P-Glycoprotein Expression in Mouse Brain Increases with Maturation

Abstract

The mdr1a isoform of P-glycoprotein (Pgp) is an integral plasma membrane efflux pump expressed in adult brain capillary endothelial cells and astrocytes of the blood-brain barrier. We determined the developmental pattern of Pgp expression in brain tissue at embryonic day 16 (E16), day of life 0 (D0), day of life 7 (D7), day of life 21 (D21), and adults (Ad). The relative expression of Pgp mRNA and protein was indexed as a percent (mean ± SEM) of D0 levels. Pgp mRNA levels increased significantly (p < 0.01) with maturation (E16: 75 ± 8%; D21: 303 ± 37%, and Ad: 1,160 ± 120%). Similarly, Pgp protein expression was observed at E16 and increased significantly (p < 0.01) during development (E16: 52 ± 8%; D7: 187 ± 23%; D21: 440 ± 48%, and Ad: 441 ± 56%). This developmental pattern of enhanced blood-brain barrier Pgp expression with maturation was confirmed by immunohistochemistry. We conclude that (i) Pgp expression in mouse brain is limited during late embryogenesis and the newborn period; (ii) Pgp expression increases markedly with postnatal maturation, and (iii) by D21 brain Pgp protein expression approximates adult levels.

The ontogeny of P-glycoprotein in the developing human blood–brain barrier: implication for opioid toxicity in neonates

“…By 3-6 mo of life, P-gp levels in the brain endothelial cells approximated those in the adults. This developmental pattern mimics what has been reported in the mouse brain (23). P-gp expression in the mouse brain was limited during late embryogenesis and the newborn period and increased remarkably with postnatal maturation reaching adult levels by day 21 of life (23).…”

“…This developmental pattern mimics what has been reported in the mouse brain (23). P-gp expression in the mouse brain was limited during late embryogenesis and the newborn period and increased remarkably with postnatal maturation reaching adult levels by day 21 of life (23). In humans, the intensity of P-gp immunostaining in the microvessel endothelial cell increased from GA 22 wk up to term but the P-gp intensity at term was still significantly lower when compared to adults (25).…”

“…P-gp has been detected as early as embryonic day 10.5 in the mouse brain and served as the earliest marker for endothelial cell differentiation during BBB development (22). P-gp gene expression in the mouse brain is low during late gestation and reaches adult levels by 3 wk of life (22)(23)(24).…”

Biological risks for neurological abnormalities associated with hyperbilirubinemia

“…Interestingly, studies that have examined the P-glycoprotein expression in mouse brain, another protein that participates in limiting the accumulation of substances in the central nervous system cells and in the cerebrospinal fluid, 6 verified a marked increase with postnatal maturation. 22 In addition, inhibition of Mrp1 function by MK571 in mature neurons and astrocytes was associated with an increase in UCB-induced nerve cell toxicity and immunostimulant effects, as observed by an enhanced loss of both cell viability and function, together with a higher secretion of IL-1b, TNF-a and glutamate, reinforcing the protective role of Mrp1 against UCB neurotoxic effects. 21 Collectively, these observations are a start-up point for the research, which hopefully will generate a better understanding of the proneness of premature infants to UCB encephalopathy.…”

The mechanisms of sudden-onset type adverse reactions to oseltamivir

“…Carboxylesterase [48] and brain P-gp [49] of new-borns are particularly immature, and new-born infants are at very high risk of brain exposure of oseltamivir. The topic of adverse effects on pregnant mothers, foetuses, and new-borns will be discussed elsewhere, as space in this review is limited.…”