Exploring the interstitial system in the brain: the last mile of drug delivery

Abstract

Brain interstitial system (ISS) is a nanoscale network of continuously connected tubes and sheets surrounding each neural cell in the central nervous system. ISS usually accounts for ∼20% of the brain volume, far more than the cerebral blood vessels, which account for 3%. The neuronal function, signaling pathways, and drug delivery are all closely related to the microenvironment provided by ISS. The objective of this paper is to give the readers a clear outline of detection, anatomy, function, and applications of ISS. This review describes the techniques propelling the exploration for ISS in chronological order, physiological function and pathological dysfunction of ISS, and strategies for drug delivery based on ISS. Biophysical features are the focus of ISS research, in which the diffusion characteristics have dominated. The various techniques that explore ISS take advantage of this feature. ISS provides an essential microenvironment for the health of cells and brain homeostasis, which plays an important functional role in brain health and disease. Direct intracranial administration allows the diffusion of drugs directly through ISS to successfully bypass the blood–brain barrier that prevents most drugs from reaching the brain. With the deepening of understanding of the brain ISS, the new research model that takes into account brain cells, cerebral vessels, and ISS will provide a new perspective and direction for understanding, utilizing, and protecting the brain.

The glymphatic system: Current understanding and modeling

“…The latest technical approach utilizes single particle tracking of carbon nanotubes. A review of transport in the ECS appeared in 2008 (Sykova ´and Nicholson, 2008), and more recent ones are now available (Nicholson and Hrab etova ´, 2017; Soria et al, 2020;Sun and Sun, 2021).…”

The use of continuous brain parenchymal impedance dispersion to measure glymphatic function in humans

“…Therefore, the increase in interstitial space fluid with glymphatic function will increase the cross-sectional area of the interstitial space channels and proportionally decrease the transcranial electrical resistance. In humans, the measurements range from 15-20% 79 but changes with sleep/wake have not been assessed. Using the rodent data as a proxy to what we might expect in humans, we would expect a 66% increase in interstitial volume with sleep to occur from of a 66% increase in cross-sectional area of the interstitial channels.…”

Peptides as Pharmacological Carriers to the Brain: Promises, Shortcomings and Challenges

“…While the exchange of small as well as larger molecules is essential to support the high metabolic demands of the brain, the structure of the BBB makes the delivery of drugs to the brain difficult. The problem of overcoming it to deliver psychotropic agents or drugs against CNS cancers, neurodegeneration, neuroinflammatory states, autoimmune disorders, and so on has vexed generations of researchers and physicians. − It is estimated that only 2% of “small” molecules can cross the BBB, regardless of their beneficial or noxious effects …”