How do drugs enter and leave the central nervous system?

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How drugs enter and leave tissues is critical to their usefulness in treating disease. The most effective, low toxicity treatment is no use if it cannot reach its target, and a highly toxic drug can be used safely if its toxic form is rapidly removed from the body. In this project, we aim to understand how drugs can enter and leave the central nervous system (CNS).The movement of almost all molecules in and out of the CNS is tightly regulated by the blood brain barrier, which restricts movement between the vascular system and the brain. In addition, there is the choroid plexus that produces cerebral spinal fluid (CSF) in the brain ventricles and the arachnoid villi that remove CSF. This regulation is critical in limiting entry of compounds that exhibit neuro toxicity but is also a significant barrier to pharmacological manipulation of disease via the central nervous system. Furthermore, toxicity and drug efficacy must be balanced, epitomised by the treatment of infective meningitis where antimicrobials often have significant toxicity. However, despite its importance, how most drugs enter and leave the central nervous system is unknown.In this project, we will investigate how an antimicrobial enters and the leaves the CNS during the treatment of meningitis. This will inform the use, and potentially the refinement, of this drug but will also increase our knowledge of the wider mechanisms of drug movement in and out of the CNS. The form of CNS infection we will focus on is cryptococcal meningitis (Johnston and Gibson, 2016; http://goo.gl/bJaQco).Treating cryptococcal meningitis (CM) is hindered by late presentation and diagnosis late in disease. The best available therapy is a liposomal formulation of amphotericin B (AmpB) but its toxicity and cost make it prohibitive for use in most low and middle income countries, where there is the largest burden of disease. Recent work from the Hope laboratory has shown that AmpB has a long half-life, and that a shorter course of treatment would not be therapeutically inferior but may be less toxic (Lestner et al., 2017 (http://goo.gl/hR8kLU) ; AMBITON:cm clinical trial; Molefi et al., 2015). Furthermore, the Johnston lab has generated a unique in vivo experimental model in zebrafish for studying the entry and exit of therapeutic compounds into the CNS (Lestner et al., 2017; van Leeuwen et al., 2017, in preparation). Therefore, we will study the mechanism of AmpB CNS entry and exit to identify opportunities for improving AmpB treatment, increasing therapeutic dose without increasing toxicity. The project will have 3 parts: 1. Zebrafish have a well conserved blood brain barrier and fluid exchange structures with humans. We have recently developed a new in vivo model of the blood brain barrier and choroid plexus that enables us to directly image both structures over a long period of time. We will use fluorescently labelled AmpB injected into the blood stream and live image its dynamics throughout the body. We will be able to quantify localisation and drug dynamics to develop potential models for AmpB dynamics in the CNS 2. We will test our models for AmpB dynamics using well-established experimental models of cryptococcal meningitis in rodent and leporine hosts by performing mass spectrometry on brain samples of the different areas of the CNS and at different time points to confirm findings in zebrafish. 3. With our non-academic partner Gilead, we will investigate potential modifications to the liposomal AmpB formulation and how our mechanistic studies might impact therapy using AmpB.