GVS‐111 prevents oxidative damage and apoptosis in normal and Down's syndrome human cortical neurons

The neuroprotective activity of a novel N‐acylprolyl‐containing dipeptide analog of the nootropic 2‐oxo‐1‐pyrrolidine acetamide (Piracetam) designated as GVS‐111 (DVD‐111/Noopept) was tested in two in vitro models of neuronal degeneration mediated by oxidative stress: normal human cortical neurons treated with H2O2, and Down's syndrome (DS) cortical neurons. Incubation of normal cortical neurons with 50 μM H2O2 for 1 h resulted in morphological and structural changes consistent with neuronal apoptosis and in the degeneration of more than 60% of the neurons present in the culture. GVS‐111 significantly increased neuronal survival after H2O2‐treatment displaying a dose‐dependent neuroprotective activity from 10 nM to 100 μM, and an IC50 value of 1.21±0.07 μM. GVS‐111 inhibited the accumulation of intracellular free radicals and lipid peroxidation damage in neurons treated with H2O2 or FeSO4, suggesting an antioxidant mechanism of action. GVS‐111 exhibited significantly higher neuroprotection compared to the standard cognition enhancer Piracetam, or to the antioxidants Vitamin E, propyl gallate and N‐tert‐butyl‐2‐sulpho‐phenylnitrone (s‐PBN). In DS cortical cultures, chronic treatment with GVS‐111 significantly reduced the appearance of degenerative changes and enhanced neuronal survival. The results suggest that the neuroprotective effect of GVS‐111 against oxidative damage and its potential nootropic activity may present a valuable therapeutic combination for the treatment of mental retardation and chronic neurodegenerative disorders.