Possibilities of enhancing the neuroprotective effect of autophagy activation in the brain by stimulation of an mTOR-independent pathway of its regulation in a transgenic mouse model of Parkinson’s disease

Akopyan A.A.1, Pupyshev A. B2, Tikhonova M.A.31Scientific Research Institute of Physiology and Basic Medicine Novosibirsk, Russia, annaaleksanovna@mail.ru2Scientific Research Institute of Physiology and Basic Medicine Novosibirsk, Russia, apupyshev@mail.ru3Scientific Research Institute of Physiology and Basic Medicine Novosibirsk, Russia, mar-a-tikh@mail.ru Autophagy induction promotes cell survival that is especially important for neurons which have a limited proliferative resource. Autophagy is regulated by the classical mTOR-dependent mechanism activated by rapamycin, and also via mTOR-independent pathways triggered by trehalose, lithium, metformin, etc. The neuroprotective effect was shown upon combined activation of these pathways in vitro. However, the possibilities of enhancing the therapeutic effect of autophagy activation in vivo remain unclear. Transgenic mice of B6.Cg-Tg (Prnp-SNCA*A53T)23Mkle/J strain with overexpression of alpha-synuclein were used as a model of Parkinson’s disease (PD) in the study. In the striatum and substantia nigra, which are mainly affected in PD, trehalose caused an increase in autophagy, as measured by the expression of the autophagy marker LC3-II. Trehalose in combination with rapamycin increased LC3-II expression by two to three times in comparison with the action of rapamycin alone. In the frontal cortex no changes in LC3-II expression were observed neither under the action of trehalose nor with the combined treatment with trehalose and rapamycin. The most pronounced neuroprotective effect was observed upon the combined use of rapamycin and trehalose by the tyrosine hydroxylase expression in the nigrostriatal system marking the restoration of dopaminergic neurons. In the Rotarod test, the mice were tested for motor function. Animals treated with rapamycin, trehalose, or their combination stayed much longer on a rotating drum, compared to controls. Autophagy contribution to the therapeutic effects was confirmed by administration of autophagy inhibitor 3-methyladenine, which completely blocks the neuroprotective effects of the drugs. Acknowledgments This work was supported  by a grant No. 16-04-01423 from the Russian Foundation for Basic Research.

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Diabetes Type 2 as a Risk Factor of Neurodegeneration Development and Cognitive Impairment in db/db Mice

Poster (download) Tatyana A. Korolenko1, Nina I. Dubrovina2, Marina V. Ovsyukova3, Natalya P. Bgatova4, Chih-Li Lin5, Alexander B. Pupyshev6, Evgeniy L. Zavjalov7, Elena V. Anufrienko Scientific Research Institute81Scientific Research Institute of Physiology and Basic Medicine Novosibirsk, Russia, t.a.korolenko@physiol.ru2Scientific Research Institute of Physiology and Basic Medicine Novosibirsk, Russia, dubrov@physiol.ru3Scientific Research Institute of Physiology and Basic Medicine Novosibirsk, Russia, ovsyukovamv@physiol.ru4Federal Research Center “ICG SB RAS”, Novosibirsk, Russia, n.bgatova@ngs.ru5Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, dll@csmu.edu.tw6Scientific Research Institute of Physiology and Basic Medicine Novosibirsk, Russia, apupyshev@physiol.ru7Federal Research Center “ICG SB RAS”, Novosibirsk, Russia, zavjalov@bionet.nsc.ru8Scientific Research Institute of Physiology and Basic Medicine Novosibirsk, Russia, anufrienko@ngs.ru Diabetes T2 with insulin resistance is a serious disease all over the world with a tendency to steady increase the number of cases and a risk factor of neurodegenerative diseases development, among them firstly Alzheimer’s disease. The aim of this study was to investigate behavior and general characteristic of genetic model of diabetes T2 mice db/db, trying to reveal beginning of development early symptoms of neurodegeneration development and characteristic of symptoms of diabetes T2 during treatment by liraglutide or autophagy inducer trehalose. Mice age was 3 and 5 months. Db/db mice had an increase in body weight, which progressed with age, a decrease in brain mass. Blood glucose levels were increased in db/db mice. Treatment with trehalose or liraglutide reduces its level. Db/db mice were characterized by decrease of overall orientation-exploratory and locomotor activities, increase in anxiety in the open field test. Liraglutide treatment showed positive change in open field test in db/db mice. Passive avoidance test revealed significant decrease in motivation, locomotor and exploratory activity, decreased learning in db/db mice. Db/db mice of both ages were characterized by an increase in the relative number of PMN and monocytes and a decrease in the number of lymphocytes, indicating an inflammatory response. Treatment with trehalose or liraglutide restored these indicators. Thus, the identified behavioral changes in db/db mice reflected the development of neurodegeneration signs. Some positive effects of liraglutide on behavioral processes have been shown. Trehalose and liraglutide reduced blood glucose levels and the severity of the inflammatory response.

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