Abstract
BackgroundP-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) play a critical role in keeping neurotoxic substances from entering the brain. We and others have previously reported an impact of inflammation on the regulation of adult blood–brain barrier (BBB) efflux transporters. However, studies in children have not been done. From the pediatric clinical perspective, it is important to understand how the central nervous system (CNS) and BBB drug efflux transporters differ in childhood from those of adults under normal and inflammatory conditions. Therefore, we examined and compared the regulation of P-gp and BCRP expression and transport activity in young and adult BBB and investigated the molecular mechanisms underlying inflammatory responses.MethodsRats at postnatal day (P) P21 and P84, corresponding to the juvenile and adult stages of human brain maturation, respectively, were treated with endothelin-1 (ET-1) given by the intracerebroventricular (icv) route. Twenty-four hours later, we measured P-gp and BCRP protein expression in isolated brain capillary by immunoblotting as well as by transport activity in vivo by measuring the unbound drug partitioning coefficient of the brain (Kp,uu,brain) of known efflux transporter substrates administered intravenously. Glial activation was measured by immunohistochemistry. The release of cytokines/chemokines (interleukins-1α, 1-β (IL-1β), -6 (IL-6), -10 (IL-10), monocyte chemoattractant protein (MCP-1/CCL2), fractalkine and tissue inhibitor of metalloproteinases-1 (TIMP-1)) were simultaneously measured in brain and serum samples using the Agilent Technology cytokine microarray.ResultsWe found that juvenile and adult BBBs exhibited similar P-gp and BCRP transport activities in the normal physiological conditions. However, long-term exposure of the juvenile brain to low-dose of ET-1 did not change BBB P-gp transport activity but tended to decrease BCRP transport activity in the juvenile brain, while a significant increase of the activity of both transporters was evidenced at the BBB in the adult brain. Moreover, juvenile and adult brain showed differences in their expression profiles of cytokines and chemokines mediated by ET-1.ConclusionsBBB transporter activity during neuroinflammation differs between the juvenile and adult brains. These findings emphasize the importance of considering differential P-gp and BCRP transport regulation mechanisms between adult and juvenile BBB in the context of neuroinflammation.
Highlights
P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) play a critical role in keeping neurotoxic substances from entering the brain
Blood–brain barrier integrity assessment after intracerebroventricular injection of endothelin-1 in rats An intact blood–brain barrier (BBB) simplifies the assessment of BBB-efflux transporter activity
There was no change in the quantitative real-time PCR analysis of zonula occludens-1 (ZO-1) mRNA from freshly isolated rat brain microvessels after ET-1 treatment. These results suggest that ET-1 under the conditions of these experiments does not change BBB permeability
Summary
P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) play a critical role in keeping neurotoxic substances from entering the brain. Adenosine triphosphate-binding cassette (ABC) transporters play a critical role in keeping neurotoxic substances from entering the brain and in transporting toxic metabolites out of the brain [1,2]. These transporters are largely responsible for the multidrug resistance (MDR) phenomenon, which plays a crucial role in treatment failure for several brain diseases such as seizure [3] and human immunodeficiency (HIV-1) infection disease [4,5]. In response to injury or brain diseases [6], the central nervous system (CNS) exhibits inflammatory features, which have effects on the expression and function of BBB efflux transporters in adults [7,8,9]. There is a wealth of evidence that age could have a significant effect on response to cytokines, which, in turn, could modulate BBB efflux transporters expression and activity [10,11,12,13] in an age-dependent manner
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