![]() Some studies have implied that ISF originates from the cerebrospinal fluid (CSF), cell metabolism, and the vascular system. The source of ISF is still being investigated. The ISF provides a direct medium for the supply of nutrients, removal of waste, and intercellular communication by encasing and incessantly soaking the neural cells. The brain ISF, a water solvent containing ions, and gaseous and organic molecules such as proteins, peptides, enzymes, dopamine, and extracellular vesicles (EVs) secreted by cells, and the moving chains of glycoproteins attached to the ECM ( Fig. The constituents of the ISS comprise ISF, ECM, and diffusely distributed interstitial matrix (ISM) ( Fig. Such changes may also contribute to the maintenance of epilepsy because an accumulation of macromolecules within the brain parenchyma could alter the extracellular ionic equilibrium, and impact neuronal excitability. ![]() In conditions such as epilepsy, the synchronized firing of a population of neurons may considerably change the geometry of ISS as well as the ISF drainage. The geometry of the brain ISS also undergoes modification in aging due to the loss of synapses, neurons, dendritic regression, changes in morphology and numbers of glia, senoinflammation, and deposition of amyloid plaques. Significant transformations ensue in ISS during the development of the brain due to events such as neurogenesis, neuronal migration and differentiation, expansion of dendritic tree, synapto-genesis, gliogenesis, synaptic stripping by microglia, and myelination. However, the magnitude, locus, and proportions of the brain ISS are not static. The ISS is circumscribed by the plasma membrane of neurons or glia and the wall of blood vessels ( Fig. The brain is made up of neural cells such as neurons, astrocytes, oligodendrocytes, and microglia, the vasculature comprising arteries, arterioles, capillaries, venules and veins, and the interstitial system (ISS) The brain cells are cushioned and supported by two forms of brain-specific fluids, the brain interstitial fluid (ISF) and the cerebrospinal fluid (CSF) The ISF occupies the brain ISS, whereas the CSF fills the cerebral ventricles and the subarachnoid space The brain ISS is a dynamic and complex space connecting the vascular system and neural networks, which is composed of ISF and the extracellular matrix (ECM) ( Fig 1) The ISS is the primary compartment of the brain microenvironment that provides the immediate accommodation space for neural cells, which accounts for 15-20% of the overall brain volume The space between the adjacent neurons, contiguous glia, or the adjoining neurons and glia is also known as the extracellular space (ECS) ![]() Moreover, the role of ISS in the passage of extracellular vesicles (EVs) released from neural cells and the rapid targeting of therapeutic EVs into neural cells in the entire brain following an intranasal administration, and the promise and limitations of ISS based drug delivery approaches are discussed Besides, accumulation of tau in the brain ISS in conditions such as Alzheimer’s disease and its link to the sleep-wake cycle and sleep deprivation, clearance of ISF in a deep sleep via increased CSF flow, novel approaches to remove beta-amyloid from the brain ISS, and obstruction to the ISF drainage in neurological conditions are deliberated. The brain ISF in the deep brain regions has recently been demonstrated to drain in a compartmentalized ISS instead of a highly connected system, together with the drainage of ISF into the cerebrospinal fluid (CSF) at the surface of the cerebral cortex and the transportation from CSF into cervical lymph nodes. The goal of this review is to confer recent advances in our understanding of the brain ISS, including its structure, function, and the various processes mediating or disrupting ISF drainage in physiological and pathological conditions. Recently, with a newly developed in vivo measuring technique, a series of discoveries have been made in the brain ISS and the drainage of ISF. The brain ISS is an asymmetrical, tortuous, and exceptionally confined space between neural cells and the brain microvasculature. The ISF occupies the brain interstitial system (ISS), whereas the CSF fills the brain ventricles and the subarachnoid space. The brain interstitial fluid (ISF) and the cerebrospinal fluid (CSF) cushion and support the brain cells. ![]()
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