Design, synthesis, and neuroprotective effects of a dimeric dipeptide mimetic of the third loop of the nerve growth factor
- Authors: Gudasheva T.A.1, Tarasiuk A.V.1, Sazonova N.M.1, Pomogaibo S.V.1, Shumskiy A.N.1, Logvinov I.O.1, Nikolaev S.V.1, Povarnina P.Y.1, Konstantinopolsky M.A.1, Antipova T.A.1, Seredenin S.B.1
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Affiliations:
- Zakusov Research Institute of Pharmacology
- Issue: Vol 43, No 3 (2017)
- Pages: 235-247
- Section: Article
- URL: https://journals.rcsi.science/1068-1620/article/view/228506
- DOI: https://doi.org/10.1134/S1068162017030050
- ID: 228506
Cite item
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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About the authors
T. A. Gudasheva
Zakusov Research Institute of Pharmacology
Author for correspondence.
Email: tata-sosnovka@mail.ru
Russian Federation, Moscow, 125315
A. V. Tarasiuk
Zakusov Research Institute of Pharmacology
Email: tata-sosnovka@mail.ru
Russian Federation, Moscow, 125315
N. M. Sazonova
Zakusov Research Institute of Pharmacology
Email: tata-sosnovka@mail.ru
Russian Federation, Moscow, 125315
S. V. Pomogaibo
Zakusov Research Institute of Pharmacology
Email: tata-sosnovka@mail.ru
Russian Federation, Moscow, 125315
A. N. Shumskiy
Zakusov Research Institute of Pharmacology
Email: tata-sosnovka@mail.ru
Russian Federation, Moscow, 125315
I. O. Logvinov
Zakusov Research Institute of Pharmacology
Email: tata-sosnovka@mail.ru
Russian Federation, Moscow, 125315
S. V. Nikolaev
Zakusov Research Institute of Pharmacology
Email: tata-sosnovka@mail.ru
Russian Federation, Moscow, 125315
P. Yu. Povarnina
Zakusov Research Institute of Pharmacology
Email: tata-sosnovka@mail.ru
Russian Federation, Moscow, 125315
M. A. Konstantinopolsky
Zakusov Research Institute of Pharmacology
Email: tata-sosnovka@mail.ru
Russian Federation, Moscow, 125315
T. A. Antipova
Zakusov Research Institute of Pharmacology
Email: tata-sosnovka@mail.ru
Russian Federation, Moscow, 125315
S. B. Seredenin
Zakusov Research Institute of Pharmacology
Email: tata-sosnovka@mail.ru
Russian Federation, Moscow, 125315