Mechanisms of neuroprotective action of incretin mimetics
Timur Dmitrievich Vlasov, 
Anna Vladimirovna Simanenkova,
Svetlana Vladimirovna Dora,
Evgeniy Vladimirovich Shlyakhto
Anna Vladimirovna Simanenkova,
Svetlana Vladimirovna Dora,
Evgeniy Vladimirovich Shlyakhto https://doi.org/10.14341/DM7192
Abstract
Recently, on the pharmacological market, new drugs from the class of incretin mimetics, or glucagon-like peptide-1 (GLP-1) receptor agonists, which have proven their high effectiveness in type 2 diabetes mellitus therapy, have appeared. At present, much attention has been paid to the pleotropic effects of incretin mimetics. In a number of both experimental and clinical studies, cardioprotective effects of this medication group have been demonstrated. The present review elucidates existing data about neuroprotective effects of GLP-1 receptor agonists in brain ischaemia and in nonischaemic nervous system diseases such as diabetic neuropathy and neurodegenerative disorders. The possible mechanisms for these effects, which appear to be primarily antioxidant effects, anti-inflammatory effects, antiapoptotic effects and an increase in neurons differentiation, are discussed.
About the Authors
Timur Dmitrievich Vlasov
Pavlov First Saint-Petersburg State medical University;
Federal North-West Medical Research Center
Russian Federation
MD, PhD, Professor
Competing Interests: Автор декларирует отсутствие конфликта интересов.
Russian Federation
MD, PhD, Professor
Competing Interests: Автор декларирует отсутствие конфликта интересов.
Anna Vladimirovna Simanenkova
Pavlov First Saint-Petersburg State medical University;
Russian Federation
MD, PhD-student
Competing Interests: Автор декларирует отсутствие конфликта интересов.
Russian Federation
MD, PhD-student
Competing Interests: Автор декларирует отсутствие конфликта интересов.
Svetlana Vladimirovna Dora
Pavlov First Saint-Petersburg State medical University;
Federal North-West Medical Research Center
Russian Federation
MD
Competing Interests: Автор декларирует отсутствие конфликта интересов.
Russian Federation
MD
Competing Interests: Автор декларирует отсутствие конфликта интересов.
Evgeniy Vladimirovich Shlyakhto
Pavlov First Saint-Petersburg State medical University;
Federal North-West Medical Research Center
Russian Federation
MD, PhD, Professor
Competing Interests: Автор декларирует отсутствие конфликта интересов.
Russian Federation
MD, PhD, Professor
Competing Interests: Автор декларирует отсутствие конфликта интересов.
References
1. IDF Diabetes Atlas. 6-th edition. 2013. Available from: http://www.idf.org/diabetesatlas
2. Калашникова М.Ф., Сунцов Ю.И., Белоусов Д.Ю., и др. Анализ эпидемиологических показателей сахарного диабета 2 типа среди взрослого населения города Москвы. // Сахарный диабет. – 2014. – Т. 17. – №3 – С.5-16.[Kalashnikova MF, Suntsov YuI, Belousov DYu, et al. Analysis of epidemiological indices of type 2 diabetes mellitus in the adult population of Moscow. Diabetes mellitus. 2014;17(3):5-16. (In Russ).] doi: 10.14341/dm201435-16
3. Дедов И.И., Шестакова М.В. Инкретины: новая веха в лечении сахарного диабета 2-го типа. Практическое руководство для врачей. – М.: Дипак; 2010. [Dedov II, Shestakova MV. Inkretiny: novaya vekha v lechenii sakharnogo diabeta 2-go tipa. Prakticheskoe rukovodstvo dlya vrachei. Moscow: Dipak; 2010. (In Russ).]
4. Шестакова Е.А. Инкретиновая и «антиинкретиновая» системы в патогенезе сахарного диабета 2 типа: факты и гипотезы. // Сахарный диабет. – 2011. – Т. 14. – №3 – С.26-29. [Shestakova EA. New glance at pathogenesis of type 2 diabetes mellitus: incretin and antiincretin systems. Diabetes mellitus. 2011;14(3):26-29. (In Russ).] doi: 10.14341/2072-0351-6220
5. Holst JJ. The physiology and pharmacology of incretins in type 2 diabetes mellitus. Diabetes, Obesity and Metabolism. 2008;10:14-21. doi: 10.1111/j.1463-1326.2008.00920.x
6. Аметов А.С., Бращенкова А.В. Роль и место инкретинов в достижении всестороннего гликемического контроля. // Русский медицинский журнал. – 2011. – Т. 19. – №27 — С.1690-1693. [Ametov AS, Brashchenkova AV. Rol’ i mesto inkretinov v dostizhenii vsestoronnego glikemicheskogo kontrolya. Russkii meditsinskii zhurnal. 2011;19(27):1690-1693. (In Russ).]
7. Toft-Nielsen MB, Damholt MB, Madsbad S, et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. The Journal of clinical endocrinology and metabolism. 2001;86(8):3717-3723. doi: 10.1210/jcem.86.8.7750
8. Li Y, Tweedie D, Mattson MP, et al. Enhancing the GLP-1 receptor signaling pathway leads to proliferation and neuroprotection in human neuroblastoma cells. Journal of neurochemistry. 2010;113(6):1621-1631. doi: 10.1111/j.1471-4159.2010.06731.x
9. Анциферов М.Б., Дорофеева Л.Г. Новые подходы к лечению сахарного диабета типа 2: глюкагоноподобный пептид-1 и эксенатид (Баета). // Фарматека. – 2007. – №11 – С.14-19. [Antsiferov MB, Dorofeeva LG. Novye podkhody k lecheniyu sakharnogo diabeta tipa 2: glyukagonopodobnyi peptid-1 i eksenatid (Baeta). Farmateka. 2007;(11):14-19. (In Russ).]
10. Drucker DJ. Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology. 2002;122(2):531-544. doi: 10.1053/gast.2002.31068
11. Schwasinger-Schmidt T, Robbins DC, Williams SJ, et al. Long-term liraglutide treatment is associated with increased insulin content and secretion in β-cells, and a loss of α-cells in ZDF rats. Pharmacological Research. 2013;76:58-66. doi: 10.1016/j.phrs.2013.07.005
12. Wei Q, Sun YQ, Zhang J. Exendin-4, a glucagon-like peptide-1 receptor agonist, inhibits cell apoptosis induced by lipotoxicity in pancreatic β-cell line. Peptides. 2012;37(1):18-24. doi: 10.1016/j.peptides.2012.06.018
13. Bao W, Aravindhan K, Alsaid H, et al. Albiglutide, a long lasting glucagon-like peptide-1 analog, protects the rat heart against ischemia/reperfusion injury: evidence for improving cardiac metabolic efficiency. PloS one. 2011;6(8):e23570. doi: 10.1371/journal.pone.0023570
14. Dokken BB, La Bonte LR, Davis-Gorman G, et al. Glucagon-like peptide-1 (GLP-1), immediately prior to reperfusion, decreases neutrophil activation and reduces myocardial infarct size in rodents. Hormone and metabolic research.2011;43(5):300-305. doi: 10.1055/s-0031-1271777
15. Noyan-Ashraf MH, Momen MA, Ban K, et al. GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes. 2009;58(4):975-983. doi: 10.2337/db08-1193
16. Liu Q, Anderson C, Broyde A, et al. Glucagon-like peptide-1 and the exenatide analogue AC3174 improve cardiac function, cardiac remodeling, and survival in rats with chronic heart failure. Cardiovascular diabetology. 2010;9:76. doi: 10.1186/1475-2840-9-76
17. Lonborg J, Vejlstrup N, Kelbaek H, et al. Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. European heart journal. 2012;33(12):1491-1499. doi: 10.1093/eurheartj/ehr309
18. Read PA, Khan FZ, Dutka DP. Cardioprotection against ischaemia induced by dobutamine stress using glucagon-like peptide-1 in patients with coronary artery disease. Heart. 2012;98(5):408-413. doi: 10.1136/hrt.2010.219345
19. Nathanson D, Ullman B, Lofstrom U, et al. Effects of intravenous exenatide in type 2 diabetic patients with congestive heart failure: a double-blind, randomised controlled clinical trial of efficacy and safety. Diabetologia. 2012;55(4):926-935. doi: 10.1007/s00125-011-2440-x
20. Banerjee C, Moon YP, Paik MC, et al. Duration of diabetes and risk of ischemic stroke: the Northern Manhattan Study. Stroke. 2012;43(5):1212-1217. doi: 10.1161/STROKEAHA.111.641381
21. Salcedo I, Tweedie D, Li Y, Greig NH. Neuroprotective and neurotrophic actions of glucagon-like peptide-1: an emerging opportunity to treat neurodegenerative and cerebrovascular disorders. British journal of pharmacology. 2012;166(5):1586-1599. doi: 10.1111/j.1476-5381.2012.01971.x
22. Briyal S, Gulati K, Gulati A. Repeated administration of exendin-4 reduces focal cerebral ischemia-induced infarction in rats. Brain research. 2012;1427:23-34. doi: 10.1016/j.brainres.2011.10.026
23. Holst JJ, Burcelin R, Nathanson E. Neuroprotective properties of GLP-1: theoretical and practical applications. Current medical research and opinion. 2011;27(3):547-558. doi: 10.1185/03007995.2010.549466
24. Holscher C. Potential role of glucagon-like peptide-1 (GLP-1) in neuroprotection. CNS drugs. 2012;26(10):871-882. doi: 10.2165/11635890-000000000-00000
25. Teramoto S, Miyamoto N, Yatomi K, et al. Exendin-4, a glucagon-like peptide-1 receptor agonist, provides neuroprotection in mice transient focal cerebral ischemia. Journal of cerebral blood flow and metabolism. 2011;31(8):1696-1705. doi: 10.1038/jcbfm.2011.51
26. Darsalia V, Mansouri S, Ortsater H, et al. Glucagon-like peptide-1 receptor activation reduces ischaemic brain damage following stroke in Type 2 diabetic rats. Clinical science. 2012;122(10):473-483. doi: 10.1042/CS20110374
27. Hara H, Huang PL, Panahian N, et al. Reduced brain edema and infarction volume in mice lacking the neuronal isoform of nitric oxide synthase after transient MCA occlusion. Journal of cerebral blood flow and metabolism. 1996;16(4):605-611. doi: 10.1097/00004647-199607000-00010
28. Sato K, Kameda M, Yasuhara T, et al. Neuroprotective effects of liraglutide for stroke model of rats. International journal of molecular sciences. 2013;14(11):21513-21524. doi: 10.3390/ijms141121513
29. Baba T, Kameda M, Yasuhara T, et al. Electrical stimulation of the cerebral cortex exerts antiapoptotic, angiogenic, and anti-inflammatory effects in ischemic stroke rats through phosphoinositide 3-kinase/Akt signaling pathway. Stroke. 2009;40(11):e598-605. doi: 10.1161/STROKEAHA.109.563627
30. Bederson JB, Pitts LH, Tsuji M, et al. Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke. 1986;17(3):472-476. doi: 10.1161/01.str.17.3.472
31. Симаненкова А.В., Жигалова А.А., Шумеева А.Г., и др. Нейропротективное действие агониста рецептора глюкагоноподобного пептида-1 // Медицинский вестник Башкортостана. – 2014. – Т. 9. – №5 – С.156-159 [Simanenkova AV, Zhigalova AA, Shumeeva AG, et al. Neuroprotecrive effect of glucagon like peptide-1 receptor agonist. Meditsinskii vestnik Bashkortostana. 2014;9(5):156-159. (In Russ).]
32. Koizumi J, Yoshida Y, Nakazawa T, et al. Experimental studies of ischemic brain edema, I: a new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischemic area. Japanese Journal of Stroke. 1986;(8):1-8.
33. Коржевский Д.Э., Кирик О.В., Байса А.Е., и др. Моделирование одностороннего ишемического повреждения нейронов стриатума с помощью непродолжительной окклюзии средней мозговой артерии // Бюллетень экспериментальной биологии и медицины. – 2009. – Т. 147. – №2 – С.217-219. [Korzhevskii DE, Kirik OV, Baisa AE, et al. Simulation of unilateral ischemic injury to the striatal neurons inflicted by short-term occlusion of the middle cerebral artery. Bulletin of experimental biology and medicine. 2009;147(2):217-219. (In Russ).] doi: 10.1007/s10517-009-0487-1
34. Коржевский Д.Э., Кирик О.В., Сухорукова Е.Г., и др. Структурная организация микроглиоцитов стриатума после транзиторной фокальной ишемии // Морфология. – 2012. – Т. 141. – №2 – С.28-32. [Korzhevskii DE, Kirik OV, Sukhorukova YeG, et al. Structural organization of striatal microgliocytes following focal ischemia. Morfologiya. 2012;141(2):28-32. (In Russ).]
35. Garcia GH, Wagner S, Liu KF, et al. Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats: statistical validation. Stroke. 1995;26(4):627-634. doi: 10.1161/01.str.26.4.627
36. Warner DS, Sheng H, Batinic-Haberle I. Oxidants, antioxidants and the ischemic brain. The Journal of experimental biology. 2004;207(Pt 18):3221-3231. doi: 10.1242/jeb.01022
37. Love S. Oxidative Stress in Brain Ischemia. Brain Pathology. 1999;9(1):119-131. doi: 10.1111/j.1750-3639.1999.tb00214.x
38. Andrabi SA, Sayeed I, Siemen D, et al. Direct inhibition of the mitochondrial permeability transition pore: a possible mechanism responsible for anti-apoptotic effects of melatonin. FASEB journal. 2004;18(7):869-871. doi: 10.1096/fj.03-1031fje
39. Perry T, Haughey NJ, Mattson MP, et al. Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4. The Journal of pharmacology and experimental therapeutics. 2002;302(3):881-888. doi: 10.1124/jpet.102.037481
40. Perry T, Lahiri DK, Chen D, et al. A Novel Neurotrophic Property of Glucagon-Like Peptide 1: A Promoter of Nerve Growth Factor-Mediated Differentiation in PC12 Cells. Journal of Pharmacology and Experimental Therapeutics. 2002;300(3):958-966. doi: 10.1124/jpet.300.3.958
41. Perry T, Lahiri DK, Sambamurti K, et al. Glucagon-like peptide-1 decreases endogenous amyloid-beta peptide (Abeta) levels and protects hippocampal neurons from death induced by Abeta and iron. Journal of neuroscience research. 2003;72(5):603-612. doi: 10.1002/jnr.10611
42. Yamada S, Funada T, Shibata N, et al. Protein-bound 4-hydroxy-2-hexenal as a marker of oxidized n-3 polyunsaturated fatty acids. Journal of lipid research. 2004;45(4):626-634. doi: 10.1194/jlr.M300376-JLR200
43. Kitagawa K. CREB and cAMP response element-mediated gene expression in the ischemic brain. The FEBS journal. 2007;274(13):3210-3217. doi: 10.1111/j.1742-4658.2007.05890.x
44. Yin F, Liu JH, Zheng XX, Guo LX. GLP-1 receptor plays a critical role in geniposide-induced expression of heme oxygenase-1 in PC12 cells. Acta Pharmacol Sin. 2010;31(5):540-545. doi: 10.1038/aps.2010.28
45. Stocker R, Yamamoto Y, McDonagh AF, et al. Bilirubin is an antioxidant of possible physiological importance. Science. 1987;235(4792):1043-1046. doi: 10.1126/science.3029864
46. Ferris CD, Jaffrey SR, Sawa A, et al. Haem oxygenase-1 prevents cell death by regulating cellular iron. Nature cell biology. 1999;1(3):152-157. doi: 10.1038/11072
47. Park SH, Jang JH, Li MH, et al. Nrf2-mediated heme oxygenase-1 induction confers adaptive survival response to tetrahydropapaveroline-induced oxidative PC12 cell death. Antioxidants & redox signaling. 2007;9(12):2075-2086. doi: 10.1089/ars.2007.1828
48. Surh YJ, Kundu JK, Li MH, et al. Role of Nrf2-mediated heme oxygenase-1 upregulation in adaptive survival response to nitrosative stress. Archives of pharmacal research. 2009;32(8):1163-1176. doi: 10.1007/s12272-009-1807-8
49. Liu JH, Yin F, Guo LX, et al. Neuroprotection of geniposide against hydrogen peroxide induced PC12 cells injury: involvement of PI3 kinase signal pathway. Acta Pharmacol Sin. 2009;30(2):159-165. doi: 10.1038/aps.2008.25
50. Liu WJ, Jin HY, Lee KA, et al. Neuroprotective effect of the glucagon-like peptide-1 receptor agonist, synthetic exendin-4, in streptozotocin-induced diabetic rats. British journal of pharmacology. 2011;164(5):1410-1420. doi: 10.1111/j.1476-5381.2011.01272.x
51. Hamilton A, Patterson S, Porter D, et al. Novel GLP-1 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain. Journal of neuroscience research. 2011;89(4):481-489. doi: 10.1002/jnr.22565
52. Салмина А.Б., Яузина Н.А., Кувачева Н.В., и др. Инсулин и инсулинорезистентность: новые молекулы-маркеры и молекулы-мишени для диагностики и терапии заболеваний центральной нервной системы // Бюллетень сибирской медицины. – 2013. – Т. 12. – №5 – С. 104-118. [Salmina AB, Yauzina NA, Kuvacheva NV, et al. Insulin and insulin resistance: new molecule markers and target molecule for the diagnosis and therapy of diseases of the central nervous system. Bulletin of Siberian Medicine. 2013;12(5):104–118. (In Russ).]
53. Shah K, Desilva S, Abbruscato T. The role of glucose transporters in brain disease: diabetes and Alzheimer’s Disease. International journal of molecular sciences. 2012;13(10):12629-12655. doi: 10.3390/ijms131012629
54. Harkavyi A, Whitton PS. Glucagon-like peptide 1 receptor stimulation as a means of neuroprotection. British journal of pharmacology. 2010;159(3):495-501. doi: 10.1111/j.1476-5381.2009.00486.x
55. Malhotra JD, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxidants & redox signaling. 2007;9(12):2277-2293. doi: 10.1089/ars.2007.1782
56. Yusta B, Baggio LL, Estall JL, et al. GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress. Cell Metab. 2006;4(5):391-406. doi: 10.1016/j.cmet.2006.10.001
57. Harding HP, Zhang Y, Bertolotti A, et al. Perk Is Essential for Translational Regulation and Cell Survival during the Unfolded Protein Response. Molecular Cell. 2000;5(5):897-904. doi: 10.1016/S1097-2765(00)80330-5
58. Hou J, Manaenko A, Hakon J, et al. Liraglutide, a long-acting GLP-1 mimetic, and its metabolite attenuate inflammation after intracerebral hemorrhage. Journal of cerebral blood flow and metabolism. 2012;32(12):2201-2210. doi: 10.1038/jcbfm.2012.133
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Vlasov T.D., Simanenkova A.V., Dora S.V., Shlyakhto E.V. Mechanisms of neuroprotective action of incretin mimetics. Diabetes mellitus. 2016;19(1):16-23. (In Russ.) https://doi.org/10.14341/DM7192
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