A Neuroprotective Dose of Isatin Causes Multilevel Changes Involving the Brain Proteome: Prospects for Further Research

Abstract

Isatin (indole-2,3-dione) is an endogenous regulator, exhibiting a wide range of biological and pharmacological activities. At doses of 100 mg/kg and above, isatin is neuroprotective in different experimental models of neurodegeneration. Good evidence exists that its effects are realized via interaction with numerous isatin-binding proteins identified in the brain and peripheral tissues studied. 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. Isatin administration to mice caused downregulation of 31 proteins. However, these changes cannot be attributed to altered expression of corresponding genes. 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. Comparative proteomic analysis of brain isatin-binding proteins of control and isatin-treated mice revealed representative groups of proteins sensitive to isatin administration. Control-specific proteins (n = 55) represent specific targets that interact directly with isatin. 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). 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. Further studies are needed for deeper insight into the mechanisms of the multilevel changes in the brain proteome induced by isatin. 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.

Bacterial Metabolites of Human Gut Microbiota Correlating with Depression

“…Microbial indole triggered enteroendocrine L-cells to produce glucagon-like peptide 1 (GLP-1), which in turn stimulated colonic vagal afferent activity [189]. The administration of Isatin, an indole derivative seen as a neuroprotective agent, to mice altered the expression of many genes as well as the proteome in their brains [190]. Indole-3-lactic acid, which is another indole derivative produced by lactobacilli and bifidobacteria [191], exerted an enhancing effect on neuron differentiation in PC12 cells via AhR receptors [192].…”

Atypical Ubiquitination and Parkinson’s Disease

“…Some DUB inhibitors have been found among isatin O-acyl oximes [ 194 ]. These are especially interesting because various components of the UPS (as well as some PD-related proteins) have been identified earlier as isatin-binding proteins [ 195 , 196 ]. Isatin is an endogenous indole exhibiting various biological and pharmacological activities [ 197 ].…”

“…When administered in vivo, isatin attenuates manifestations of MPTP-induced parkinsonism in experimental animal models [ 23 , 79 , 195 , 196 , 197 ]. Considering its interaction with various proteins of the UPS, it would be interesting to investigate various isatin analogs for their possible activity as regulators of the UPS and AU and as potential antiparkinsonian agents.…”

Mechanism of the Affinity-Enhancing Effect of Isatin on Human Ferrochelatase and Adrenodoxin Reductase Complex Formation: Implication for Protein Interactome Regulation

“…This suggests that at pharmacologically relevant concentrations this regulator will increase the affinity of some PPIs and thus change the interactome. Such mechanism provides reasonable explanation of the altered profile of isatin binding proteins observed after administration of a high neuroprotective dose of isatin to animals [ 18 ]: appearance of isatin-binding proteins specific for isatin-treated animals due to the formation of new clusters of PPI and/or novel ligand-induced binding sites.…”