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Dear All:
I will appreciate if someone could give me some help for the
following questions during my experiments in the lab.
What kind of cell line can I use for screening CNS drug? they are
similar to real brain endothelial cells physiologically or in genotype
What's the mechanism for screening CNS drug
How can I build up biomarker for CNS drug
What kind of model can best reflect CNS drug action?
Thank you very much.
Zheng
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The following message was posted to: PharmPK
Dear Zheng,
We use the human in vitro Blood Brain Barrier model developped by
Doctor Mabondzo A. for our internal or contract studies.
This model is based on a co-culture of astrocytes and endothelial
human primary cells.
It is prooven to be correlated with the in vivo behavior.
References:
Josserand and al.
Evaluation of drug penetration into the brain: a double study by in
vivo imaging with positron emission tomography and using an in vitro
model of the human blood-brain barrier.
J Pharmacol Exp Ther. 2006 Jan;316(1):79-86
Megard and al.
A co-culture-based model of human blood-brain barrier: application to
active transport of indinavir and in vivo-in vitro correlation.
Brain Res. 2002 Feb 15;927(2):153-67.
The results we used to assess are permeability, active transport and
metabolism.
For further informations, don't hesitate to contact me (of course,
off the list),
Best regards,
Laurent BAUDUIN
SPI-BIO
Physico-chemical analysis department
CEA - Saclay
DSV/iBiTec-S/SPI/LEMM
Batiment 136
F- 91191 Gif sur Yvette cedex
FRANCE
E-mail: laurent.bauduin.at.cea.fr
Web: www.spibio.com
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The following message was posted to: PharmPK
When dealing with the concept of BLOOD BRAIN BARRIER please consider:
It is not just a matter of endothelial and glial behavior.
Drugs may enter through the cerebro-spinal-fluid compartment (we
demonstrated that for Dexamethasone); the CSF-barrier is not uniform
and varies anatomically and functionally.
Drugs may also enter through regions of circumventricular organs that
have no blood brain barrier.
Drug uptake and distribution in the brain cannot be assessed with a
co-culture-based model and also not with positron emission
tomography. Sites of uptake may remain hidden if target cell
populations are dispersed, which is typical for hormone and drug
sites of action in the brain and spinal cord. For instance, a blood
brain barrier was considered for vitamin D based on results from
biochemical assays and whole body autoradiography, while with high
resolution receptor microautoradiography maps of target circuits have
been provided and CNS effects of vitamin D are now well recognized.
Walter E Stumpf (www.walterstumpf.com)
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The following message was posted to: PharmPK
Dr. Stumpf,
It is very good information. Do you have more information about how the
CSF-barrier is not uniform and varies anatomically and functionally.
What are regions of circumventricular organs and where are they located?
Many thanks
James
Dear Dr. Yang,
Misconceptions about the blood brain barrier are widespread. Lack of
detailed anatomical-functional considerations with undue
simplifications in concepts and methods prevail. An adequate
discussion is not possible in the present context. Some answers to
your questions are contained in:
Ermisch A, Landgraf R, and Ruehle H.J (Eds.): Circumventricular
Organs and Brain Fluid Environment. Progress in Brain Research,
Volume 91, Elsevier, 1992
Becker RP and Johari O (Eds): Scanning Electron Microscope Studies of
the Brain Ventricular Surface, in Scanning Electron Microscopy 1978,
II, published by Scanning Electron Microscopy Inc., AMF O?Hare, IL
(this may be difficult to obtain und it is quite special)
Data on brain penetration of dexamethasone are in:
Stumpf WE and Grant LD (Eds.): Anatomical Neuroendocrinolgy,
S.Karger, Basel, 1975, p, 262-269.
The best general source of information may be the volume by Ermisch
et al.
It turns out that there is no simple answer and high resolution and
sensitivity approaches may have to be considered in order to avoid
pitfalls; topographical-regional cut and burn assays may be the next
best to microscopic autoradiography. Radioassay of hemispheres or
whole body autoradiography are inadequate. There is just no simple
and uniform blood brain barrier! Most compounds will enter the brain
or regions of the brain, depending on dose and time (Drug Discovery
Today,11(2006):550-555) Best wishes, Walter E Stumpf
-- End forwarded message
Walter E Stumpf
2612 Damascus Church Rd
Chapel Hill, NC 27516
Tel/Fax: 919 942 8646
www.walterstumpf.com
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Dear Zheng,
5 HT4 receptor binding assay might be helpful at screening CNS drugs.
Suresh
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Dear Colleague,
Drug uptake and distribution in the brain could be assessed with a co-
culture based model of human BBB. The brain capillary composed by the
brain endothelial cells is the major route of drug entry in the
brain. For example, zidovudine (AZT) use currently in the clinical
managment of HIV-1 infection crosses the choroid plexus epithelial
barrier, which form the blood cerebrospinal fluid (CSF) barrier, and
enters the CSF (Klecker et al., 1987). However, AZT penetration in
the brain is limited (Ahmed et al., 1991; unpublished lab data).
These findings highlight that drug distribution in the CSF reflects
transport across the blood-CSF barrier, but not drug transport across
the BBB. Drugs may readily enter CSF but might penetrate brain very
poorly . Drug entry into CSF should not be used as an index of BBB
transport of the drug. The biological transport properties of the BBB
and the blood-CSF barrier are fundamentally very different. Once the
drug enters into the spinal fluid compartment via transport across
the blood-CSF barrier, the drug is rapidly eliminated via absorption
across the arachnoid villi into the superior sagital sinus. The
cocultured based model of human BBB or rat BBB is a practical
solution to a growing need and is powerfull tool for screening CNS drug
Dr Aloise MABONDZO,
CEA-Saclay
DSV/iBiTec-S/SPI
Batiment 136
91191 Gif sur Yvette Cedex (France)
Aloise.mabondzo.-a-.cea.fr
33 (0)1 69 08 13 21
Laurent BAUDUIN,
SPI-BIO
Physico-chemical analysis department
CEA - Saclay
DSV/iBiTec-S/SPI/LEMM
Batiment 136
F- 91191 Gif sur Yvette cedex
FRANCE
laurent.bauduin.-a-.cea.fr
Web: www.spibio.com
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