Stemazole Promotes Oligodendrocyte Precursor Cell Survival In Vitro and Remyelination In Vivo.

Maintaining the normal function of oligodendrocyte precursor cells (OPCs) and protecting OPCs from damage is the basis of myelin regeneration in multiple sclerosis (MS). In this paper, we investigated the effect of stemazole, a novel small molecule, on the promotion of oligodendrocyte precursor cell survival and remyelination. The results show that stemazole enhanced the survival rate and the number of clone formation in a dose-dependent manner and decreased the percentage of cell apoptosis. In particular, the number of cell clones was increased up to 6-fold (p < 0.001) in the stemazole group compared with the control group. In vivo, we assessed the effect of stemazole on recovering the motor dysfunction and demyelination induced by cuprizone (CPZ). The results show that stemazole promoted the recovery of motor dysfunction and the repair of myelin sheaths. Compared with the CPZ group, the stemazole group showed a 30.46% increase in the myelin area (p < 0.001), a 37.08% increase in MBP expression (p < 0.01), and a 1.66-fold increase in Olig2 expression (p < 0.001). Histologically, stemazole had a better effect than the positive control drugs. In conclusion, stemazole promoted OPC survival in vitro and remyelination in vivo, suggesting that this compound may be used as a therapeutic agent against demyelinating disease.

A quantitative proteomics analysis for small molecule Stemazole's effect on human neural stem cells.

BACKGROUND: Stemazole is a novel small molecule that has been suggested to have the ability to protect multiple stem cells. The proliferation-promoting activity and promising neuroprotective effects of stemazole make it a prospective drug for neurodegenerative disease treatment. METHODS: Since previous studies have shown that it protective effect in extreme conditions, to understand more aspects of stemazole, in this study, a systematic tandem mass tags (TMT)-labelled proteomics approach was used to address the whole proteome expression profile with or without stemazole in normal conditions instead of extreme conditions. Bioinformatics analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and protein-protein interaction (PPI) network analyses, were employed. RESULTS: The effect of stemazole on the expression profiles of neural stem cells was obtained. A total of 408 proteins with changes at the abundance level of two groups were identified: 178 proteins increase in abundance and 240 proteins decrease in abundance, respectively. Low abundance of some mitochondrial respiratory chain enzyme, overproduction of reactive oxygen species (ROS) and reduction of mitochondrial membrane potential may indicate stemazole has cytotoxicity. CONCLUSIONS: It is the first proteomics research about stemazole, and the possible cytotoxicity of stemazole has been reported for the first time. The information about proteins that were affected by stemazole and more characteristics of stemazole will help obtain a complete picture of this small molecule drug. These findings provide a scientific basis for further stemazole treatment research.

Uncovering the Pharmacological Mechanism of Stemazole in the Treatment of Neurodegenerative Diseases Based on a Network Pharmacology Approach.

Stemazole exerts potent pharmacological effects against neurodegenerative diseases and protective effects in stem cells. However, on the basis of the current understanding, the molecular mechanisms underlying the effects of stemazole in the treatment of Alzheimer's disease and Parkinson's disease have not been fully elucidated. In this study, a network pharmacology-based strategy integrating target prediction, network construction, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and molecular docking was adopted to predict the targets of stemazole relevant to the treatment of neurodegenerative diseases and to further explore the involved pharmacological mechanisms. The majority of the predicted targets were highly involved in the mitogen-activated protein kinase (MAPK) signaling pathway. RAC-alpha serine/threonine-protein kinase (AKT1), caspase-3 (CASP3), caspase-8 (CASP8), mitogen-activated protein kinase 8 (MAPK8), and mitogen-activated protein kinase 14 (MAPK14) are the core targets regulated by stemazole and play a central role in its anti-apoptosis effects. This work provides a scientific basis for further elucidating the mechanism underlying the effects of stemazole in the treatment of neurodegenerative diseases.

A Quantitative Proteomic Approach Explores the Possible Mechanisms by Which the Small Molecule Stemazole Promotes the Survival of Human Neural Stem Cells.

Neurodegenerative disorders have become a serious healthcare problem worldwide and there is no efficacious cure. However, regulating the fate of stem cells is an effective way to treat these neurological diseases. In previous work, stemazole was reported to maintain the survival of human neural stem cells in the absence of growth factors and to have therapeutic effects on neurodegenerative diseases. However, although it is a promising small molecule, the molecular mechanisms against apoptosis are ambiguous. In this study, tandem mass tag (TMT)-based proteomics were performed to obtain whole protein expression profiles of human neural stem cells in different groups under extreme conditions. Bioinformatics analysis based on protein-protein interaction (PPI) network construction, gene ontology (GO) and the Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis were adopted to explore crucial proteins and possible pharmacological mechanisms. A total of 77 differentially expressed proteins were identified, comprising 38 upregulated proteins and 39 downregulated proteins. Combined with a diseases database of Alzheimer's disease (AD), caspase-2 (CASP2), PKA C-alpha (PRKACA), fibronectin (FN1), large neutral amino acid transporter small subunit 1 (SLC7A5), which are involved in cell proliferation and apoptosis, this was further validated by enzyme activity assay and molecular docking, and regarded as putative targets regulated by stemazole. The present results give an insight into this small molecule and a better understanding for further elucidating the underlying mechanisms in the treatment of stem cells and neurodegenerative diseases.