Cotcha Yankinov
Bluelight Crew
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- Jul 21, 2015
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A recent study is suggesting that activation of Hypoxia Inducible Factor 1 (HIF-1) is the main mechanism by which Noopept (GVS-111) exerts its efficacy for degenerating disease states https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4837574/
"The mechanism of Noopept action has been studied since its synthesis. It has been established that the drug increases the expression of NGF and BDNF in the hippocampus [8], exhibits choline-positive properties at behavioral and neuronal levels [9], reduces oxidative stress and enhances the activity of antioxidant systems [7, 10], and represses kinases pSAPK/JNK and pERK1 induced by stress [11]. However, the study of the primary interactions of Noopept with more than 100 known receptors conducted according to our protocol by the CEREP company (France) did not lead to the expected identification of the primary targets. At the same time, the wide range of the neurochemical and pharmacological effects of Noopept prompted the further search for its targets.
In order to obtain more exhaustive information on the targets of Noopept, we analyzed in vitro the influence of the drug on the DNA-binding activity of pharmacologically significant biological targets, the transcription factors (TF) CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, HSF1, and HIF-1. Having identified the selective influence of Noopept on HIF-1, we examined the effect of the drug on the activity of this transcription factor under conditions mimicking the hypoxia in vitro.
The data presented in Fig. 2A indicate that incubation with Noopept at a concentration of 10 μM for 24 hours enhances the DNA-binding activity of HIF-1 by 43% and does not caused any statistically significant changes in the DNA-binding activity of the factors CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, and HSF1. As follows from the data presented in Fig. 3, Noopept at concentrations of 10 and 100 μM increases the level of luciferase induction. It was shown that Piracetam at either an equimolar (10 μM, data not shown) or higher concentration (1 μM) does not cause statistically significant changes in the DNA-binding activity of the studied transcription factors (Fig. 2B).
Since prolyl hydroxylase is directly involved in HIF-1 deactivation, and proline analogs are described as effective inhibitors of this enzyme [31], it can be assumed that the increase in the DNAbinding activity of HIF-1 by Noopept is associated with the inhibition of this enzyme.
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-amyloid25-35 [ 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]. All these numerous effects can be explained by the activation of the HIF-1 transcription factor.
The data obtained on the ability of the effective nootropic and neuroprotective drug Noopept to cause an increase in the DNA-binding activity of HIF-1 allow one to advance a novel interpretation of the wide spectrum of its action: namely, assume that the HIF-1-positive effect of the drug can be considered as the primary mechanism of its action. Clarification of the molecular mechanisms underlying the HIF-1-positive action of Noopept certainly requires further investigation; but the presence of this effect definitely has a significant value, since it allows one to explain almost all known to date effects of Noopept and, probably, the effects of other biologically active Pro-Gly peptides. These data provide additional evidence for current concepts of the importance of the components of the HIF-1-dependent signaling pathway and the compensation processes activated by this transcription factor in the mechanisms of neuroprotection."
Besides increased cancer risk from angiogenesis, Noopept certainly seems like an interesting drug if the (primarily Russian) research holds true. Increased neurotrophic factors like BDNF/NGF seem like a good thing for most any state, whether diseased or not, but especially for neurodegenerative disease and mental illness where there is excessive pruning or atrophy. Restoration of normal GABA interneuron functionality seems promising (https://www.ncbi.nlm.nih.gov/pubmed/22232906) and there is potentiation of sodium valproate's anticonvulsant properties (https://www.ncbi.nlm.nih.gov/pubmed/20095393) as well as enhancement of inhibitory synaptic transmission in the hippocampus (https://www.ncbi.nlm.nih.gov/pubmed/25573367 https://www.ncbi.nlm.nih.gov/pubmed/22390072).
Last but not least there are the beneficial effects on Alzheimer's disease conditions https://www.ncbi.nlm.nih.gov/pubmed/25096780
Any discussion is welcome.
"The mechanism of Noopept action has been studied since its synthesis. It has been established that the drug increases the expression of NGF and BDNF in the hippocampus [8], exhibits choline-positive properties at behavioral and neuronal levels [9], reduces oxidative stress and enhances the activity of antioxidant systems [7, 10], and represses kinases pSAPK/JNK and pERK1 induced by stress [11]. However, the study of the primary interactions of Noopept with more than 100 known receptors conducted according to our protocol by the CEREP company (France) did not lead to the expected identification of the primary targets. At the same time, the wide range of the neurochemical and pharmacological effects of Noopept prompted the further search for its targets.
In order to obtain more exhaustive information on the targets of Noopept, we analyzed in vitro the influence of the drug on the DNA-binding activity of pharmacologically significant biological targets, the transcription factors (TF) CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, HSF1, and HIF-1. Having identified the selective influence of Noopept on HIF-1, we examined the effect of the drug on the activity of this transcription factor under conditions mimicking the hypoxia in vitro.
The data presented in Fig. 2A indicate that incubation with Noopept at a concentration of 10 μM for 24 hours enhances the DNA-binding activity of HIF-1 by 43% and does not caused any statistically significant changes in the DNA-binding activity of the factors CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, and HSF1. As follows from the data presented in Fig. 3, Noopept at concentrations of 10 and 100 μM increases the level of luciferase induction. It was shown that Piracetam at either an equimolar (10 μM, data not shown) or higher concentration (1 μM) does not cause statistically significant changes in the DNA-binding activity of the studied transcription factors (Fig. 2B).
Since prolyl hydroxylase is directly involved in HIF-1 deactivation, and proline analogs are described as effective inhibitors of this enzyme [31], it can be assumed that the increase in the DNAbinding activity of HIF-1 by Noopept is associated with the inhibition of this enzyme.
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-amyloid25-35 [ 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]. All these numerous effects can be explained by the activation of the HIF-1 transcription factor.
The data obtained on the ability of the effective nootropic and neuroprotective drug Noopept to cause an increase in the DNA-binding activity of HIF-1 allow one to advance a novel interpretation of the wide spectrum of its action: namely, assume that the HIF-1-positive effect of the drug can be considered as the primary mechanism of its action. Clarification of the molecular mechanisms underlying the HIF-1-positive action of Noopept certainly requires further investigation; but the presence of this effect definitely has a significant value, since it allows one to explain almost all known to date effects of Noopept and, probably, the effects of other biologically active Pro-Gly peptides. These data provide additional evidence for current concepts of the importance of the components of the HIF-1-dependent signaling pathway and the compensation processes activated by this transcription factor in the mechanisms of neuroprotection."
Besides increased cancer risk from angiogenesis, Noopept certainly seems like an interesting drug if the (primarily Russian) research holds true. Increased neurotrophic factors like BDNF/NGF seem like a good thing for most any state, whether diseased or not, but especially for neurodegenerative disease and mental illness where there is excessive pruning or atrophy. Restoration of normal GABA interneuron functionality seems promising (https://www.ncbi.nlm.nih.gov/pubmed/22232906) and there is potentiation of sodium valproate's anticonvulsant properties (https://www.ncbi.nlm.nih.gov/pubmed/20095393) as well as enhancement of inhibitory synaptic transmission in the hippocampus (https://www.ncbi.nlm.nih.gov/pubmed/25573367 https://www.ncbi.nlm.nih.gov/pubmed/22390072).
Last but not least there are the beneficial effects on Alzheimer's disease conditions https://www.ncbi.nlm.nih.gov/pubmed/25096780
Any discussion is welcome.
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