Abstract
BackgroundNoopept (N-phenyl-acetyl-L-prolylglycine ethyl ester) was constructed as a dipeptide analog of the standard cognition enhancer, piracetam. Our previous experiments have demonstrated the cognition restoring effect of noopept in several animal models of Alzheimer disease (AD). Noopept was also shown to prevent ionic disbalance, excitotoxicity, free radicals and pro-inflammatory cytokines accumulation, and neurotrophine deficit typical for different kinds of brain damages, including AD. In this study, we investigated the neuroprotective action of noopept on cellular model of AD, Aβ25–35-induced toxicity in PC12 cells and revealed the underlying mechanisms.ResultsThe neuroprotective effect of noopept (added to the medium at 10 μM concentration, 72 hours before Аβ25–35) was studied on Аβ25–35-induced injury (5 μM for 24 h) in PC12 cells. The ability of drug to protect the impairments of cell viability, calcium homeostasis, ROS level, mitochondrial function, tau phosphorylation and neurite outgrowth caused by Аβ25–35 were evaluated.Following the exposure of PC12 cells to Аβ25–35 an increase of the level of ROS, intracellular calcium, and tau phosphorylation at Ser396 were observed; these changes were accompanied by a decrease in cell viability and an increase of apoptosis. Noopept treatment before the amyloid-beta exposure improved PC12 cells viability, reduced the number of early and late apoptotic cells, the levels of intracellular reactive oxygen species and calcium and enhanced the mitochondrial membrane potential. In addition, pretreatment of PC12 cell with noopept significantly attenuated tau hyperphosphorylation at Ser396 and ameliorated the alterations of neurite outgrowth evoked by Аβ25–35.ConclusionsTaken together, these data provide evidence that novel cognitive enhancer noopept protects PC12 cell against deleterious actions of Aβ through inhibiting the oxidative damage and calcium overload as well as suppressing the mitochondrial apoptotic pathway. Moreover, neuroprotective properties of noopept likely include its ability to decrease tau phosphorylation and to restore the altered morphology of PC12 cells. Therefore, this nootropic dipeptide is able to positively affect not only common pathogenic pathways but also disease-specific mechanisms underlying Aβ-related pathology.
Highlights
Noopept (N-phenyl-acetyl-L-prolylglycine ethyl ester) was constructed as a dipeptide analog of the standard cognition enhancer, piracetam
In the present study we investigated the protective effect of noopept against Аβ25–35-mediated damage of PC12 cells, measuring the cellular viability, apoptosis, intracellular Ca2+, reactive oxygen species (ROS), mitochondrial membrane potential, tau protein phosphorylation level and neurite outgrowth
Differentiated PC12 cells were pretreated with noopept at concentration of 10 μM for 72 h, cells were rinsed with the medium and exposed to amyloid-β-peptide (Аβ25–35, 5 μM; Tocris Bioscience, UK) for 24 h
Summary
Noopept (N-phenyl-acetyl-L-prolylglycine ethyl ester) was constructed as a dipeptide analog of the standard cognition enhancer, piracetam. Our previous experiments have demonstrated the cognition restoring effect of noopept in several animal models of Alzheimer disease (AD). Noopept was shown to prevent ionic disbalance, excitotoxicity, free radicals and pro-inflammatory cytokines accumulation, and neurotrophine deficit typical for different kinds of brain damages, including AD. Mechanisms underlying the progression of late-onset AD consist of a number of interacting events including excessive accumulation of amyloid, aberrant tau-protein phosphorylation, oxidative stress, chronic inflammatory conditions, excitotoxicity, disruption of neurotrophine signaling, impairments in cytoskeleton stability and axonal transport, synaptic and neuronal loss [2]. Drugs targeting tau-protein are known to be divided into several groups: modulators of tau phosphorylation, inhibitors of tau-phosphorylating kinases (e.g. glycogen-synthase-kinase-3β, cyclin-dependent kinase-5, p70-S6-kinase) and compounds that prevent tau aggregation and misfolding [4]
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