Neuroprotective and Nootropic Drug Noopept Rescues α-Synuclein Amyloid Cytotoxicity

Jia, Xueen; Gharibyan, Anna L.; Öhman, Anders; Liu, Yonggang; Olofsson, Anders; Morozova‐Roche, Ludmilla A.

doi:10.1016/j.jmb.2011.09.044

Cited by 19 publications

(12 citation statements)

References 48 publications

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“…Using Annexin V-FITC/PI double staining for the distinction of early- and late-apoptotic cells, we demonstrated that noopept attenuates both early and late apoptotic events induced by Aβ. Our findings of antiapoptotic effect of noopept against Aβ induced apoptosis are consistent with those obtained with this dipeptide in SH-SY5Y cells underwent to the toxic effect of another misfolded protein, α-synuclein amyloids [ 24 ].…”

Section: Discussionsupporting

confidence: 90%

“…Noopept significantly increased neuronal survival and prevented the accumulation of intracellular free radicals and apoptosis in experiments on cultured Down’s syndrome neurons [ 16 ]. The drug counteracted also the free radicals accumulation caused by α-synuclein on cultured neuroblastoma SH-SY5Y cells [ 24 ]. Interestingly, noopept was demonstrated to increase immunoreactivity to β-amyloid in mice with olfactory bulbectomy, considered as one of AD animal models [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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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.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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“…SH-SY5Y neuroblastoma cells were cultured with and without amyloids as described previously [20]. Cell viability was measured by WST-1 assay (Roche) after 24 h co-incubation with amyloids.…”

Section: Methodsmentioning

confidence: 99%

The role of pro-inflammatory S100A9 in Alzheimer’s disease amyloid-neuroinflammatory cascade

et al. 2013

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Pro-inflammatory S100A9 protein is increasingly recognized as an important contributor to inflammation-related neurodegeneration. Here, we provide insights into S100A9 specific mechanisms of action in Alzheimer’s disease (AD). Due to its inherent amyloidogenicity S100A9 contributes to amyloid plaque formation together with Aβ. In traumatic brain injury (TBI) S100A9 itself rapidly forms amyloid plaques, which were reactive with oligomer-specific antibodies, but not with Aβ and amyloid fibrillar antibodies. They may serve as precursor-plaques for AD, implicating TBI as an AD risk factor. S100A9 was observed in some hippocampal and cortical neurons in TBI, AD and non-demented aging. In vitro S100A9 forms neurotoxic linear and annular amyloids resembling Aβ protofilaments. S100A9 amyloid cytotoxicity and native S100A9 pro-inflammatory signaling can be mitigated by its co-aggregation with Aβ, which results in a variety of micron-scale amyloid complexes. NMR and molecular docking demonstrated transient interactions between native S100A9 and Aβ. Thus, abundantly present in AD brain pro-inflammatory S100A9, possessing also intrinsic amyloidogenic properties and ability to modulate Aβ aggregation, can serve as a link between the AD amyloid and neuroinflammatory cascades and as a prospective therapeutic target.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-013-1208-4) contains supplementary material, which is available to authorized users.

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“…In order to produce cytotoxic amyloid oligomers [4,18], α-synuclein (3 mg/ml) was incubated in 10 m m Na 2 HPO 4 at pH 7.4 and 37°C with continuous agitation at 300 rpm for 7 days and fibrils for 14 days.…”

Section: Methodsmentioning

confidence: 99%

Correlation between Protective Immunity to α-Synuclein Aggregates, Oxidative Stress and Inflammation

Gruden

Yanamandra

Kucheryanu

et al. 2012

Neuroimmunomodulation

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Objective: Protein aggregation leading to central amyloid deposition is implicated in Parkinson’s disease (PD). During disease progression, inflammation and oxidative stress may well invoke humoral immunity against pathological aggregates of PD-associated α-synuclein. The aim was to investigate any possible concurrence between autoimmune responses to α-synuclein monomers, oligomers or fibrils with oxidative stress and inflammation. Methods: The formation of α-synuclein amyloid species was assessed by thioflavin-T assay and atomic force microscopy was employed to confirm their morphology. Serum autoantibody titers to α-synuclein conformations were determined by ELISA. Enzyme activity and concentrations of oxidative stress/inflammatory indicators were evaluated by enzyme and ELISA protocols. Results: In PD patient sera, a differential increase in autoantibody titers to α-synuclein monomers, toxic oligomers or fibrils was associated with boosted levels of the pro-inflammatory cytokine interleukin-6 and tumour necrosis factor-α, but a decrease in interferon-γ concentration. In addition, levels of malondialdehyde were elevated whilst those of glutathione were reduced along with decrements in the activity of the antioxidants: superoxide dismutase, catalase and glutathione transferase. Conclusions: It is hypothesized that the generation of α-synuclein amyloid aggregates allied with oxidative stress and inflammatory reactions may invoke humoral immunity protecting against dopaminergic neuronal death. Hence, humoral immunity is a common integrative factor throughout PD progression which is directed towards prevention of further neurodegeneration, so potential treatment strategies should attempt to maintain PD patient immune status.

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Neuroprotective and Nootropic Drug Noopept Rescues α-Synuclein Amyloid Cytotoxicity

Cited by 19 publications

References 48 publications

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

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

The role of pro-inflammatory S100A9 in Alzheimer’s disease amyloid-neuroinflammatory cascade

Correlation between Protective Immunity to α-Synuclein Aggregates, Oxidative Stress and Inflammation

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