Abstract
Previously, we prepared dimeric dipeptide mimetics of the first and the fourth loops of the nerve growth factor (NGF): hexamethylenediamides of bis(N-aminocaproyl-glycyl-L-lysine) (GK-6) and bis(N-monosuccinyl-L-glutamyl-L-lysine) (GK-2). Both mimetics activated TrkA-receptors, but induced different postreceptor signal pathways. GK-2 selectively activated PI3K/AKT, whereas GK-6 activated both PI3K/AKT and MAPK/ERK. Both mimetics exhibited a neuroprotective activity. In this study, we continued the investigation of a contribution of separate loop-like structures in the NGF functions and created and studied dimeric dipeptide mimetics based on a beta-turn of the NGF third loop: hexamethylenediamides of bis(N-gamma-hydroxybutyryl-L-lysyl-L-histidine) (GTS-115) and bis(N-acetyl-L-lysyl-L-histidine) (GTS-113). GTS-115 was shown to exhibit the neuroprotective activity in the concentration range from 10–5 to 10–7 М towards the HT-22 cell culture under the conditions of oxidative stress. The acetyl-containing GTS-113 mimetic proved to be inactive. GTS-115 (1 mg/kg/day intraperitoneally, for 7 days, the administration was started 4 h after the operation) exhibited the neuroprotective properties and decreased the infarction volume by 25% on the model of a stroke that was induced by a transient occlusion of the medial cerebral artery of rats. The action mechanism of GTS-115 was studied by Western-blot analysis and this mimetic in a concentration of 10–6 М was shown to activate the TrkA-receptor and both MAPK/ERK and PI3K/AKT basic postreceptor signal pathways. The inhibitory analysis revealed different contributions of these pathways into the GTS-115 neuroprotective effect. The LY294002 selective inhibitor of PI3K completely blocked the neuroprotective effect of GTS-115 in vitro, whereas the PD98059 specific inhibitor of MEK1 and MEK2 decreased this effect only by 10–15%. GTS-115 peptide stimulated a differentiation of the PC12 cells and caused a hyperalgesia in rats. These facts were in a good agreement with the literature data on the participation of the MAP-kinase pathway in these effects. Thus, the third NGF loop and the neighboring first NGF loop activated the postreceptor pathways in a similar way and exhibited the similar activities.
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Abbreviations
- BuONO:
-
n-butyl nitrite
- DCС:
-
1,3-dicyclohexylcarbodiimide
- DCU:
-
1,3-dicyclohexylurea
- DIEA:
-
N,N-diisopropylethylamine
- DMAPA:
-
3-(dimethylamino)propylamine
- GHB:
-
gamma–hydroxybutyric acid
- MAPK/ERK:
-
the mitogen-activated proteinkinase pathway
- NGF:
-
the nerve growth factor
- PI3K/AKT:
-
phosphatidyl inositol-3-kinase pathway
- TEA:
-
triethylamine
- TFA:
-
trifluoroacetic acid
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Original Russian Text © T.A. Gudasheva, A.V. Tarasiuk, N.M. Sazonova, S.V. Pomogaibo, A.N. Shumskiy, I.O. Logvinov, S.V. Nikolaev, P.Yu. Povarnina, M.A. Konstantinopolsky, T.A. Antipova, S.B. Seredenin, 2017, published in Bioorganicheskaya Khimiya, 2017, Vol. 43, No. 3, pp. 236–249.
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Gudasheva, T.A., Tarasiuk, A.V., Sazonova, N.M. et al. Design, synthesis, and neuroprotective effects of a dimeric dipeptide mimetic of the third loop of the nerve growth factor. Russ J Bioorg Chem 43, 235–247 (2017). https://doi.org/10.1134/S1068162017030050
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DOI: https://doi.org/10.1134/S1068162017030050