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

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.

Nootropic dipeptide, Noopept can modulate hyperalgesia by effecting on spinal microglia dependent Brain Derived Neurotropic Factor (BDNF) and pro-BDNF expression and apoptosis during persistent inflammation

“…It is of interest to note that during this study the administration of Noopept not only reduced spinal Iba1 level, as a microglial activity marker, but also reduced microglia dependent BDNF and pro-BDNF expression levels in the lumbar part of the spinal cord. Although there are considerable studies on the anti-inflammatory effect of Noopept [28,61], the current study stated the novel dipeptide anti-hyperalgesic and anti-inflammatory effects were mediated via inhibition of microglia activity and apoptosis. Ostrovskaya et al showed that Noopept, through normalizing incretin system parameters, had an anti-apoptotic effect on pancreatic β cells in the context of experimental Diabetes [63], and in another study they indicated neuroprotective effects [64].…”

“…Our observations in the second step of the study suggested that the long-term administration of Noopept during persistent peripheral inflammation not only decreases the activity of spinal microglia but also decreases microglia dependent BDNF and pro-BDNF expressions in parallel with thermal hyperalgesia and dorsal horn cell apoptosis. Despite the many studies done on the effects of Nootropics, such as Noopept, on cognitive disorders like Attention-Deficit/Hyperactivity Disorder (ADHD), Alzheimer's and Parkinson's diseases [61,62], the mechanism of the effect of this novel dipeptide on persistent inflammatory pain and its involved central mechanisms remained largely uncharacterized. Our results demonstrated that Noopept treatment was not only effective in reducing pain behaviors but also reduced spinal cell apoptosis, which is related to pain behavior variations in the context of CFA-induced inflammation.…”

Molecular Mechanism Underlying the Action of Substituted Pro-Gly Dipeptide Noopept

“…Following the ability of Noopept to increase animal survival in hyperbaric hypoxia [ 37 ] detected at the beginning of the study of this dipeptide, it has been shown that it reduces the volume of ischemic brain damage in circulatory hypoxia models: for example, cortical photochemically induced thrombosis [ 6 ] and ligation of the middle artery [ 5 ]. The ability of Noopept to attenuate the severity of oxidative stress was established in neuronal cultures of various types: granular cerebellar cells [ 35 ], cortical neuron culture of aborted fetuses with diagnosed Down syndrome [ 7 ], PC12 culture [ 38 ], SH-SY5Y culture [ 39 ], and in vivo experiments on brain tissue and rat plasma [ 40 ]. The ability to enhance superoxide dismutase and catalase activity was shown both in the experiment [ 10 ] and in clinical conditions [ 34 ].…”

“…The ability of Noopept not only to eliminate the manifestations of cognitive deficit [ 41 ], but to exert also a neuroprotective effect was shown in models of Alzheimer’s disease: it attenuated the disturbance of oxidative processes and calcium homeostasis, enhanced neurogenesis, prevented the tau protein aggregation caused by a fragment of β-amyloid 25-35 [ 38 ], and eliminated NGF and BDNF deficit caused by diabetogenic toxin streptozotocin administration into brain ventricles [ 42 ]. Noopept is capable of reducing the cytotoxic effect of aggregated α-synuclein in a cell model of Parkinson’s disease [ 39 ].…”

The use of nootropics in Alzheimer’s disease: is there light at the end of the tunnel?

“…Further, Piracetam exerts its neuroprotective effects on PC12 cells, SH-SY5Y cells, and SH-SY5Y APPwt cells by improving synaptic plasticity, maintaining mitochondrial dynamic and neuritogenesis 58 . In addition, Noopept protects PC12 cells against Aβ25-35 induced toxicity by inhibiting of oxidative damage, preventing of calcium overload, suppressing apoptosis, attenuating hyperphosphorylation of tau, and ameliorating the neural outgrowth induced by Aβ25-35 59 . In addition to the preclinical studies, several clinical trials were also conducted on nootropics in AD patients and related dementias with impressive results.…”