Detoxification systems, passive and specific transport for drugs at the blood–CSF barrier in normal and pathological situations

Abstract

The production by the choroid plexuses of the cerebrospinal fluid (CSF), its circulation and resorption are unique characteristics of the central nervous system (CNS). In conjunction with the blood–brain barrier, the blood–cerebrospinal fluid barrier and the flow dynamic of this fluid are the main elements setting the cerebral availability of drugs. The exchanges between the blood and the cerebrospinal fluid across the choroidal epithelium are tightly regulated, in the presence of interepithelial tight junctions, by various transport and metabolic processes. In this article, we describe the different pathways of biotransformation present at the choroid plexus for drug and toxic compounds, and review the evidence that they indeed can act as a mechanism of neuroprotection. Then, we focus on the expression of nucleoside transporters and multispecific drug transporters at the choroid plexus, and the influence of these various transport systems on the cerebral availability of pharmacologically active anti-HIV nucleoside analogs. Pharmacological strategies that can be developed to increase either brain protection or brain drug delivery at the choroid plexus will be presented. Finally, the status of drug transport in the context of CNS diseases and the consequences of their possible alteration will be discussed.

Introduction

In the central nervous system (CNS), the highly specialized neural cells require a fine homeostasis of the brain extracellular fluid (ECF) to fulfill their physiological functions. The maintenance of this homeostasis, despite the variations in plasma concentrations of ions and other solutes, is achieved by the specific properties of the blood–brain interfaces, i.e. the cerebral capillaries, the choroid plexuses and the meningeal arachnoid, which control the exchange processes between the blood and the brain, and by the existence of the cerebrospinal fluid (CSF) circulatory system which is specific to the CNS. The CSF fulfills several functions, ranging from mechanical (buoyancy, volume adjustment of the brain) to sink and drainage action, nutrient and protein supply, osmolyte and buffering regulation. It also appears to be involved in neuro-immune regulation and in volume transmission of neuroactive compounds. It allows in particular the delivery of active endogenous substances and drugs to subarachnoid spaces, velae and brain arteries, and to periventricular areas [1], [2], [3], [4].

Four choroid plexuses, located in the lateral, third and fourth ventricles of the brain, form the interface between the blood and the ventricular CSF that they secrete. They are formed by a tight epithelium surrounding a conjunctive stroma containing large fenestrated vessels and immune cells. The real barrier between the blood and the CSF (i.e. BCSFB) is located at the epithelium, whose cells are sealed by tight junctions [4], [5].

The choroidal epithelium develops locally a large surface area, as it organizes into numerous villi, and as the epithelial cells develop a thick apical brush border membrane and basolateral infoldings [6]. The choroid plexuses are thus a very powerful site of transport, the importance of which is increased by the fact that both the CSF and the blood are circulating fluids, and the blood flow in the choroidal tissue is the highest among the brain structures [7], [8]. The exchanges across the choroidal epithelium appear however tightly regulated, in the presence of tight junctions linking the cells together, by different types of transport and metabolic processes.

Exchanges across the choroidal epithelium can occur in both directions. The choroid plexuses are indeed involved in the CSF delivery of nutrients and biologically active compounds, or can synthesize and secrete compounds such as trophic factors or specific proteins into the CSF [5], [9]. They also protect the CSF by preventing the entry of other potentially toxic substances, they actively eliminate brain-borne compounds, thus participating to the sink action attributed to the CSF, and overall they assume an important neuroprotective function.

The different regulatory mechanisms that could influence exchange processes at the blood–CSF barrier are summarized in Fig. 1. The presence of tight junctions will restrict the paracellular route, and thus the entry of polar compounds, which are not substrates for transporters (a). Passive diffusion across the cell membrane will occur for more lipophilic compounds of low to medium molecular weight (b). Like for any cell monolayer, and providing no regulatory mechanism other than diffusion is involved, the rate of transfer of these compounds will be roughly function of their octanol/water partition coefficient divided by their diffusion coefficient [10], with the exception of some highly lipophilic compounds which may behave differently and not diffuse easily out of the cells. Bidirectional or inwardly directed basolateral transport proteins can facilitate the entry of compounds (usually nutrients or micronutrients) into the CSF. They may work in conjunction with other apical transporters (c). Outwardly directed basolateral transport proteins may prevent the entry into the epithelial cell, and thus into the CSF, of undesired compounds which may include drugs and toxic xenobiotics (d). Bidirectional or inwardly directed apical transport proteins can increase the elimination rate of CSF-borne endogenous metabolites, but also of drugs, across the epithelium into the blood. They may also limit the penetration of blood-borne compounds into the CSF. These apical proteins may work in concert with other transport systems, located at the basolateral membrane of the cells (e). Finally, metabolic processes occurring within the cells can biotransform different types of potentially toxic compounds into-usually-less deleterious metabolites (f). This process may be coupled to transporters allowing the extrusion out of the cells of the produced metabolites. Drugs can be concerned by such pathways, and enzymes responsible for drug metabolism are usually multispecific and accept a broad range of substrates.

In this review, we will comment on these different mechanisms that are involved in transport regulation for drugs and toxic compounds at the choroid plexuses. We will especially describe the role of biotransformation processes as a mechanism of neuroprotection at the choroid plexus. Then, the choroidal transporters that can influence drug availability into the CNS will be briefly described, and the example of pharmacologically active nucleoside analogs transport at the choroid plexuses presented in detail. Pharmacological strategies that can be developed to increase either brain protection or brain drug delivery at the choroid plexus will be discussed. Finally, in a physiopathological context, the interaction between drugs and endogenous substrates for transporters, and the alteration of the permeability and transport properties of the choroid plexuses will be discussed.