Blood-Brain Barrier Breakdown in Stress and Neurodegeneration: Biochemical Mechanisms and New Models for Translational Research.

Blood-brain barrier (BBB) is a structural and functional element of the neurovascular unit (NVU), which includes cells of neuronal, glial, and endothelial nature. The main functions of NVU include maintenance of the control of metabolism and chemical homeostasis in the brain tissue, ensuring adequate blood flow in active regions, regulation of neuroplasticity processes, which is realized through intercellular interactions under normal conditions, under stress, in neurodegeneration, neuroinfection, and neurodevelopmental diseases. Current versions of the BBB and NVU models, static and dynamic, have significantly expanded research capabilities, but a number of issues remain unresolved, in particular, personification of the models for a patient. In addition, application of both static and dynamic models has an important problem associated with the difficulty in reproducing pathophysiological mechanisms responsible for the damage of the structural and functional integrity of the barrier in the diseases of the central nervous system. More knowledge on the cellular and molecular mechanisms of BBB and NVU damage in pathology is required to solve this problem. This review discusses current state of the cellular and molecular mechanisms that control BBB permeability, pathobiochemical mechanisms and manifestations of BBB breakdown in stress and neurodegenerative diseases, as well as the problems and prospects of creating in vitro BBB and NVU models for translational studies in neurology and neuropharmacology. Deciphering BBB (patho)physiology will open up new opportunities for further development in the related areas of medicine such as regenerative medicine, neuropharmacology, and neurorehabilitation.

Establishment of neurogenic microenvironment in the neurovascular unit: the connexin 43 story.

Connexins (Cx) play an important role in the coordination of intercellular communication, and autocrine and paracrine regulation of cells within the neurovascular unit (NVU). Gap junctional mechanisms control proliferation and differentiation processes underlying neurogenesis and angiogenesis in the brain. Cx43 possesses some unique properties [the ability to form either intercellular channels permeable for regulatory molecules and ions or hemichannels open to the extracellular space to provide release of cell metabolites; functional coupling with nicotinamide adenine dinucleotide (NAD+)-consuming and NAD+-dependent enzymatic processes] which may be of great importance for the fate of the stem cells. Dynamic changes in Cx43 expression are associated with different stages of brain cells development either at embryonic or adult periods of ontogenesis. This review summarizes recent data on Cx43-controlled neurogenesis in the context of NVU development and functioning. Understanding the molecular mechanisms of gap junctional intercellular communication will support translational studies focused on the development of regeneration-based approaches for the therapy of central nervous system pathology.