The PI3K/Akt Cascade Is Involved in the Antidiabetic Effect of Compound GSB-214, a Low-Molecular-Weight BDNF Mimetic
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Bulletin of Experimental Biology and Medicine, Vol. 169, No. 6, October, 2020
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PHARMACOLOGY AND TOXICOLOGY The PI3K/Akt Cascade Is Involved in the Antidiabetic Effect of Compound GSB-214, a Low-Molecular-Weight BDNF Mimetic
S. S. Yagubova, R. U. Ostrovskaya, T. A. Gudasheva, and S. B. Seredenin Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 169, No. 6, pp. 712-715, June, 2020 Original article submitted December 23, 2019 In our previous studies on the streptozotocin model of diabetes we hypothesized that activation of the PI3K/Akt signaling pathway is essential for the realization of the antidiabetic effect of low-molecular-weight NGF and BDNF mimetics. Here we analyze the effect of a specific PI3K/Akt pathway inhibitor (LY 294002) on the antidiabetic effect of the BDNF loop 1 mimetic GSB-214. The experiments on C57BL/6 mice with streptozotocin-induced diabetes showed that GSB-214 attenuated the hyperglycemic effect of streptozotocin and prevented weight loss typical of diabetes, while LY 294002 eliminated these effects of GSB-214. These findings clearly demonstrate the involvement of PI3K/Akt pathway in the implementation of the effects of this low-molecular-weight BDNF mimetic. Key Words: diabetes; C57BL/6; streptozotocin; low-molecular-weight BDNF mimetic; LY 294002
It is known that BDNF supports the viability and functioning of β cells and stimulates insulin secretion [13]. BDNF as well as insulin-like growth factor induce expression of genes promoting β-cell survival and reducing activity of the cell death systems [12]. It was shown that the diabetogenic toxin streptozotocin (STZ) reduces survival and insulin-producing function of β cells in in vitro experiments on RIN5F insulinoma cells, while BDNF (10-100 ng/ml) restores these functions [5]. Thus, it can be assumed that neurotrophin could have a therapeutic potential for the treatment of diabetes mellitus (DM) and its complications. However, clinical use of native BDNF molecule is limited due to its pharmacokinetic properties. This disadvantage of native BDNF molecule determines the expediency of creating V. V. Zakusov Research Institute of Pharmacology, Moscow, Russia. Address for correspondence: [email protected]. R. U. Ostrovskaya
low-molecular-weight compounds simulating the effects of BDNF. Dimeric dipeptide GSB-214 (bis-(N-monosuccinyl-L-methionyl-L-serine) hexamethylenediamide) was designed at the V.V. Zakusov Research Institute of Pharmacology based on a β-turn of the BDNF loop 1 [2,4]. It was shown that GSB-214 interacts with TrkB receptors activating the PI3K/Akt posttranslational signaling pathway [1,11]. GSB-214 was shown to exert the neuroprotective activity in experiments in vitro on the model of oxidative stress [2] and in vivo on the model of the middle cerebral artery occlusion [11]. Our previous studies of the antidiabetic effects of NGF and BDNF mimetics (including GSB-214) activating different post-receptor pathways [3] allow us to formulate a preliminary suggestion that activation of the PI3K/Akt
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