[The structure and permeability of the hemato-encephalic barrier and the prospects for drug delivery across it].
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Biomedical subjects
Publications and source records attributed to O A Goriukhina.
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Experiments on 30 Wistar female rats with tetrachloromethane-induced cirrhosis of the liver revealed structural changes in the hematoencephalic barrier presenting as peri- and endocapillary changes and changes in vascular peduncles of astrocytes shown by light and electron microscopy. Hematoencephalic barrier destabilization is conducive to penetration of cerebrotoxins and other metabolic toxins, this explaining the development of hepatic encephalopathy.
The effects of various cAMP modifiers on the changes in the intracellular cAMP level and on the coupling of the cAMP system with realization of macrophage cytotoxicity depending on their functional activity were studied. Nonactivated and activated by E. coli polysaccharides peritoneal macrophages of BALB/c mice and macrophage-like cells of J744 mice were incubated in the presence of cAMP modifiers and further assayed for cytolytic and cytostatic activities. Cells of tetraploid strain of Ehrlich carcinoma G10 were used as target cells. Among other modifiers only dibutyryl-cAMP caused a steady increase of the intracellular nucleotide content, whereas methylisobutylxanthine and isoproterenol in combination with methylisobutylxanthine caused only a temporary increase of the cAMP level. Isoproterenol did not induce any appreciable changes in the intracellular cAMP level. All modifiers under study suppressed the cytotoxic activity of macrophages irrespective of the nature of changes in the intracellular cAMP content. It was assumed that cAMP accomplishes a triggering function in the regulation of the cytotoxic activity of macrophages and that the cAMP system is universal in the regulation of cytotoxicity at various functional states of macrophages.
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The proteinase activities of nuclei isolated from tissues differing in their mitotic activities (brain, thymus, liver, ascite lymphoma) towards the histones and non-histone acid -- extractable proteins were studied. The sensitivity of different histone fractions to nuclear proteinase depends on temperature and time of nuclei incubation under conditions providing for complete dissociation of chromatin proteins from DNA (2 M NaCl--5 M urea). The proteinase activity in the brain and thymus nuclei is revealed only under prolonged (43 hrs) incubation of the nuclei at 25 degrees C, which is accompanied by partial proteolysis of histone H1. Histone H4 from brain nuclei and histone H2a from thymus nuclei are preferably degraded. In the nuclei isolated from the mice ascite cell lymphoma NK/ly and from rat liver the enzyme activity is revealed mainly towards the arginine-enriched histones H3 and H4. The proteolysis of the arginine-enriched histones in tumour cell nuclei is more complete. A high sensitivity to proteolysis was observed for non-histone acid-extractable proteins with low electrophoretic mobility, which were found in brain and tumour cell nuclei.
Repeated intravenous injection of total histone of calf thymus preparation led to sensitization of experimental animals accompanied by formation of complement fixing antibodies. Sera examination by the complement fixation test demonstrated antigenicity of the total histone preparation protein components to decrease in the following order: nonhistone proteins admixture greater than histone fraction HI greater than mixture of histone fractions H3 : H2b : H2a (1 : 1 : 1). The presence in the total histone preparation of nonhistone protein admixture chiefly conditioned the immunogenic, and possibly, the allergenic activity of the preparation.
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A complex containing total histone and antibiotic kanamycin was produced under optimal conditions using glutaric aldehyde. The obtained water-soluble covalently bound conjugates of these substances were identified by means of enzyme labelled immunoassay and their molecular mass estimated. The validity of new class of highly effective drugs, which may be produced basing on the principles studied, was substantiated considering that histones exhibit the transport properties and are able to augment hematoencephalic barrier permeability.
Cation-containing proteins, which possessed the bacteriostatic activity against Grampositive microorganism Bacillus subtilis SHGW, were isolated from rabbit thrombocytes by means of selective extraction. These substances were of heterogenous nature (as shown by polyacrylamide gel disc electrophoresis), including two groups of proteins with molecular weight about 8=10-10(3) and 20=30-10(3) daltons. The bacteriostatic activity of each group of these proteins was studied after gel filtration of the total preparation on Sephadex G=75. The group of proteins with molecular weight 8=10-10(3) daltons was responsible for bacteriostatic activity of the total cation-containing protein from thrombocytes.