerd

et al. 2017

Plant Biotechnology Journal

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SummaryThe biomedical applications of antibody engineering are developing rapidly and have been expanded to plant expression platforms. In this study, we have generated a novel antibody molecule in planta for targeted delivery across the blood–brain barrier (BBB). Rabies virus (RABV) is a neurotropic virus for which there is no effective treatment after entry into the central nervous system. This study investigated the use of a RABV glycoprotein peptide sequence to assist delivery of a rabies neutralizing single‐chain antibody (ScFv) across an in cellulo model of human BBB. The 29 amino acid rabies virus peptide (RVG) recognizes the nicotinic acetylcholine receptor (nAchR) at neuromuscular junctions and the BBB. ScFv and ScFv‐RVG fusion proteins were produced in Nicotiana benthamiana by transient expression. Both molecules were successfully expressed and purified, but the ScFv expression level was significantly higher than that of ScFv‐RVG fusion. Both ScFv and ScFv‐RVG fusion molecules had potent neutralization activity against RABV in cellulo. The ScFv‐RVG fusion demonstrated increased binding to nAchR and entry into neuronal cells, compared to ScFv alone. Additionally, a human brain endothelial cell line BBB model was used to demonstrate that plant‐produced ScFv‐RVGP fusion could translocate across the cells. This study indicates that the plant‐produced ScFv‐RVGP fusion protein was able to cross the in cellulo BBB and neutralize RABV.

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“…Numerous pharmacologic studies have shown that DG, mainly composed of ginkgolides A, B and K (in the standardized extract EGb761), is responsible for the main pharmacologic (neuroprotective) effects of GBE. 12 , 19 – 21 DG Meglumine Injection, a novel medicinal plant product, primarily contains ginkgolides A, B and K.…”

Section: Introductionmentioning

confidence: 99%

Metabolite-related antidepressant action of diterpene ginkgolides in the prefrontal cortex

Hu¹,

Shen²,

Bai³

et al. 2018

NDT

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PurposeGinkgo biloba extract (GBE) contains diterpene ginkgolides (DGs), which have been shown to have neuroprotective effects by a number of previous studies. We previously demonstrated part of the action of DG. However, the impact of DG on the prefrontal cortex (PFC) remains unclear. Here, we evaluated the effects of DG and venlafaxine (for comparison) on behavioral and metabolite changes in the PFC using mice models and gas chromatography–mass spectrometry-based metabolomics.Materials and methodsMice were randomly divided into control (saline), DG (12.18 mg/kg) and venlafaxine (16 mg/kg) groups. After 2 weeks of treatment, depression and anxiety-related behavioral tests were performed. Metabolic profiles of the PFC were detected by gas chromatography–mass spectrometry.ResultsThe DG group exhibited positive effects in the sucrose preference test. The differential metabolites were mainly related to amino acid metabolism, energy metabolism and lipid metabolism. The results indicated that the DG group exhibited perturbed lipid metabolism, molecular transport and small-molecule biochemistry in the PFC. Compared with the control group, pathway analysis indicated that venlafaxine and DG had similar effects on alanine, aspartate and glutamate metabolism.ConclusionThese findings demonstrate that DG has antidepressant-like, but not anxiolytic-like, effects in mice, suggesting that it might have therapeutic potential for the treatment of major depressive disorder.

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Transport of ginkgolides with different lipophilicities based on an hCMEC/D3 cell monolayer as a blood–brain barrier cell model

Cited by 25 publications

References 31 publications

Assessment of HBEC-5i endothelial cell line cultivated in astrocyte conditioned medium as a human blood-brain barrier model for ABC drug transport studies

Assessment of HBEC-5i endothelial cell line cultivated in astrocyte conditioned medium as a human blood-brain barrier model for ABC drug transport studies

Enhanced transport of plant‐produced rabies single‐chain antibody‐RVG peptide fusion protein across an in cellulo blood–brain barrier device

Metabolite-related antidepressant action of diterpene ginkgolides in the prefrontal cortex

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