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

Vakhitova YV, Sadovnikov SV, Borisevich SS, Ostrovskaya RU, A Gudasheva T, Seredenin SB - Acta Naturae (2016 Jan-Mar)

Bottom Line: Piracetam (1 mM) failed to affect significantly any of the TF under study.The results of molecular docking showed that Noopept (L-isomer), as well as its metabolite, L-isomer of N-phenyl-acetylprolyl, unlike its pharmacologically ineffective D-isomer, is able to bind to the active site of prolyl hydroxylase 2.The obtained data allow one to propose the HIF-positive effect as the primary mechanism of the activity of this Pro-Gly-containing dipeptide.

View Article: PubMed Central - PubMed

Affiliation: State Zakusov Institute of Pharmacology , Baltiyskaya Str., 8, 125315, Moscow, Russia ; Institute of Biochemistry and Genetics of Ufa Scientific Centre RAS, Prospekt Oktyabrya, 71, 450065 , Ufa, Russia.

ABSTRACT
This study was performed in order to reveal the effect of Noopept (ethyl ester of N-phenylacetyl-Lprolylglycine, GVS-111) on the DNA-binding activity of transcriptional factors (TF) in HEK293 cells transiently transfected with luciferase reporter constructs containing sequences for CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, HSF1, and HIF-1. Noopept (10 μM) was shown to increase the DNA-binding activity of HIF-1 only, while lacking the ability to affect that of CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, and HSF1. Noopept provoked an additional increase in the DNA-binding activity of HIF-1 when applied in conditions of CoCl2-induced HIF- 1 stabilization. The degree of this HIF-positive effect of Noopept was shown to be concentration-dependent. Piracetam (1 mM) failed to affect significantly any of the TF under study. The results of molecular docking showed that Noopept (L-isomer), as well as its metabolite, L-isomer of N-phenyl-acetylprolyl, unlike its pharmacologically ineffective D-isomer, is able to bind to the active site of prolyl hydroxylase 2. Taking into account the important role of the genes activated by HIF-1 in the formation of an adaptive response to hypoxia, data on the ability of Noopept to provoke a selective increase in the DNA-binding activity of HIF-1 explain the wide spectrum of neurochemical and pharmacological effects of Noopept revealed before. The obtained data allow one to propose the HIF-positive effect as the primary mechanism of the activity of this Pro-Gly-containing dipeptide.

No MeSH data available.


Related in: MedlinePlus

The effect of Noopept on the basal and induced activity of HIF-1.“Control” group – values of the basal activity of HIF-1 inunstimulated cells; “CoCl2” group – HIF-1 activityvalues in CoCl2-stimulated cells. The data are presented asarithmetic mean ± standard error of the mean (n =3; *p  < 0.05 with respect to “control” group;#p  < 0.05 with respect to “CoCl2”group)
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Figure 3: The effect of Noopept on the basal and induced activity of HIF-1.“Control” group – values of the basal activity of HIF-1 inunstimulated cells; “CoCl2” group – HIF-1 activityvalues in CoCl2-stimulated cells. The data are presented asarithmetic mean ± standard error of the mean (n =3; *p < 0.05 with respect to “control” group;#p < 0.05 with respect to “CoCl2”group)

Mentions: The data presentedin Fig. 2A indicatethat incubation with Noopept at a concentration of 10 μM for 24 hours enhancesthe DNA-binding activity of HIF-1 by 43% and does not caused any statisticallysignificant changes in the DNA-binding activity of the factors CREB, NFAT, NF-κB,p53, STAT1, GAS, VDR, and HSF1. As follows from the data presentedin Fig. 3,Noopept at concentrations of 10 and 100 μM increases the levelof luciferase induction. It was shown that Piracetam at either an equimolar (10μM, data not shown) or higher concentration (1 μM) does not causestatistically significant changes in the DNA-binding activity of the studiedtranscription factors(Fig. 2B).


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

Vakhitova YV, Sadovnikov SV, Borisevich SS, Ostrovskaya RU, A Gudasheva T, Seredenin SB - Acta Naturae (2016 Jan-Mar)

The effect of Noopept on the basal and induced activity of HIF-1.“Control” group – values of the basal activity of HIF-1 inunstimulated cells; “CoCl2” group – HIF-1 activityvalues in CoCl2-stimulated cells. The data are presented asarithmetic mean ± standard error of the mean (n =3; *p  < 0.05 with respect to “control” group;#p  < 0.05 with respect to “CoCl2”group)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4837574&req=5

Figure 3: The effect of Noopept on the basal and induced activity of HIF-1.“Control” group – values of the basal activity of HIF-1 inunstimulated cells; “CoCl2” group – HIF-1 activityvalues in CoCl2-stimulated cells. The data are presented asarithmetic mean ± standard error of the mean (n =3; *p < 0.05 with respect to “control” group;#p < 0.05 with respect to “CoCl2”group)
Mentions: The data presentedin Fig. 2A indicatethat incubation with Noopept at a concentration of 10 μM for 24 hours enhancesthe DNA-binding activity of HIF-1 by 43% and does not caused any statisticallysignificant changes in the DNA-binding activity of the factors CREB, NFAT, NF-κB,p53, STAT1, GAS, VDR, and HSF1. As follows from the data presentedin Fig. 3,Noopept at concentrations of 10 and 100 μM increases the levelof luciferase induction. It was shown that Piracetam at either an equimolar (10μM, data not shown) or higher concentration (1 μM) does not causestatistically significant changes in the DNA-binding activity of the studiedtranscription factors(Fig. 2B).

Bottom Line: Piracetam (1 mM) failed to affect significantly any of the TF under study.The results of molecular docking showed that Noopept (L-isomer), as well as its metabolite, L-isomer of N-phenyl-acetylprolyl, unlike its pharmacologically ineffective D-isomer, is able to bind to the active site of prolyl hydroxylase 2.The obtained data allow one to propose the HIF-positive effect as the primary mechanism of the activity of this Pro-Gly-containing dipeptide.

View Article: PubMed Central - PubMed

Affiliation: State Zakusov Institute of Pharmacology , Baltiyskaya Str., 8, 125315, Moscow, Russia ; Institute of Biochemistry and Genetics of Ufa Scientific Centre RAS, Prospekt Oktyabrya, 71, 450065 , Ufa, Russia.

ABSTRACT
This study was performed in order to reveal the effect of Noopept (ethyl ester of N-phenylacetyl-Lprolylglycine, GVS-111) on the DNA-binding activity of transcriptional factors (TF) in HEK293 cells transiently transfected with luciferase reporter constructs containing sequences for CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, HSF1, and HIF-1. Noopept (10 μM) was shown to increase the DNA-binding activity of HIF-1 only, while lacking the ability to affect that of CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, and HSF1. Noopept provoked an additional increase in the DNA-binding activity of HIF-1 when applied in conditions of CoCl2-induced HIF- 1 stabilization. The degree of this HIF-positive effect of Noopept was shown to be concentration-dependent. Piracetam (1 mM) failed to affect significantly any of the TF under study. The results of molecular docking showed that Noopept (L-isomer), as well as its metabolite, L-isomer of N-phenyl-acetylprolyl, unlike its pharmacologically ineffective D-isomer, is able to bind to the active site of prolyl hydroxylase 2. Taking into account the important role of the genes activated by HIF-1 in the formation of an adaptive response to hypoxia, data on the ability of Noopept to provoke a selective increase in the DNA-binding activity of HIF-1 explain the wide spectrum of neurochemical and pharmacological effects of Noopept revealed before. The obtained data allow one to propose the HIF-positive effect as the primary mechanism of the activity of this Pro-Gly-containing dipeptide.

No MeSH data available.


Related in: MedlinePlus