Novel pentacyclic triterpenes exhibiting strong neuroprotective activity in SH-SY5Y cells in salsolinol- and glutamate-induced neurodegeneration models

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-beta-D-glucose substituent showed a highly potent neuroprotective effect. Further studies revealed that removal of tetraacetyl-beta-D-glucose part (free triazole derivative 10) resulted in strong neuroprotection in the SAL model at 1 mu M, 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. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

Novel triterpene derivatives showed potent neuroprotective effects in models of neurodegeneration, but also exhibited cytotoxicity at higher concentrations. These compounds modulated oxidative stress and apoptosis activity, with some derivatives demonstrating superior neuroprotective effects compared to traditional inhibitors.