GLYMPHARMA · Modulation of the glymphatic system: a novel tool for drug delivery to the central nervous system
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2018-10-01 → 2020-12-21
- EU contribution
- €200,195
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
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Results in brief
Modulation of the glymphatic system: a novel tool for drug delivery to the central nervous system
Several neurodegenerative diseases are characterised by the accumulation of harmful toxic waste in the brain. The prevalence and costs of Alzheimer's disease, for example, are rapidly expanding. On the other hand, no effective treatments for neurodegenerative diseases exist. Importantly, the blood-brain barrier has been a major limiting obstacle to the delivery of novel drug candidates to the brain, limiting the development of therapeutics. Due to this, novel administration routes for drugs have been used, including direct administration to the cerebrospinal fluid (intrathecal administration). The glymphatic system is a newly discovered network of perivascular spaces in the brain that enables the passage of cerebrospinal fluid into the brain to deliver nutrients and to clear the brain of harmful waste that accumulates during wakefulness. The glymphatic system is particularly active during sleep or certain anesthesia. This project focused on the pharmacology of the glymphatic system, addressing two crucial questions: 1) how to manipulate the glymphatic flow to optimise the clearance of toxic waste from the brain and 2) how to effectively deliver drugs administered to the central nervous system after their administration to the cerebrospinal fluid in intrathecal delivery. The objective of the project was to study the effects of glymphatic flow on the pharmacokinetics of drugs that have targets within the central nervous system and to investigate whether the glymphatic pathway could act as an efficient drug delivery pathway. This was achieved by utilizing novel methods such as microdialysis coupled with liquid chromatography-tandem mass spectrometry, semiquantitative spatial total drug concentration analyses by matrix-assisted laser desorption ionization mass spectrometry, and positron emission tomography imaging of radiolabeled drugs/cerebrospinal fluid tracers. Understanding the effects of glymphatic activity on drug central nervous system pharmacokinetics can be exploited in drug development to enhance drug availability in the brain or to decrease adverse effects.
Data: CORDIS, © European Union
Project objective
The prevalence of neurological diseases in the world is greatly increasing. However, drug development for central nervous system (CNS) diseases is difficult due to its protected nature behind the blood-brain barrier. The recently discovered glymphatic pathway consists of a para-arterial cerebrospinal fluid influx path and a para-venous interstitial fluid clearance route, coupled through convective flow of interstitial fluid supported by astrocytic aquaporin 4 (Aqp4) water channels. This macroscopic waste clearance system activates during sleep or anaesthesia. It also facilitates brain-wide distribution of endogenous compounds. Its function may explain the importance of sleep to mammals. GLYMPHARMA proposes that the glymphatic system essentially affects the concentrations of drugs in the CNS and that it can be exploited to facilitate CNS drug availability. Enhancing glymphatic fluxes have already been shown to increase the availability of CNS-targeted antibodies in deep brain structures.Studies will be performed at University of Copenhagen, Nedergaard lab, known for the discovery of the glymphatic system. I will use three state-of-the-art techniques to study glymphatic pharmacokinetics in mice: microdialysis to measure free drug concentrations, novel mass spectrometric techniques enabling spatial resolution, and microPET imaging to measure real-time 3D drug movements. Several glymphatic modulators (anaesthesia, sleep, Aqp4 knockout mice) will be used.GLYMPHARMA will be an excellent opportunity for my career development and it will facilitate real two-way knowledge transfer. I will be trained by the world-leading experts in the field. GLYMPHARMA will interest both basic researchers and clinicians and may impact the everyday life of citizens. The study may lead to the discovery of a novel drug delivery route and it may increase efficacy and safety of current drug therapies. These studies will lay the basis on our understanding of glymphatic pharmacokinetics.
Original text from CORDIS.
Participants
- KOBENHAVNS UNIVERSITET · KOBENHAVNCoordinatorDenmark
Links
Data: CORDIS, © European Union