Neuroprotective effect of novel cognitive enhancer noopept on AD-related cellular model involves the attenuation of apoptosis and tau hyperphosphorylation

Rita U Ostrovskaya, Yulia V Vakhitova, Uliyana Sh Kuzmina, Milyausha Kh Salimgareeva, Liana F Zainullina, Tatiana A Gudasheva, Vener A Vakhitov, Sergey B Seredenin

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, Aß25¿35-induced toxicity in PC12 cells and revealed the underlying mechanisms.ResultsThe neuroprotective effect of noopept (added to the medium at 10 ¿M concentration, 72 hours before ¿ß25¿35) was studied on ¿ß25¿35-induced injury (5 ¿M 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 ¿ß25¿35 were evaluated.Following the exposure of PC12 cells to ¿ß25¿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 ¿ß25¿35.ConclusionsTaken together, these data provide evidence that novel cognitive enhancer noopept protects PC12 cell against deleterious actions of Aß 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 Aß-related pathology.