[Development of blood-brain barrier under the modulation of HIF activity in astroglialand neuronal cells in vitro]. / Osobennosti formirovaniia gematoéntsefalicheskogo bar'era pri moduliatsii aktivnosti HIF v kletkakh astroglial'noi i neironal'noi prirody in vitro.

Barriergenesis is the process of maturation of the primary vascular network of the brain responsible for the establishment of the blood-brain barrier. It represents a combination of factors that, on the one hand, contribute to the process of migration and tubulogenesis of endothelial cells (angiogenesis), on the other hand, contribute to the formation of new connections between endothelial cells and other elements of the neurovascular unit. Astrocytes play a key role in barriergenesis, however, mechanisms of their action are still poorly examined. We have studied the effects of HIF-1 modulators acting on the cells of non-endothelial origin (neurons and astrocytes) on the development of the blood-brain barrier in vitro. Application of FM19G11 regulating expression of HIF-1 activity and GSI-1 suppressing gamma-secretase and/or proteasomal activity resulted in the elevated expression of thrombospondins and matrix metalloproteinases in the developing blood-brain barrier. However, it caused the opposite effect on VEGF expression thus promoting barrier maturation in vitro.

TIGHT JUNCTIONS PROTEINS IN CEREBRAL ENDOTHELIAL CELLS DURING EARLY POSTNATAL DEVELOPMENT.

Formation and functional plasticity of the blood-brain barrier is associated with the molecular events that occur in the brain neurovascular unit in the embryonic and early postnatal development. To study the characteristics of barriergenesis under physiological conditions, as well as recovering from perinatal hypoxia and early life stress, we examined the expression of proteins of cerebral endothelial tight junctions (JAM, ZO1, CLDN5) in rats aged 7, 28 and 70 days of postnatal development (P7­P70). Under physiological conditions, we have found that the number of endothelial cells expressing JAM, ZO1, CLDN5 slightly increases in the cortex, hippocampus and amygdala of the brain in the period from P7 to P70. Perinatal hypoxia significantly increased the number of cells expressing proteins of tight junction proteins (JAM, CLDN5) up to the age P28­P70, whereas the number of cells expressing ZO1 was reduced in the same period of time. Early life stress led to an imbalance between the number of cells expressing ZO1 proteins and that expressing tight junctions proteins, but these changes were in opposite direction to that observed in perinatal hypoxia

[CURRENT OPPORTUNITIES IN THE IDENTIFICATION OF NOVEL MOLECULAR TARGETS FOR PHARMACOLOGICAL CORRECTION OF BLOOD-BRAIN BARRIER PERMEABILITY].

Review covers current achievements in the methodology of target discovery and validation for the development of drugs restoring structural and functional integrity of the blood-brain barrier (BBB) in cases of brain injury and neuroinflammation. Some new targets (in the context of BBB permeability) are discussed, which are involved in the regulation of signal transduction involving HIF-1, JNK, NF-κB, Rac, 1 etc., expression of tight-junction proteins, and activity of enzymes producing molecules with pro-inflammatory effects in the BBB cells.