Geroprotective properties of neuroprotective and neurotrophic peptides
https://doi.org/10.14412/2074-2711-2020-1-61-67
Abstract
Objective: to elucidate whether cerebrolysin contains peptide fragments that promote geroprotection.
Material and methods. The peptide composition of cerebrolysin underwent a comprehensive mass spectrometric analysis, followed by a systemic biological assessment.
Results and discussion. Thirty-six peptides with geroprotective properties were isolated in the multipeptide composition of cerebrolysin. These peptides included those of mimetics of adrenomedullin and enkephalins; those of inhibitors of seven targeted human proteins (the protein kinases MAPK1, VPRBP, and PKC, the gamma-secretase PS1, the kinases CDK1, SGK1 and mTOR). The established cerebrolysin peptides were shown to be competitive inhibitors of the seven targeted proteins. In particular, inhibition of PKC and mTOR stimulated the increased autophagy (the utilization of waste and abnormal proteins), which contributes to an increase in the survival of cells and model organisms.
Conclusion. Cerebrolysin can have geroprotective effects, by inhibiting the seven targeted proteins, by activating endorphinergic neurotransmission, and can be indirectly involved in vascular tone normalization.
Material and methods. The peptide composition of cerebrolysin underwent a comprehensive mass spectrometric analysis, followed by a systemic biological assessment.
Results and discussion. Thirty-six peptides with geroprotective properties were isolated in the multipeptide composition of cerebrolysin. These peptides included those of mimetics of adrenomedullin and enkephalins; those of inhibitors of seven targeted human proteins (the protein kinases MAPK1, VPRBP, and PKC, the gamma-secretase PS1, the kinases CDK1, SGK1 and mTOR). The established cerebrolysin peptides were shown to be competitive inhibitors of the seven targeted proteins. In particular, inhibition of PKC and mTOR stimulated the increased autophagy (the utilization of waste and abnormal proteins), which contributes to an increase in the survival of cells and model organisms.
Conclusion. Cerebrolysin can have geroprotective effects, by inhibiting the seven targeted proteins, by activating endorphinergic neurotransmission, and can be indirectly involved in vascular tone normalization.
About the Authors
O. A. Gromova
Federal Research Center «Informatics and Management», Russian Academy of Sciences;
Big Data Storage and Analysis Center, M.V. Lomonosov Moscow State University
Russian Federation
Russian Federation
44, Vavilov St., Build. 2, Moscow 119333
1, Leninskie Gory, Moscow 119234
I. Yu. Torshin
Federal Research Center «Informatics and Management», Russian Academy of Sciences;
Big Data Storage and Analysis Center, M.V. Lomonosov Moscow State University
Russian Federation
Russian Federation
44, Vavilov St., Build. 2, Moscow 119333
1, Leninskie Gory, Moscow 119234
V. G. Zgoda
V.N. Orekhovich Research Institute of Biomedical Chemistry
Russian Federation
10, Pogodinskaya St., Build. 8, Moscow 119121
Russian Federation
10, Pogodinskaya St., Build. 8, Moscow 119121
A. I. Sorokin
Big Data Storage and Analysis Center, M.V. Lomonosov Moscow State University
Russian Federation
Russian Federation
1, Leninskie Gory, Moscow 119234
O. V. Tikhonova
V.N. Orekhovich Research Institute of Biomedical Chemistry
Russian Federation
10, Pogodinskaya St., Build. 8, Moscow 119121
Russian Federation
10, Pogodinskaya St., Build. 8, Moscow 119121
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78. Tamori Y, Bialucha CU, Tian AG, et al. Involvement of Lgl and Mahjong/VprBP in cell competition. PLoS Biol. 2010 Jul 13;8(7): e1000422. doi: 10.1371/journal.pbio.1000422.
79. Chen CH, Wang WJ, Kuo JC, et al. Bidirectional signals transduced by DAPKERK interaction promote the apoptotic effect of DAPK. EMBO J. 2005 Jan 26;24(2):294-304. Epub 2004 Dec 16. doi: 10.1038/sj.emboj.7600510.
80. Voskresenskaya ON, Zakharov NB, Tarasova YuS, et al. Possible mechanisms of cognitive dysfunction in patients with chronic forms of cerebrovascular diseases. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2018;10(1):32-36. (In Russ.). doi: 10.14412/2074-2711-2018-1-32-36
81. Nandi S, Reinert LS, Hachem A, et al. Phosphorylation of MCT-1 by p44/42 MAPK is required for its stabilization in response to DNA damage. Oncogene. 2007 Apr 5;26(16): 2283-9. doi: 10.1038/sj.onc.1210030.
82. Gromova OA, Torshin IYu, Fedotova LE. Geriatric information analysis of the molecular properties of mexidole. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2017;9(4):46–54. (In Russ.). doi: 10.14412/2074-2711-2017-4-46-54.
83. Steiner H, Romig H, Pesold B, et al. Amyloidogenic function of the Alzheimer's disease-associated presenilin 1 in the absence of endoproteolysis. Biochemistry. 1999 Nov 2; 38(44):14600-5. doi: 10.1021/bi9914210.
84. Marambaud P, Shioi J, Serban G, et al. A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J. 2002 Apr 15;21(8):1948-56. doi: 10.1093/emboj/21.8.1948.
85. Torshin IYu, Gromova OA, Fedotova LE, Gromov AN. Comparative chemoreactome analysis of dexketoprofen, ketoprofen, and diclofenac. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2018;10(1):47-54. (In Russ.). doi: 10.14412/2074-2711-2018-1-47-54.
86. Dovey HF, John V, Anderson JP, et al. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J Neurochem. 2001 Jan;76(1):173-81. doi: 10.1046/j.1471-4159.2001.00012.x.
87. Ye J, Rawson RB, Komuro R, et al. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell. 2000 Dec;6(6):1355-64. doi: 10.1016/s1097-2765(00)00133-7.
88. He P, Lee SJ, Lin S, et al. Serum- and glucocorticoid-induced kinase 3 in recycling endosomes mediates acute activation of Na+/H+ exchanger NHE3 by glucocorticoids. Mol Biol Cell. 2011 Oct;22(20):3812-25. doi: 10.1091/mbc.E11-04-0328.
89. Yoo D, Kim BY, Campo C, et al. Cell surface expression of the ROMK (Kir 1.1) channel is regulated by the aldosterone-induced kinase, SGK-1, and protein kinase A. J Biol Chem. 2003 Jun 20;278(25):23066-75. doi: 10.1074/jbc.M212301200.
90. Lee JM, Lee JS, Kim H, et al. EZH2 generates a methyl degron that is recognized by the DCAF1/DDB1/CUL4 E3 ubiquitin ligase complex. Mol Cell. 2012 Nov 30;48(4):572-86. doi: 10.1016/j.molcel.2012.09.004.
91. Tamori Y, Bialucha CU, Tian AG, et al. Involvement of Lgl and Mahjong/VprBP in cell competition. PLoS Biol. 2010 Jul 13;8(7): e1000422. doi: 10.1371/journal.pbio.1000422.
92. Voskresenskaya ON, Zakharov NB, Tarasova YuS, et al. Possible mechanisms of cognitive dysfunction in patients with chronic forms of cerebrovascular diseases. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2018;10(1):32-36. (In Russ.). doi: 10.14412/2074-2711-2018-1-32-36
93. Gromova OA, Torshin IYu, Fedotova LE. Geriatric information analysis of the molecular properties of mexidole. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2017;9(4):46–54. (In Russ.). doi: 10.14412/2074-2711-2017-4-46-54.
94. Torshin IYu, Gromova OA, Fedotova LE, Gromov AN. Comparative chemoreactome analysis of dexketoprofen, ketoprofen, and diclofenac. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2018;10(1):47-54. (In Russ.). doi: 10.14412/2074-2711-2018-1-47-54.
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Gromova O.A., Torshin I.Yu., Zgoda V.G., Sorokin A.I., Tikhonova O.V. Geroprotective properties of neuroprotective and neurotrophic peptides. Neurology, Neuropsychiatry, Psychosomatics. 2020;12(1):61-67. (In Russ.) https://doi.org/10.14412/2074-2711-2020-1-61-67
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