Abstract
The choroid plexuses (CPs), located in the brain ventricles, form an interface between the blood and the cerebrospinal fluid named the blood-cerebrospinal barrier, which, by the presence of tight junctions, detoxification enzymes, and membrane transporters, limits the traffic of molecules into the central nervous system. It has already been shown that sex hormones regulate several CP functions, including the oscillations of its clock genes. However, it is less explored how the circadian rhythm regulates CP functions. This study aimed to evaluate the impact of sex hormones and circadian rhythms on the function of CP membrane transporters. The 24 h transcription profiles of the membrane transporters rAbca1, rAbcb1, rAbcc1, rAbcc4, rAbcg2, rAbcg4, and rOat3 were characterized in the CPs of intact male, intact female, sham-operated female, and gonadectomized rats. We found that rAbcc1 is expressed in a circadian way in the CPs of intact male rats, rAbcg2 in the CPs of intact female rats, and both rAbcc4 and rOat3 mRNA levels were expressed in a circadian way in the CPs of intact male and female rats. Next, using an in vitro model of the human blood–cerebrospinal fluid barrier, we also found that methotrexate (MTX) is transported in a circadian way across this barrier. The circadian pattern of Abcc4 found in the human CP epithelial papilloma cells might be partially responsible for MTX circadian transport across the basal membrane of CP epithelial cells.
Highlights
To adapt to the environmental changes, living organisms have developed circadian rhythms, which, correspond to daily oscillations in biological processes [1,2,3].The mammalian circadian system is conceptualized in a hierarchical way, in which the suprachiasmatic nucleus (SCN) of the hypothalamus operates as the master clock
To explore the idea that the ABCC4 function varies according to the time of day, we studied the transport of MTX across the blood–CSF barrier (BCSFB) using an in vitro uptake assay
We have proven that membrane transporters present a circadian rhythmic expression in the choroid plexuses (CPs) of rats
Summary
To adapt to the environmental changes, living organisms have developed circadian rhythms, which, correspond to daily oscillations in biological processes [1,2,3].The mammalian circadian system is conceptualized in a hierarchical way, in which the suprachiasmatic nucleus (SCN) of the hypothalamus operates as the master clock. The circadian system has an impact on the disposal and action of drugs, determining the efficacy and toxicity of several therapeutic agents [6,7]. This evidence lends support to the idea that daily variations of drug-metabolizing enzymes and transport systems may interfere with drug pharmacokinetics, in the absorption, distribution, metabolism, and elimination mechanisms [8,9,10]. Some authors have raised interest in studying and understanding the molecular pathways involved in the circadian control of detoxifying enzymes and specific influx/efflux transporters to enhance therapeutic efficacy and minimize side effects [8,9,11,12] by adjusting drug administration schedules to follow circadian rhythms
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