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. 2008 Aug;39(4):211-8.
doi: 10.1055/s-0028-1103272. Epub 2009 Jan 22.

ABC transporter (P-gp/ABCB1, MRP1/ABCC1, BCRP/ABCG2) expression in the developing human CNS

M Daood  1 , C Tsai, M Ahdab-Barmada, J F Watchko
Affiliations

ABC transporter (P-gp/ABCB1, MRP1/ABCC1, BCRP/ABCG2) expression in the developing human CNS

M Daood et al. Neuropediatrics. 2008 Aug.

Abstract

P-glycoprotein (P-gp/ABCB1), multidrug resistance associated protein 1 (MRP1/ABCC1), and breast cancer resistance protein (BCRP/ABCG2) are plasma membrane efflux pumps that limit the intracellular uptake and retention of numerous lipophilic, amphipathic xeno- and endobiotics. Little is known about the neonatal and developmental expression of P-gp/ABCB1, MRP1/ABCC1, and BCRP/ABCG2 in the human central nervous system (CNS), therefore post-mortem CNS tissue from infants born at 22 (0/7)-42 (0/7) weeks of gestation and adults was immunostained to determine their ontogeny and cellular localization. P-gp/ABCB1 immunostaining was observed in microvessel endothelial cells as early as 22 (0/7) weeks, increasing in prevalence and intensity with maturation, and later in gestation in large pyramidal neurons. MRP1/ABCC1 immunostaining was prominent early in the choroid plexus and ventricular ependyma, and noted later in large pyramidal neurons. BCRP/ABCG2 expression was limited to microvessel endothelial cells. P-gp/ABCB1, MRP1/ABCC1 and BCRP/ABCG2 in adult brain matched term newborn CNS but with more intense immunostaining. We conclude that P-gp/ABCB1, MRP1/ABCC1, and BCRP/ABCG2 are expressed in a developmental, cell specific, fashion in the human CNS. The complementary pattern of P-gp/ABCB1 and BCRP/ABCG2 at the blood-brain with MRP1/ABCC1 at the blood-CSF barriers may limit CNS uptake and retention of drugs and toxins in neonates.

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Figures

Figure 1
Figure 1
P-gp/ABCB1 immunostaining in sections of human brainstem as a function of age, using 3,3’-diaminobenzidine as chromogen: (A) adult vessel cross-section demonstrates staining of endothelium; (B) adult microvessels; (C) 42 week gestation; (D) 35 week gestation; (E) 30 week gestation; and (F) 26 week gestation newborns. Magnification is 400 X.
Figure 1
Figure 1
P-gp/ABCB1 immunostaining in sections of human brainstem as a function of age, using 3,3’-diaminobenzidine as chromogen: (A) adult vessel cross-section demonstrates staining of endothelium; (B) adult microvessels; (C) 42 week gestation; (D) 35 week gestation; (E) 30 week gestation; and (F) 26 week gestation newborns. Magnification is 400 X.
Figure 1
Figure 1
P-gp/ABCB1 immunostaining in sections of human brainstem as a function of age, using 3,3’-diaminobenzidine as chromogen: (A) adult vessel cross-section demonstrates staining of endothelium; (B) adult microvessels; (C) 42 week gestation; (D) 35 week gestation; (E) 30 week gestation; and (F) 26 week gestation newborns. Magnification is 400 X.
Figure 1
Figure 1
P-gp/ABCB1 immunostaining in sections of human brainstem as a function of age, using 3,3’-diaminobenzidine as chromogen: (A) adult vessel cross-section demonstrates staining of endothelium; (B) adult microvessels; (C) 42 week gestation; (D) 35 week gestation; (E) 30 week gestation; and (F) 26 week gestation newborns. Magnification is 400 X.
Figure 1
Figure 1
P-gp/ABCB1 immunostaining in sections of human brainstem as a function of age, using 3,3’-diaminobenzidine as chromogen: (A) adult vessel cross-section demonstrates staining of endothelium; (B) adult microvessels; (C) 42 week gestation; (D) 35 week gestation; (E) 30 week gestation; and (F) 26 week gestation newborns. Magnification is 400 X.
Figure 1
Figure 1
P-gp/ABCB1 immunostaining in sections of human brainstem as a function of age, using 3,3’-diaminobenzidine as chromogen: (A) adult vessel cross-section demonstrates staining of endothelium; (B) adult microvessels; (C) 42 week gestation; (D) 35 week gestation; (E) 30 week gestation; and (F) 26 week gestation newborns. Magnification is 400 X.
Figure 2
Figure 2
3-D bar graph of Pgp/ABCB1 microvessel endothelial cell immunostaining prevalence and intensity as a function of age for the thalamus (A) and cerebral cortex (B) demonstrating earlier Pgp/ABCB1 expression in posterior forebrain and increasing P-gp/ABCB1 immunostaining intensity with maturation in both CNS regions. Immunostaining intensity was scored as negative (0), detectable (+1), low (+2), intermediate (+3), or high (+4).
Figure 2
Figure 2
3-D bar graph of Pgp/ABCB1 microvessel endothelial cell immunostaining prevalence and intensity as a function of age for the thalamus (A) and cerebral cortex (B) demonstrating earlier Pgp/ABCB1 expression in posterior forebrain and increasing P-gp/ABCB1 immunostaining intensity with maturation in both CNS regions. Immunostaining intensity was scored as negative (0), detectable (+1), low (+2), intermediate (+3), or high (+4).
Figure 3
Figure 3
P-gp/ABCB1 immunostaining of large pyramidal neurons in brainstem (36 week gestation, magnification is 400 X) (A), and choroid plexus (36 week gestation, magnification is 200 X) (B), using 3,3’-diaminobenzidine as chromogen. Pyramidal cells evidenced both membranous and cytoplasmic P-gp/ABCB1 immunostaining.
Figure 3
Figure 3
P-gp/ABCB1 immunostaining of large pyramidal neurons in brainstem (36 week gestation, magnification is 400 X) (A), and choroid plexus (36 week gestation, magnification is 200 X) (B), using 3,3’-diaminobenzidine as chromogen. Pyramidal cells evidenced both membranous and cytoplasmic P-gp/ABCB1 immunostaining.
Figure 4
Figure 4
MRP1/ABCC1 immunostaining using 3,3’-diaminobenzidine as chromogen of choroid plexus (35 week gestation; magnification is 200 X) (A); large pyramidal neurons in thalamus (35 week gestation; magnification is 400 X) (B); and ventricular ependyma (35 week gestation; magnification is 200 X) (C). Pyramidal cells evidenced both membranous and cytoplasmic MRP1/ABCC1 immunostaining. MRP1/ABCC1 immunostaining was not observed in brain microvessel endothelial cells at any gestational age or in adults (adult, magnification is 400X) (D).
Figure 4
Figure 4
MRP1/ABCC1 immunostaining using 3,3’-diaminobenzidine as chromogen of choroid plexus (35 week gestation; magnification is 200 X) (A); large pyramidal neurons in thalamus (35 week gestation; magnification is 400 X) (B); and ventricular ependyma (35 week gestation; magnification is 200 X) (C). Pyramidal cells evidenced both membranous and cytoplasmic MRP1/ABCC1 immunostaining. MRP1/ABCC1 immunostaining was not observed in brain microvessel endothelial cells at any gestational age or in adults (adult, magnification is 400X) (D).
Figure 4
Figure 4
MRP1/ABCC1 immunostaining using 3,3’-diaminobenzidine as chromogen of choroid plexus (35 week gestation; magnification is 200 X) (A); large pyramidal neurons in thalamus (35 week gestation; magnification is 400 X) (B); and ventricular ependyma (35 week gestation; magnification is 200 X) (C). Pyramidal cells evidenced both membranous and cytoplasmic MRP1/ABCC1 immunostaining. MRP1/ABCC1 immunostaining was not observed in brain microvessel endothelial cells at any gestational age or in adults (adult, magnification is 400X) (D).
Figure 4
Figure 4
MRP1/ABCC1 immunostaining using 3,3’-diaminobenzidine as chromogen of choroid plexus (35 week gestation; magnification is 200 X) (A); large pyramidal neurons in thalamus (35 week gestation; magnification is 400 X) (B); and ventricular ependyma (35 week gestation; magnification is 200 X) (C). Pyramidal cells evidenced both membranous and cytoplasmic MRP1/ABCC1 immunostaining. MRP1/ABCC1 immunostaining was not observed in brain microvessel endothelial cells at any gestational age or in adults (adult, magnification is 400X) (D).
Figure 5
Figure 5
Immunofluoresence of MRP1/ABCC1 (A), the Purkinje cell marker calbinin (B), and their co-localization (C) in Purkinje cells of the thalamus (36 week gestation; magnification is 100 X).
Figure 5
Figure 5
Immunofluoresence of MRP1/ABCC1 (A), the Purkinje cell marker calbinin (B), and their co-localization (C) in Purkinje cells of the thalamus (36 week gestation; magnification is 100 X).
Figure 5
Figure 5
Immunofluoresence of MRP1/ABCC1 (A), the Purkinje cell marker calbinin (B), and their co-localization (C) in Purkinje cells of the thalamus (36 week gestation; magnification is 100 X).
Figure 6
Figure 6
MRP1/ABCC1 immunostaining using 3,3’-diaminobenzidine as chromogen demonstrating localization to the Purkinje cell layer of the cerebellum (35 week gestation; magnification is 200 X (A); magnification is 400 X (B).
Figure 6
Figure 6
MRP1/ABCC1 immunostaining using 3,3’-diaminobenzidine as chromogen demonstrating localization to the Purkinje cell layer of the cerebellum (35 week gestation; magnification is 200 X (A); magnification is 400 X (B).
Figure 7
Figure 7
BCRP/ABCG2 immunostaining using 3,3’-diaminobenzidine as chromogen was observed in brain microvessel endothelial cells (A) in all age groups and brain regions (adult thalamus; magnification is 400 X). There was no evidence of BCRP/ABCG2 immunostaining in neurons (B) (adult thalamus; magnification is 400 X) or choroid plexus epithelium (C) (adult; magnification is 200 X).
Figure 7
Figure 7
BCRP/ABCG2 immunostaining using 3,3’-diaminobenzidine as chromogen was observed in brain microvessel endothelial cells (A) in all age groups and brain regions (adult thalamus; magnification is 400 X). There was no evidence of BCRP/ABCG2 immunostaining in neurons (B) (adult thalamus; magnification is 400 X) or choroid plexus epithelium (C) (adult; magnification is 200 X).
Figure 7
Figure 7
BCRP/ABCG2 immunostaining using 3,3’-diaminobenzidine as chromogen was observed in brain microvessel endothelial cells (A) in all age groups and brain regions (adult thalamus; magnification is 400 X). There was no evidence of BCRP/ABCG2 immunostaining in neurons (B) (adult thalamus; magnification is 400 X) or choroid plexus epithelium (C) (adult; magnification is 200 X).
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