Periodic Reporting for period 1 - GLYMPHARMA (Modulation of the glymphatic system: a novel tool for drug delivery to the central nervous system)
Berichtszeitraum: 2018-10-01 bis 2020-09-30
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.
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.
During the project a significant number of important techniques was set up, including electroencephalogram of awake and anesthetized rodents and microdialysis of small-molecule drugs from the brain parenchyma. An especially important and novel line of work included the combination of single-photon emission tomography (SPECT) and magnetic resonance imaging (MRI) of small molecule drugs and large biological molecules to track the flow of cerebrospinal fluid either in the head and neck area or the whole animal.
We found that the SPECT imaging can provide quantitative data about the influx of cerebrospinal fluid in the brain but also map the different efflux routes of cerebrospinal fluid from the intracranial space. The resolution of SPECT is poorer than MRI imaging, but on the other hand the whole animal can be covered quantitatively. We found that the anesthetic state per se is not enough to induce high glymphatic state and efficient glymphatic delivery of drugs from the cerebrospinal fluid space, instead, several other physiological factors govern glymphatic flow. We found the manipulation of plasma osmolarity to be a highly relevant method for enhancing glymphatic flow and delivering drugs from the cerebrospinal fluid to the brain.
Part of the results obtained are published in international journals as peer-reviewed articles. So far, one articles are already published, one review article has been submitted to a high-profile journal and four more are in preparation. Two collaborative papers (related to the project, but not included as main scientific output) and one article directed to physicians (in Finnish) are published as well. In addition, results have been presented at international conferences, and also in several smaller clinic meetings. In addition, the glymphatic system and its implications were presented in several press interviews.
The project did not yield specific intellectual property. However, benefits for the research community, achieved through presentations of results at local meetings and international conferences, include the important consideration for the field that the glymphatic system holds potential in the delivery of drugs to the brain in preclinical models. The next step in this line of research is aiming at more thorough understanding of the physiological factors governing glymphatic flow, but also studying concepts of glymphatic drug delivery in clinical trials.
We found that the SPECT imaging can provide quantitative data about the influx of cerebrospinal fluid in the brain but also map the different efflux routes of cerebrospinal fluid from the intracranial space. The resolution of SPECT is poorer than MRI imaging, but on the other hand the whole animal can be covered quantitatively. We found that the anesthetic state per se is not enough to induce high glymphatic state and efficient glymphatic delivery of drugs from the cerebrospinal fluid space, instead, several other physiological factors govern glymphatic flow. We found the manipulation of plasma osmolarity to be a highly relevant method for enhancing glymphatic flow and delivering drugs from the cerebrospinal fluid to the brain.
Part of the results obtained are published in international journals as peer-reviewed articles. So far, one articles are already published, one review article has been submitted to a high-profile journal and four more are in preparation. Two collaborative papers (related to the project, but not included as main scientific output) and one article directed to physicians (in Finnish) are published as well. In addition, results have been presented at international conferences, and also in several smaller clinic meetings. In addition, the glymphatic system and its implications were presented in several press interviews.
The project did not yield specific intellectual property. However, benefits for the research community, achieved through presentations of results at local meetings and international conferences, include the important consideration for the field that the glymphatic system holds potential in the delivery of drugs to the brain in preclinical models. The next step in this line of research is aiming at more thorough understanding of the physiological factors governing glymphatic flow, but also studying concepts of glymphatic drug delivery in clinical trials.
The project dramatically improved the organisatory, technical, and networking skills of the researcher. In addition, the project set the basis for proficient collaborations between the different parties involved in the project. For instance, the researcher and the host institution are actively collaborating to put the results of the present project into an independent research line, with the involvement of national and international institutions and scientists. Results of the action paved the way for the acquisition of several research grants and allowed the researcher to start an own research line.
Besides the impact in planning and executing further scientific activities, the project provided information of interest for the society. During public engagement activities, results were discussed to emphasize the importance of sleep and brain states to brain health and the efficacy of drugs targeting the brain.
Besides the impact in planning and executing further scientific activities, the project provided information of interest for the society. During public engagement activities, results were discussed to emphasize the importance of sleep and brain states to brain health and the efficacy of drugs targeting the brain.