Neuroprotective effects of novel nitrones: In vitro and in silico studies

摘要

Neurodegenerative diseases affect millions of people around the world. Several studies point out caspase-3 as a key player in the development and progression of neurological disorders including amyotrophic lateral sclerosis, Alzheimer's, Parkinson's and Huntington's diseases. Furthermore, oxidative stress and mitochondrial dysfunction plays an important role in neurodegenerative pathologies leading to neuronal damage and cell death. Pharmacological properties of nitrones such as free radical trapping and neuroprotection has been previously described. In the present work, we have assessed ten non-cytotoxic nitrones for their ability to inhibit apoptosis plus their potential to reduce active caspase-3 and oxidative stress in the hippocampal neuronal cell line HT22. Our results highlight the faculty of nitrones to inhibit apoptosis by a mechanism that involves active caspase-3 reduction and decrease of reactive oxygen species. Moreover, docking and molecular dynamics approaches lead to a detailed analysis at the atomic level of the nitrones binding mode to caspase-3 suggesting that compounds bind in a region close to the catalytic site. All these data place these molecules as excellent hits for further efforts to redesign novel compounds in the search of a new therapy against neurodegenerative disorders.