Blood-brain barrier methodology

Pardridge WM (ed.) (1998). Introduction to the blood-brain barrier. Methodology, Biology and Pathology. Cambridge University Press, Cambridge, UK. 

Introduction to the blood-brain barrier Methodology and biology, ed. W.H. Pardridge, 345. UK Cambridge University Press. 

Tsuji, A. Tamai, I. In Introduction to the Blood-Brain Barrier Methodology, Biology and Pathology, W. M. Pardridge, Ed. Cambridge University Press Cambridge, 1998, pp. 238-247. 

Pardridge WM. Transport of small molecules through the blood-brain barrier biology and methodology. Adv Drug Del Rev 1995 17 713-731. 

An important methodologic point about the majority of these studies is that they use a reduced preparation, in which the spinal cord is neurally isolated from the brain by a complete transection (129). The rationale for using this simplified preparation is that spinal reflex activity can be analyzed in the absence of supraspinal influences. However, transection may introduce other variables (i.e., ischemia, disruption of the blood-brain barrier, loss of tonic neural activity from supraspinal systems), which may result in drug effects on spinal reflexes that are quantitatively or even qualitatively different than those seen in the intact animal. Thus the following review of hallucinogen effects on spinal reflexes is organized into two main categories (a) studies in transected animals, and (b) those in decerebrate or intact preparations. 

Pardridge W (1999) Blood-brain barrier biology and methodology. J Neurovirol 5 556-569... 

M. Danhof, J.C. Verhoef, and D.D. Brei-mer. 1990. Transport of desglycinamide-arginine vasopressin across the blood-brain barrier in rats as evaluated by the unit impulse response methodology. Pharm. Res. 7 293-298. 

TerasakiT, Ohtsuki S. Brain-to-blood transporters for endogenous substrates and xenobiotics at the blood-brain barrier an overview of biology and methodology. NeuroRx 2005 2(l) 63-72. 

Broadwell RD, Baker BJ, Ebert PS, Hickey WF (1994) Allografts of CNS tissue possess a blood-brain barrier III. Neuropathological, methodological, and immunological considerations. Microsc Res Tech 27 471 94. 

The simplest methodology is two-dimensional (2D) quantitative structure-activity relationships (QSAR), in which calculated descriptors of molecules are related to an end point of interest via a mathematical relationship to estimate a numerical or categorical value for that end point. The mathematical relationship is fitted to a training set of compounds for which data for the end point has been measured experimentally. New molecules can then be described with the descriptors used in the model and their end point values predicted. 2D QSAR methods can be used to predict the interaction of compoimds with protein targets or antitargets and are widely used for prediction of physicochemical and ADME properties, such as hpophilicity, solubility, hiunan intestinal absorption, and blood-brain barrier penetration [18]. An excellent review of the strategies and pitfalls of 2D QSAR has been published by Lewis and Wood [19]. 

From a methodological point of view, tite PAMPA-BBB system is quite simple. The lipids, dissolved in dodecane, are soaked with a filter mounted in a two-compartment chamber. The drug is added to the donor compartment (which can be either the upper or lower chamber), and its passage through the artificial membrane is measured in the acceptor compartment (Fig. 14.17). A standard compound with well-characterized permeability proper-hes (e.g., verapamil) is tested in parallel. Compounds that readily cross the blood-brain barrier have an in vitro permeability (P,) > 2.7 10" cm s in the PAMPA assay. On the opposite, drugs with low blood-brain barrier permeation have a < 0.710 cm s". Beside... 

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