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Molecular Mechanisms of the Effects of Metformin on the Functional Activity of Brain Neurons

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Metformin (MF) is the most widely used drug for the treatment of type 2 diabetes mellitus and metabolic syndrome (MS). In the peripheral tissues, MF inhibits mitochondrial respiratory chain complex I and increases the activity of AMP-activated protein kinase (AMPK), leading to suppression of gluconeogenesis in the liver, increased insulin sensitivity, increased glucose utilization, and normalization of lipid metabolism. Recent years have seen the appearance of experimental and clinical evidence showing that the CNS is also a major target of MF, such that the action of MF on the functional state of neurons can be mediated both via AMPK-dependent and via AMPK-independent signal cascades. In contrast to the periphery, MF does not activate but suppresses AMPK activity in hypothalamic neurons, this influencing the ratio of anorexigenic (melanocortin peptides) and orexigenic (neuropeptide Y) factors and altering feeding behavior. A significant contribution to this effect is made by MF-induced activation of the leptin-dependent STAT3 signal cascade. As the leptin and melanocortin systems targeted by MF interact closely with the insulin and monoamine systems, MF, acting through them, affects the entire integrative signal system of the brain, on which the functioning of the nervous, endocrine, cardiovascular, and other body systems depend. This review analyzes and systematizes data on the molecular mechanisms and targets of the action of MF in brain neurons, and the effects of this drug, which are mediated or may be mediated by the interactions of MF with the CNS.

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  1. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia

    A. O. Shpakov & K. V. Derkach

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Correspondence to A. O. Shpakov.

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Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 103, No. 5, pp. 504–517, May, 2017.

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Shpakov, A.O., Derkach, K.V. Molecular Mechanisms of the Effects of Metformin on the Functional Activity of Brain Neurons . Neurosci Behav Physi 48, 969–977 (2018). https://doi.org/10.1007/s11055-018-0657-6

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