Nitrones as Potential Therapeutic Agents Against Neurodegenerative Diseases

摘要

Neurodegenerative disorders are characterized by progressive loss of structure or function of neurons leading to neuronal death. Oxidative stress has been implicated as a key event in the degenerative process. Toxicity of reactive oxygen species contributes to protein misfolding, mitochondrial dysfunction and subsequent cellular apoptosis. Caspase-3 activation, a crucial event in neuronal cell death, is also a feature of many neurodegenerative diseases. Moreover, recent studies reveal new non-apoptotic roles of caspase-3 in neurite pruning and synaptic plasticity. In the search of novel pharmacological approaches to treat neurodegenerative disorders, nitrone derivatives with powerful and diverse neuroprotective properties such as antioxidant, anti-apoptotic and anti-inflammatory skills have emerged. The main goal of this work was to determine the mechanism of cytoprotection by nitrones during glutamate-induced oxidative stress and camptothecin-induced apoptosis in HT22 mouse hippocampal cells. Moreover, using docking combined with molecular dynamics simulations we got insight into the ability of nitrones to directly inhibit caspase-3. All the nitrones studied in this work did not show cytotoxicity and most of them significantly inhibit apoptosis in HT22 cells by a mechanism involving active-caspase-3 reduction. In fact, according to docking and MD simulations nitrones could act as caspase-3 inhibitors. These molecules bind to a region near the substrate binding cleft, interacting with residues not conserved in other caspases and causing conformational changes at the catalytic site. In vitro caspase-3 inhibition assays to determine the ability of these nitrones to inhibit the enzyme are currently underway. Owing to its suitable pharmacological profile these molecules could become potential drugs for the treatment of diverse neurological disorders.