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The Protective Effect of Insulin on Rat Cortical Neurons in Oxidative Stress and Its Dependence on the Modulation of Akt, GSK-3beta, ERK1/2, and AMPK Activities

Department of Molecular Endocrinology and Neurochemistry, I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Thorez avenue, 44, Saint-Petersburg 194223, Russia
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Int. J. Mol. Sci. 2019, 20(15), 3702; https://doi.org/10.3390/ijms20153702
Received: 28 June 2019 / Revised: 20 July 2019 / Accepted: 24 July 2019 / Published: 29 July 2019
(This article belongs to the Special Issue Kinase Signal Transduction 2019)
Insulin is a promising drug for the treatment of diseases associated with brain damage. However, the mechanism of its neuroprotective action is far from being understood. Our aim was to study the insulin-induced protection of cortical neurons in oxidative stress and its mechanism. Immunoblotting, flow cytometry, colorimetric, and fluorometric techniques were used. The insulin neuroprotection was shown to depend on insulin concentration in the nanomolar range. Insulin decreased the reactive oxygen species formation in neurons. The insulin-induced modulation of various protein kinase activities was studied at eight time-points after neuronal exposure to prooxidant (hydrogen peroxide). In prooxidant-exposed neurons, insulin increased the phosphorylation of GSK-3beta at Ser9 (thus inactivating it), which resulted from Akt activation. Insulin activated ERK1/2 in neurons 5–30 min after cell exposure to prooxidant. Hydrogen peroxide markedly activated AMPK, while it was for the first time shown that insulin inhibited it in neurons at periods of the most pronounced activation by prooxidant. Insulin normalized Bax/Bcl-2 ratio and mitochondrial membrane potential in neurons in oxidative stress. The inhibitors of the PI3K/Akt and MEK1/2/ERK1/2 signaling pathways and the AMPK activator reduced the neuroprotective effect of insulin. Thus, the protective action of insulin on cortical neurons in oxidative stress appear to be realized to a large extent through activation of Akt and ERK1/2, GSK-3beta inactivation, and inhibition of AMPK activity increased by neuronal exposure to prooxidant. View Full-Text
Keywords: insulin; cortical neurons; oxidative stress; protection; protein kinases; Bax/Bcl-2 ratio; mitochondrial membrane potential insulin; cortical neurons; oxidative stress; protection; protein kinases; Bax/Bcl-2 ratio; mitochondrial membrane potential
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MDPI and ACS Style

Zakharova, I.O.; Sokolova, T.V.; Bayunova, L.V.; Zorina, I.I.; Rychkova, M.P.; Shpakov, A.O.; Avrova, N.F. The Protective Effect of Insulin on Rat Cortical Neurons in Oxidative Stress and Its Dependence on the Modulation of Akt, GSK-3beta, ERK1/2, and AMPK Activities. Int. J. Mol. Sci. 2019, 20, 3702. https://doi.org/10.3390/ijms20153702

AMA Style

Zakharova IO, Sokolova TV, Bayunova LV, Zorina II, Rychkova MP, Shpakov AO, Avrova NF. The Protective Effect of Insulin on Rat Cortical Neurons in Oxidative Stress and Its Dependence on the Modulation of Akt, GSK-3beta, ERK1/2, and AMPK Activities. International Journal of Molecular Sciences. 2019; 20(15):3702. https://doi.org/10.3390/ijms20153702

Chicago/Turabian Style

Zakharova, Irina O.; Sokolova, Tatiana V.; Bayunova, Liubov V.; Zorina, Inna I.; Rychkova, Maria P.; Shpakov, Alexander O.; Avrova, Natalia F. 2019. "The Protective Effect of Insulin on Rat Cortical Neurons in Oxidative Stress and Its Dependence on the Modulation of Akt, GSK-3beta, ERK1/2, and AMPK Activities" Int. J. Mol. Sci. 20, no. 15: 3702. https://doi.org/10.3390/ijms20153702

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