Extracellular matrix (ECM) is a network of macromolecules which has two forms-perineuronal nets (PNNs) and a diffuse ECM (dECM)-both influence brain development, synapse formation, neuroplasticity, CNS injury and progression of neurodegenerative diseases. ECM remodeling can influence extrasynaptic transmission, mediated by diffusion of neuroactive substances in the extracellular space (ECS). In this study we analyzed how disrupted PNNs and dECM influence brain diffusibility. Two months after oral treatment of rats with 4-methylumbelliferone (4-MU), an inhibitor of hyaluronan (HA) synthesis, we found downregulated staining for PNNs, HA, chondroitin sulfate proteoglycans, and glial fibrillary acidic protein. These changes were enhanced after 4 and 6 months and were reversible after a normal diet. Morphometric analysis further indicated atrophy of astrocytes. Using real-time iontophoretic method dysregulation of ECM resulted in increased ECS volume fraction α in the somatosensory cortex by 35%, from α = 0.20 in control rats to α = 0.27 after the 4-MU diet. Diffusion-weighted magnetic resonance imaging revealed a decrease of mean diffusivity and fractional anisotropy (FA) in the cortex, hippocampus, thalamus, pallidum, and spinal cord. This study shows the increase in ECS volume, a loss of FA, and changes in astrocytes due to modulation of PNNs and dECM that could affect extrasynaptic transmission, cell-to-cell communication, and neural plasticity.

• Klíčová slova
• extracellular diffusion, extracellular matrix, extracellular transmission, hyaluronan synthase, perineuronal nets, plasticity,
• MeSH
• astrocyty metabolismus   MeSH
• chondroitinsulfát proteoglykany metabolismus   MeSH
• extracelulární matrix * metabolismus   MeSH
• extracelulární prostor * metabolismus   MeSH
• gliový fibrilární kyselý protein metabolismus   MeSH
• hymekromon farmakologie   MeSH
• krysa rodu Rattus MeSH
• kyselina hyaluronová MeSH
• mozek metabolismus   MeSH
• nervová síť účinky léků   diagnostické zobrazování   MeSH
• potkani Sprague-Dawley MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chondroitinsulfát proteoglykany MeSH
• gliový fibrilární kyselý protein MeSH
• hymekromon MeSH
• kyselina hyaluronová MeSH

The changes in the necrotic core and the penumbra following induction of focal ischemia have been the focus of attention for some time. However, evidence shows, that ischemic injury is not confined to the primarily affected structures and may influence the remote areas as well. Yet many studies fail to probe into the structures beyond the penumbra, and possibly do not even find any significant results due to their short-term design, as secondary damage occurs later. This slower reaction can be perceived as a therapeutic opportunity, in contrast to the ischemic core defined as irreversibly damaged tissue, where the window for salvation is comparatively short. The pathologies in remote structures occur relatively frequently and are clearly linked to the post-stroke neurological outcome. In order to develop efficient therapies, a deeper understanding of what exactly happens in the exo-focal regions is necessary. The mechanisms of glia contribution to the ischemic damage in core/penumbra are relatively well described and include impaired ion homeostasis, excessive cell swelling, glutamate excitotoxic mechanism, release of pro-inflammatory cytokines and phagocytosis or damage propagation via astrocytic syncytia. However, little is known about glia involvement in post-ischemic processes in remote areas. In this literature review, we discuss the definitions of the terms "ischemic core", "penumbra" and "remote areas." Furthermore, we present evidence showing the array of structural and functional changes in the more remote regions from the primary site of focal ischemia, with a special focus on glia and the extracellular matrix. The collected information is compared with the processes commonly occurring in the ischemic core or in the penumbra. Moreover, the possible causes of this phenomenon and the approaches for investigation are described, and finally, we evaluate the efficacy of therapies, which have been studied for their anti-ischemic effect in remote areas in recent years.

• Klíčová slova
• NG2-glia, astrocyte, future outlooks, microglia, oligodendrocytes, remote areas, stroke, therapy,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Volume transmission is a form of intercellular communication that does not require synapses; it is based on the diffusion of neuroactive substances across the brain extracellular space (ECS) and their binding to extrasynaptic high-affinity receptors on neurons or glia. Extracellular diffusion is restricted by the limited volume of the ECS, which is described by the ECS volume fraction α, and the presence of diffusion barriers, reflected by tortuosity λ, that are created, for example, by fine astrocytic processes or extracellular matrix (ECM) molecules. Organized astrocytic processes, ECM scaffolds or myelin sheets channel the extracellular diffusion so that it is facilitated in a certain direction, i.e. anisotropic. The diffusion properties of the ECS are profoundly influenced by various processes such as the swelling and morphological rebuilding of astrocytes during either transient or persisting physiological or pathological states, or the remodelling of the ECM in tumorous or epileptogenic tissue, during Alzheimer's disease, after enzymatic treatment or in transgenic animals. The changing diffusion properties of the ECM influence neuron-glia interaction, learning abilities, the extent of neuronal damage and even cell migration. From a clinical point of view, diffusion parameter changes occurring during pathological states could be important for diagnosis, drug delivery and treatment.

• Klíčová slova
• astrocytes, diffusion, extracellular matrix, extracellular space, tortuosity, volume fraction,
• MeSH
• anizotropie MeSH
• astrocyty patologie   MeSH
• difuze MeSH
• extracelulární matrix fyziologie   MeSH
• lidé MeSH
• mezibuněčná komunikace fyziologie   MeSH
• nervový přenos fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Diffusion in the extracellular space (ECS) of the brain is constrained by the volume fraction and the tortuosity and a modified diffusion equation represents the transport behavior of many molecules in the brain. Deviations from the equation reveal loss of molecules across the blood-brain barrier, through cellular uptake, binding, or other mechanisms. Early diffusion measurements used radiolabeled sucrose and other tracers. Presently, the real-time iontophoresis (RTI) method is employed for small ions and the integrative optical imaging (IOI) method for fluorescent macromolecules, including dextrans or proteins. Theoretical models and simulations of the ECS have explored the influence of ECS geometry, effects of dead-space microdomains, extracellular matrix, and interaction of macromolecules with ECS channels. Extensive experimental studies with the RTI method employing the cation tetramethylammonium (TMA) in normal brain tissue show that the volume fraction of the ECS typically is approximately 20% and the tortuosity is approximately 1.6 (i.e., free diffusion coefficient of TMA is reduced by 2.6), although there are regional variations. These parameters change during development and aging. Diffusion properties have been characterized in several interventions, including brain stimulation, osmotic challenge, and knockout of extracellular matrix components. Measurements have also been made during ischemia, in models of Alzheimer's and Parkinson's diseases, and in human gliomas. Overall, these studies improve our conception of ECS structure and the roles of glia and extracellular matrix in modulating the ECS microenvironment. Knowledge of ECS diffusion properties is valuable in contexts ranging from understanding extrasynaptic volume transmission to the development of paradigms for drug delivery to the brain.

• MeSH
• difuze MeSH
• extracelulární prostor chemie   diagnostické zobrazování   fyziologie   MeSH
• kvartérní amoniové sloučeniny MeSH
• lidé MeSH
• mozek - chemie fyziologie   MeSH
• mozek cytologie   fyziologie   MeSH
• neuroglie fyziologie   MeSH
• neurony fyziologie   MeSH
• radioisotopová scintigrafie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• kvartérní amoniové sloučeniny MeSH
• tetramethylammonium MeSH Prohlížeč