Novel pentacyclic triterpenes exhibiting strong neuroprotective activity in SH-SY5Y cells in salsolinol- and glutamate-induced neurodegeneration models
| Autor: | Milan Urban, Gabriel Gonzalez, Cosimo Walter D’Acunto, Jiří Hodoň, Miroslav Strnad, Anna Kazakova, Petr Kaňovský |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
SH-SY5Y
Cell Survival Glutamic Acid Pharmacology Mitochondrion medicine.disease_cause 01 natural sciences Neuroprotection Models Biological 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Betulinic acid Cell Line Tumor Drug Discovery medicine Humans 030304 developmental biology Membrane Potential Mitochondrial 0303 health sciences Betulin Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Organic Chemistry Glutamate receptor General Medicine Triazoles Isoquinolines Triterpenes 0104 chemical sciences Oxidative Stress Neuroprotective Agents chemistry Mitochondrial permeability transition pore Oxidative stress |
| Zdroj: | European journal of medicinal chemistry. 213 |
| ISSN: | 1768-3254 |
| Popis: | Novel triterpene derivatives were prepared and evaluated in salsolinol (SAL)- and glutamate (Glu)-induced models of neurodegeneration in neuron-like SH-SY5Y cells. Among the tested compounds, betulin triazole 4 bearing a tetraacetyl-β- d -glucose substituent showed a highly potent neuroprotective effect. Further studies revealed that removal of tetraacetyl-β- d -glucose part (free triazole derivative 10) resulted in strong neuroprotection in the SAL model at 1 μM, but this derivative suffered from cytotoxicity at higher concentrations. Both compounds modulated oxidative stress and caspase-3,7 activity, but 10 showed a superior effect comparable to the Ac-DEVD-CHO inhibitor. Interestingly, while both 4 and 10 outperformed the positive controls in blocking mitochondrial permeability transition pore opening, only 4 demonstrated potent restoration of the mitochondrial membrane potential (MMP) in the model. Derivatives 4 and 10 also showed neuroprotection in the Glu model, with 10 exhibiting the strongest oxidative stress reducing effect among the tested compounds, while the neuroprotective activity of 4 was probably due recovery of the MMP. |
| Databáze: | OpenAIRE |
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