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Anti-Inflammatory Properties of Metformin During Cultivation of Primary Rat Astrocytes in a Medium with High Glucose Concentration

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Abstract

Investigation of the relationship between inflammation and energy metabolism is important for understanding biology of chronic noncommunicable diseases. Use of metformin, a drug for treatment of diabetes, is considered as a promising direction for treatment of neurodegenerative diseases and other neuropathologies with an inflammatory component. Astrocytes play an important role in the regulation of energy metabolism and neuroinflammation; therefore, we studied the effect of metformin on the cellular responses of primary rat astrocytes cultured in a medium with high glucose concentration (22.5 mM, 48-h incubation). Lipopolysaccharide (LPS) was used to stimulate inflammation. The effects of metformin were assessed by monitoring changes in the expression of proinflammatory cytokines and synthesis of oxylipins, assayed with ultra-high-performance liquid chromatography and tandem mass spectrometry (UPLC-MS/MS). Changes at the intracellular level were assessed by analyzing phosphorylation of ERK kinase and transcription factor STAT3, as well as enzymes mediating oxylipin synthesis, cyclooxygenase 1 and 2 (COX). It was found that, independent on glucose concentration, metformin reduced the LPS-stimulated release of cytokines IL-1β and IL-6, decreased activity of the transcription factor STAT3, ERK kinase, synthesis of the derivatives of the cyclooxygenase branch of metabolism of oxylipins and anandamide, and did not affect formation of ROS. The study of energy phenotype of the cells showed that metformin activated glycolysis and inhibited mitochondrial respiration and oxidative phosphorylation, independent on LPS stimulation and cell cultivation at high glucose concentration. Thus, it has been shown that metformin exhibits anti-inflammatory effects, and its effect on the synthesis of cytokines, prostaglandins, and other lipid mediators could determine beneficial effects of metformin in models of neuropathology.

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Abbreviations

AA:

arachidonic acid

AEA:

anandamide acid

AMPK:

5′ AMP-activated protein kinase

COX:

cyclooxygenase

DHA:

docosahexaenoic acid

ECAR:

extracellular acidification rate

EPA:

eicosapentaenoic acid

HG:

high glucose concentration

IL:

interleukin

LPS:

lipopolysaccharide

NG:

normal glucose concentration

OCR:

oxygen consumption rate

PG:

prostaglandin

ROS:

reactive oxygen species

TNFα:

tumor necrosis factor alpha

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Acknowledgments

The authors are grateful to the Moscow State University Development Program for providing access to the confocal microscope Zeiss LSM900.

Funding

This study was financially supported by the Russian Science Foundation (project no. 20-74-00068).

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Authors and Affiliations

  1. Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119234, Moscow, Russia

    Vladislav O. Gorbatenko

  2. Peoples’ Friendship University of Russia (RUDN University), 117198, Moscow, Russia

    Sergey V. Goriainov

  3. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992, Moscow, Russia

    Valentina A. Babenko, Egor Y. Plotnikov, Marina G. Sergeeva & Dmitry V. Chistyakov

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  1. Vladislav O. Gorbatenko
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  2. Sergey V. Goriainov
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  3. Valentina A. Babenko
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  5. Marina G. Sergeeva
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Correspondence to Dmitry V. Chistyakov.

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Gorbatenko, V.O., Goriainov, S.V., Babenko, V.A. et al. Anti-Inflammatory Properties of Metformin During Cultivation of Primary Rat Astrocytes in a Medium with High Glucose Concentration. Biochemistry Moscow 87, 577–589 (2022). https://doi.org/10.1134/S000629792207001X

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