Brain Structure and Function

, Volume 217, Issue 3, pp 687–718 | Cite as

Brainpeps: the blood–brain barrier peptide database

  • Sylvia Van Dorpe
  • Antoon Bronselaer
  • Joachim Nielandt
  • Sofie Stalmans
  • Evelien Wynendaele
  • Kurt Audenaert
  • Christophe Van De Wiele
  • Christian Burvenich
  • Kathelijne Peremans
  • Hung Hsuchou
  • Guy De Tré
  • Bart De Spiegeleer
Review

Abstract

Peptides are able to cross the blood–brain barrier (BBB) through various mechanisms, opening new diagnostic and therapeutic avenues. However, their BBB transport data are scattered in the literature over different disciplines, using different methodologies reporting different influx or efflux aspects. Therefore, a comprehensive BBB peptide database (Brainpeps) was constructed to collect the BBB data available in the literature. Brainpeps currently contains BBB transport information with positive as well as negative results. The database is a useful tool to prioritize peptide choices for evaluating different BBB responses or studying quantitative structure–property (BBB behaviour) relationships of peptides. Because a multitude of methods have been used to assess the BBB behaviour of compounds, we classified these methods and their responses. Moreover, the relationships between the different BBB transport methods have been clarified and visualized.

Keywords

Peptides Blood–brain barrier Permeability Distribution Brainpeps database 

List of symbols

%ID

Percentage injected dose

γ

Surface tension

γ0

Surface tension in pure buffer solution

ε

Dielectric constant

λ

Terminal rate constant

π

Surface pressure

Г

Surface excess concentration

Г

Limited surface excess concentration

A

Area of the filter, membrane surface area, capillary surface area

ABC transporter

ATP-binding cassette transporter

AD

Surface area of the test compound at the air–water interface

Am

Amount of test compound in brain

As

Cross-sectional area; surface area

ATP

Adenosine triphosphate

AUC

Area under the concentration curve

AUCbrain

Area under the concentration curve in brain

AUCplasma

Area under the concentration curve in plasma

BB

Brain-to-plasma concentration ratio at steady-state, blood–brain equilibrium distribution

BBB

Blood–brain barrier

BBB-PI

Blood–brain barrier permeability index

BCRP

Breast cancer resistance protein

BCSFB

Blood–cerebrospinal fluid barrier

BEI

Brain efflux index

BMEC

Brain microvessel endothelial cells

B/P

Brain-to-plasma concentration ratio at steady-state, blood–brain equilibrium distribution

Brainpeps

Blood–brain barrier peptide database

BSA

Bovine serum albumin

BUI

Brain uptake index

BW

Body weight

C

Concentration of test compound

C0

Initial concentration in donor chamber; minimum concentration to induce surface activity

Ca, CA, Cacc

Apical (luminal) side concentration, i.e. in the acceptor chamber

Caco-2

Human colon carcinoma cell line

Calcein-AM

Calcein acetoxymethyl ester

CBF

Cerebral blood flow

Cbr, Cbrain

Brain concentration

Cbr,tot, Cbr (total)

Total brain concentration

Cbuffer

Concentration in buffer

CCSF

Concentration in the CSF

CD

Compartmental distribution

Cdonor, Cd, CD, CDO, CI

Initial concentration of test compound in donor chamber

Cdial

Concentration of the dialysate

CECF

Concentration of test compound in brain ECF

Cin

Concentration of the perfusate; concentration in the carotid injection solution

Civ

Concentration of intravascular marker

Cl

Clearance

Cleff

Efflux clearance

ClH

Hepatic clearance

Clinf

Uptake clearance

Clp

Systemic clearance

ClR

Renal clearance

ClS

Systemic clearance

Cltest

Clearance of the test experiment

Clup

Initial uptake clearance

CMC

Critical micelle concentration

CNS

Central nervous system

CNS

Low brain penetrator

CNS+

High brain penetrator

Conc(test/ref)brain

Concentration ratio of test and reference compound in brain

Conc(test/ref)injectate

Concentration ratio of test and reference compound in injection solution

Corg

Concentration test compound in organic phase

Cout, Cdial

Concentration of the dialysate

Cp (t)

Plasma concentration at time t

Cpa

Arterial plasma concentration

Cperfusion, Cperf

Concentration in the perfusion solution

Cpl

Plasma concentration

Cpl,tot

Total plasma concentration

Cref

Concentration of the reference compound

Cref,brain

Concentration of the reference compound in the brain

Cref,inj

Concentration of the reference compound in the injected solutions

Cs

Concentration of the sample

Csat

Saturated concentration at which the surface pressure collapses

CSF

Cerebrospinal fluid

Cslice

Free drug concentration in tissue slice

Ctest

Concentration of the test compound

Ctest,brain

Concentration of the test compound in the brain

Ctest,inj

Concentration of the test compound in the injected solutions

Ctissue

Tissue concentration of the indicator

Ctot

Total concentration

Cu

Unbound concentration

Cu,brain

Unbound concentration in brain

Cu,plasma

Unbound concentration in plasma

Cwat

Concentration test compound in aqueous phase

Cwat,ion

Concentration of ionic species of test compound in aqueous phase

Cwat,neut

Concentration of neutral species of test compound in aqueous phase

D

Distribution coefficient; dilution factor

dQ/dt

Transport rate of test compound

E

Extraction of the test compound

ECF

Extracellular fluid

ED50

Dose producing 50% of the maximum response

EDTA

Ethylenediaminetetraacetic acid

ER

Efflux ratio; entity-relationship

Eref

Single pass extraction of the reference compound

Erefp

Extraction of the permeable marker

Erefv

Extraction of the vascular impermeable marker

Etest

Single pass extraction of the test compound

Exp.t

Exposure time

F

Regional flow rate

f

Fraction of plasma exchangeable compound

FK

Foreign key

fu

Unbound fraction

fu,brain

Unbound fraction in brain

fu,dil

Diluted unbound fraction

fu,meas

Free fraction measured

fu,plasma

Unbound fraction in plasma

GFR

Glomerular filtration rate

GLUT-1

Glucose transporter 1

hAAG

Human α1 acid glycoprotein

HPLC

High-performance liquid chromatography

IAM

Immobilized artificial membrane

IUPAC

International Union of Pure and Applied Chemistry

J

Brain uptake rate

Jmax

Maximal flux

Kaw

Air–water partition coefficient

Kd

Dissociation constant

keff

Apparent efflux rate constant

kel

Plasma elimination rate constant

kel

Efflux rate constant

ki

Unidirectional influx rate constant determined with imaging techniques

kIAM

IAM capacity factor

Kin

Unidirectional influx rate constant

Km

Michaelis–Menten constant

kout

Brain elimination rate constant

Kp

Brain-to-plasma partition coefficient

Kp,app

Apparent brain-to-plasma partition coefficient

Kp,brain

Brain-to-plasma concentration ratio

Kp,in

Intrinsic plasma-to-brain partition coefficient

Kp,uu

Brain-to-plasma partition coefficient of the free compound concentration

LAT-1

Large neutral amino acid transporter-1

Log Pcyclohexane/water

Log P value of the cyclohexane/water system

Log Poct/water

Log P value of the 1-octanol/water system

MBUA

Mouse brain uptake assay

MCT

Monocarboxylic transporters

MDCK

Madin–Darby canine kidney cells

MDR-1

Multidrug resistance gene

MID

Method identification

MRI

Magnetic resonance imaging

MRP-1

Multidrug resistance associated protein-1

NA

Avogadro constant

Nserum

Radioactivity measured per volume serum

Ntissue

Radioactivity measured per gram tissue

OID

Origin identification

P

Partition coefficient; permeability coefficient

PAMPA

Parallel artificial membrane permeation assay

Papp

Apparent permeability coefficient, determined with BMEC, co-culture, immortalized cell lines, Caco-2, MDCK and MBUA

Papp (AB)

Apparent permeability coefficient from apical to basolateral side

Papp (B–A)

Apparent permeability coefficient from basolateral to apical side

Papp,pampa

Apparent permeability coefficient, determined with PAMPA

Par-2

Brain parietal cortex area 2

PBID

Publication identification

Pc

Intrinsic carrier-mediated permeability

\( P_{\text{c}}^{\prime } \)

Apparent net carrier-mediated permeability

Pe

Endothelial permeability, effective PAMPA permeability

Peff

Effective PAMPA permeability

Pendoth

Endothelial permeability coefficient, determined with BMEC culture

PEPT1

Peptide transporter 1

PET

Positron emission tomography

Pfilter

Permeability of the filter

Pgp

P-glycoprotein

PI

Permeability index

PID

Peptide IDentification

Pm

Monolayer permeability determined with BMEC

Pp

Passive diffusive permeability

PR

Peak response

PS

Permeability–surface area coefficient

PSe

PS product for the endothelial cell monolayer

PSf

PS product of the control filter

PSt

Total PS product

Ptotal

Total permeability

Q

Cerebral blood flow

\( \dot{Q} \)

Rate of blood flow

QAR

Quantitative autoradiography

R

Gas constant; recovery

Rateeff

In vitro efflux rate

RBE4

Immortalized primary rat brain endothelial cells

Rdial

Recovery by gain

RID

Response identification

RL

Recovery by loss, retrodialysis

RP-HPLC

Reversed-phase HPLC

RR

Relative recovery

S

Capillary surface area

SMILES

Simplified molecular input line entry specification

SPECT

Single photon emission tomography

SV40

Simian vacuolating virus 40

T

Temperature; perfusion time

t

Time

t0

Dead time

t1/2

(Terminal) half-life

t1/2eq

Equilibration half-life

t1/2eq,in

Intrinsic equilibration half-life

T

Perfusion time

TEER

Transendothelial electrical resistance

TM-BBB

Transfected mouse endothelial cells

tr

Retention time of test compound

TR-BBB

Transfected rat endothelial cells

UML

Unified modelling language

V0

Initial distribution volume; plasma distribution volume of marker

Vacc, VA

Volume of the acceptor compartment

Vbr, Vb

Distribution volume in brain

VD

Volume of donor compartment; distribution volume in brain

Ve

Volume fraction of brain

Vi

Initial distribution volume; Volume of buffer film remaining around sample slice

Vmax

Maximum uptake rate

Vp

Plasma distribution volume

VR

Volume of acceptor compartment

Vu,br

Unbound brain distribution volume

Vv

Brain vascular volume

X

Amount of test compound in acceptor compartment

Notes

Acknowledgments

This work was supported by a PhD grant of ‘Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen)’ (73402 to S.V.D.).

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Sylvia Van Dorpe
    • 1
  • Antoon Bronselaer
    • 2
  • Joachim Nielandt
    • 2
  • Sofie Stalmans
    • 1
  • Evelien Wynendaele
    • 1
  • Kurt Audenaert
    • 3
  • Christophe Van De Wiele
    • 4
  • Christian Burvenich
    • 5
  • Kathelijne Peremans
    • 5
  • Hung Hsuchou
    • 6
  • Guy De Tré
    • 2
  • Bart De Spiegeleer
    • 1
  1. 1.Drug Quality and Registration (DruQuaR) Group, Faculty of Pharmaceutical SciencesGhent UniversityGhentBelgium
  2. 2.Department of Telecommunications and Information Processing, Faculty of Engineering and ArchitectureGhent UniversityGhentBelgium
  3. 3.Department of Psychiatry and Medical Psychology, Faculty of Medicine and Health SciencesGhent Hospital UniversityGhentBelgium
  4. 4.Department of Radiotherapy and Nuclear Medicine, Faculty of Medicine and Health SciencesGhent Hospital UniversityGhentBelgium
  5. 5.Departments of Physiology and Medical Imaging, Faculty of Veterinary MedicineGhent UniversityMerelbekeBelgium
  6. 6.Pennington Biomedical Research Center, BBB GroupBaton RougeUSA

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