![]() Cell culture studies revealed that incubation with high concentrations of isatin (100 µM and above) influenced the expression of some genes. Earlier, we also demonstrated that within a slightly different scheme of the animal experiment, pretreatment of rats with a neuroprotector dose of isatin prevented brain MAO B against irreversible inhibition by the mechanism-based inhibitor phenelzine. The detected changes in the profile of isatin-binding proteins are consistent with the accumulation of administered isatin in the brain and its binding to target proteins, thus preventing subsequent protein binding to the affinity sorbent containing an isatin analogue as the affinity ligand. Our recent study has shown that treatment of mice with a neuroprotective dose of isatin significantly influenced the proteomic profile of brain isatin-binding proteins. It should be noted that after administration of the neuroprotective doses of isatin (50–100 mg/kg), its concentration in the brain may exceed 70 µM. The higher doses of isatin (from 60 mg/kg to 200 mg/kg) produced an anticonvulsive effect evaluated in different models including audiogenic seizures in rats and pentylenetetrazole administration. ![]() In contrast to mice, rats were insensitive to the anxiogenic doses of isatin in the open field and forced swim tests, and higher doses of isatin (80–160 mg/kg) caused sedation manifested as the reduced distance in the open field and increased immobility in the forced swim test. Low doses of isatin (15–20 mg/kg) were anxiogenic in open field and elevated plus maze tests in albino mice and in social interaction test in rats, while the locomotor activity of these rats remained unchanged. Isatin administered in vivo produced various (dose-dependent) physiological/pharmacological effects. ![]() In the context of the neuroprotective action, these changes may be aimed at interruption of pathological links that begin to form after initiation of pathological processes.Įxogenous isatin readily crosses the blood brain barrier for example, isatin injection to rats at a dose of 50–100 mg/kg increased the level of brain isatin up to 9 µg/g. Further studies are needed for deeper insight into the mechanisms of the multilevel changes in the brain proteome induced by isatin. Thus, isatin administration produces multiple effects in the brain, which include changes in gene expression and also profiles of isatin-binding proteins and their interactomes. Appearance of brain isatin-binding proteins specific to isatin-treated mice (n = 94) may be attributed to the formation of new clusters of protein–protein interactions and/or novel binding sites induced by a high concentration of this regulator (ligand-induced binding sites). Control-specific proteins (n = 55) represent specific targets that interact directly with isatin. Comparative proteomic analysis of brain isatin-binding proteins of control and isatin-treated mice revealed representative groups of proteins sensitive to isatin administration. Although at this time point isatin influenced the expression of more than 850 genes in brain hemispheres (including 433 upregulated and 418 downregulated genes), none of them could account for the changes in the differentially expressed proteins. However, these changes cannot be attributed to altered expression of corresponding genes. Isatin administration to mice caused downregulation of 31 proteins. In this study, we investigated the effect of a single dose administration of isatin to mice (100 mg/kg, 24 h) on differentially expressed proteins and a profile of the isatin-binding proteins in brain hemispheres. Good evidence exists that its effects are realized via interaction with numerous isatin-binding proteins identified in the brain and peripheral tissues studied. At doses of 100 mg/kg and above, isatin is neuroprotective in different experimental models of neurodegeneration. Isatin (indole-2,3-dione) is an endogenous regulator, exhibiting a wide range of biological and pharmacological activities.
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