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

Abstract

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 H(2)O(2), and Down's syndrome (DS) cortical neurons. Incubation of normal cortical neurons with 50 microM H(2)O(2) for 1h 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 H(2)O(2)-treatment displaying a dose-dependent neuroprotective activity from 10nM to 100 microM, and an IC(50) value of 1.21+/-0.07 microM. GVS-111 inhibited the accumulation of intracellular free radicals and lipid peroxidation damage in neurons treated with H(2)O(2) or FeSO(4), 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.

ets-2 Promotes the Activation of a Mitochondrial Death Pathway in Down's Syndrome Neurons

“…Normal and DS human cortical neuron (HCN) cultures were prepared as described previously Pelsman et al, 2003). The protocol for tissue procurement complied with federal and institutional guidelines.…”

“…We have shown previously that DS HCNs exhibit intracellular accumulation of reactive oxygen species, lipid peroxydation, degenerative morphological changes including neuritic retraction and fragmentation, shrinkage of cell bodies, chromatin condensations and positive terminal deoxynucleotidyl transferasemediated biotinylated UTP nick end labeling staining (Busciglio and Yankner, 1995;Pelsman et al, 2003). During the second week in culture, DS neurons undergo progressive degeneration, and by day 14, only 41 Ϯ 3% of the neurons originally present at day 7 are viable (Busciglio and Yankner, 1995).…”

The relationship of ceruloplasmin and neural tube defects

“…At this point antioxidation mechanisms become an important activity of the organism in order to prevent biofunctional disorders. In the light of previous datas about the etiology of CNS anomalies, they seem to be related to oxidant chemical and physical agents (3)(4)(5)10). Ceruloplasmin was considered to be effective as an antioxidant in NTD.…”

“…The exact etiology of NTD is rather complex and poorly understood. Recently, oxidative metabolism was considered to be related with congenital anomalies including CNS (4,5).…”

The induction of apoptosis by daunorubicin and idarubicin in human trisomic and diabetic fibroblasts

“…Several recent studies demonstrated the activation of the apoptotic pathway in patients with Down's Syndrome and diabetes. The apoptotic mechanism of cell death in DS was presented in human cortical neurons [32], the brain [33], and neuronal cultures and thymocytes [34,35]. Apoptosis in DS was shown to be mediated by caspases and the cytochrome c-independent pathway [36].…”