The glymphatic system enables the flow of cerebrospinal fluid into brain tissue, particularly during sleep, enabling the fluid to cleanse the tissue and carry with it metabolites accumulated in the bloodstream during waking hours. Previously, it has been observed that the function of the glymphatic system can be modified with drugs. This makes it an interesting target for drug development, particularly in relation to Alzheimer’s disease and other degenerative brain diseases involving the accumulation of metabolic products in the brain.
In addition to its general role in central nervous system clearance, the glymphatic system may also be relevant to the entry into the brain of drugs that affect the central nervous system. The blood-brain barrier protects the brain from exogenous compounds, which is why many drugs given orally cannot reach the brain. Instead, special routes of administration are required, such as direct administration to the cerebrospinal fluid.
Previously, drugs delivered to the cerebrospinal fluid were thought to be distributed primarily by slow diffusion into the brain and spinal cord. However, the glymphatic model challenges this notion. It has already been observed in laboratory animal models that certain drugs that activate the glymphatic system, such as the intensive care sedative dexmedetomidine, can increase the cerebral accessibility of drugs administered to the cerebrospinal fluid (article in Finnish only).
Surprisingly, a strong saline solution and other hypertonic solutions administered into the bloodstream accelerate the glymphatic flow of cerebrospinal fluid to the level of the brain. Hypertonic solutions, such as strong saline solutions and the sugar alcohol mannitol, are used, among other things, to reduce intracranial pressure in intensive care patients.
In a recently completed study, researchers from the University of Helsinki investigated how the glymphatic system and hypertonic solutions were used when administering pharmaceutical agents directly to the cerebrospinal fluid in the lower back, with the spinal cord as a drug target. how can be used. The study was published in controlled release journal,
Spinal morphine concentrations quadrupled and pain relief intensified
As a model drug, the researchers used the opioid morphine, which is used, for example, to treat postoperative pain and severe cancer pain. The spinal cord is one of the most important sites of action for morphine, which provides effective pain relief when administered locally to the cerebrospinal fluid.
The researchers simulated a typical patient-care situation in a rat model, administering morphine directly into the cerebrospinal fluid in the lumbar region, after which the rats received a hypertonic saline solution. The study showed that the combination of the two different techniques increased the concentration of morphine in the spinal cord by several folds.
Opioids are administered directly into the lumbar cerebrospinal fluid, mainly in the case of non-urgent surgery and cancer pain treatment, while hypertonic solutions are used in emergencies where vital functions are at risk. In fact, it is interesting to see that by combining the two methods used in vastly different patient groups, you can almost quadruple the spinal morphine concentration and increase pain relief.”
Kim Blomkvist, Doctoral Researcher, University of Helsinki
It is likely that this method may also be studied fairly quickly in humans, as both techniques are already in clinical use. According to the researchers, the combination of the two techniques should also be investigated with other pharmaceutical agents administered directly into the cerebrospinal fluid, many of which are in development.
Blomquist, KJ, and others. (2022) Systemic hypertonic saline enhances glymphatic spinal cord delivery of lumbar intrathecal morphine. Journal of Controlled Release. doi.org/10.1016/j.jconrel.2022.03.022.