Глифлозины как средства коррекции неврологических осложнений неалкогольной жировой болезни печени. Часть 1


DOI: https://dx.doi.org/10.18565/therapy.2024.4.151-158

В.А. Приходько, С.В. Оковитый

1) ФГБОУ ВО «Санкт-Петербургский государственный химико-фармацевтический университет» Минздрава России; 2) ФГБОУ ВО «Санкт-Петербургский государственный университет»
Аннотация. Неалкогольная жировая болезнь печени (НАЖБП) и неалкогольный стеатогепатит (НАСГ) имеют ряд общих с поражениями центральной нервной системы факторов риска, а также выступают самостоятельной причиной развития цереброваскулярных, нейродегенеративных, когнитивных и психических расстройств. Разработка лекарственных средств, применимых не только для лечения самой НАЖБП, но и коррекции ее психоневрологических осложнений, – актуальная задача современной экспериментальной биомедицины и фармакологии. Перспективной группой соединений, показавшей высокий терапевтический потенциал у больных НАЖБП, а также обладающей широким спектром плейотропных эффектов, являются ингибиторы натрий-глюкозных котранспортеров (глифлозины). В обзоре рассмотрены механизмы нейропротекторного действия глифлозинов, представляющие наибольший интерес в свете возможности коррекции неврологических осложнений НАЖБП.

Литература


1. Лазебник Л.Б., Голованова Е.В., Туркина С.В. с соавт. Неалкогольная жировая болезнь печени у взрослых: клиника, диагностика, лечение. Рекомендации для терапевтов, третья версия. Экспериментальная и клиническая гастроэнтерология. 2021; 1(1): 4−52. (Lazebnik L.B., Golovanova E.V., Turkina S.V. et al. Non-alcoholic fatty liver disease in adults: clinic, diagnostics, treatment. Guidelines for therapists, third version. Eksperimental’naya i klinicheskaya gastroenterologiya = Experimental and Clinical Gastroenterology. 2021; 1(1): 4−52 (In Russ.)).


https://doi.org/10.31146/1682-8658-ecg-185-1-4-52. EDN: KJLOJV.


2. Chan W.K., Chuah K.H., Rajaram R.B. et al. Vethakkan S.R. Metabolic dysfunction-associated steatotic liver disease (MASLD): A state-of-the-art review. J Obes Metab Syndr. 2023; 32(3): 197−213.


https://doi.org/10.7570/jomes23052. PMID: 37700494. PMCID: PMC10583766.


3. Приходько В.А., Оковитый С.В. Психоневрологические нарушения при неалкогольной жировой болезни печени. Терапия. 2022; 8(7): 64–77. (Prikhodko V.A., Okovityi S.V. Neuropsychiatric disorders of non-alcoholic fatty liver disease. Terapiya = Therapy. 2022; 8(7): 64–77 (In Russ.)).


https://doi.org/10.18565/therapy.2022.7.64–77. EDN: OQXJFZ.


4. Cushman M., Callas P.W., Alexander K.S. et al. Nonalcoholic fatty liver disease and cognitive impairment: A prospective cohort study. PLoS One. 2023; 18(4): e0282633.


https://doi.org/10.1371/journal.pone.0282633. PMID: 37058527. PMCID: PMC10104321.


5. Shang Y., Widman L., Hagstrom H. Nonalcoholic fatty liver disease and risk of dementia: A population-based cohort study. Neurology. 2022; 99(6): e574−e582.


https://doi.org/10.1212/WNL.0000000000200853. PMID: 35831178. PMCID: PMC9442617.


6. Xiao J., Lim L.K.E., Ng C.H. et al. Is fatty liver associated with depression? A meta-analysis and systematic review on the prevalence, risk factors, and outcomes of depression and non-alcoholic fatty liver disease. Front Med (Lausanne). 2021; 8: 691696.


https://doi.org/10.3389/fmed.2021.691696. PMID: 34277666. PMCID: PMC8278401.


7. Wang M., Zhou B.G., Zhang Y. et al. Association between non-alcoholic fatty liver disease and risk of stroke: A systematic review and meta-analysis. Front Cardiovasc Med. 2022; 9: 812030.


https://doi.org/10.3389/fcvm.2022.812030. PMID: 35345491. PMCID: PMC8957221.


8. Carias S., Castellanos A.L., Vilchez V. et al. Nonalcoholic steatohepatitis is strongly associated with sarcopenic obesity in patients with cirrhosis undergoing liver transplant evaluation. J Gastroenterol Hepatol. 2016; 31(3): 628−33.


https://doi.org/10.1111/jgh.13166. PMID: 26399838. PMCID: PMC6615558.


9. Greco C., Nascimbeni F., Carubbi F. et al. Association of nonalcoholic fatty liver disease (NAFLD) with peripheral diabetic polyneuropathy: A systematic review and meta-analysis. J Clin Med. 2021; 10(19): 4466.


https://doi.org/10.3390/jcm10194466. PMID: 34640482. PMCID: PMC8509344.


10. Tapper E.B., Henderson J.B., Parikh N.D. et al. Incidence of and risk factors for hepatic encephalopathy in a population-based cohort of Americans with cirrhosis. Hepatol Commun. 2019; 3(11): 1510−19.


https://doi.org/10.1002/hep4.1425. PMID: 31701074. PMCID: PMC6824059.


11. D’Amico G., Garcia-Tsao G., Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: A systematic review of 118 studies. J Hepatol. 2006; 44(1): 217−31.


https://doi.org/10.1016/j.jhep.2005.10.013. PMID: 16298014.


12. Prikhodko V.A., Bezborodkina N.N., Okovityi S.V. Pharmacotherapy for non-alcoholic fatty liver disease: Emerging targets and drug candidates. Biomedicines. 2022; 10(2): 274.


https://doi.org/10.3390/biomedicines10020274. PMID: 35203484. PMCID: PMC8869100.


13. Oku A., Ueta K., Arakawa K. et al. T-1095, an inhibitor of renal Na+-glucose cotransporters, may provide a novel approach to treating diabetes. Diabetes. 1999; 48(9): 1794−800.


https://doi.org/10.2337/diabetes.48.9.1794. PMID: 10480610.


14. Patel D.K., Strong J. The pleiotropic effects of sodium-glucose cotransporter-2 inhibitors: Beyond the glycemic benefit. Diabetes Ther. 2019; 10(5): 1771−92.


https://doi.org/10.1007/s13300-019-00686-z. PMID: 31456166. PMCID: PMC6778563.


15. Приходько В.А., Оковитый С.В., Куликов А.Н. Глифлозины при неалкогольной жировой болезни печени: перспективы применения за границами диабета, кардио- и нефропротекции. Терапия. 2023; 9(7): 130–141. (Prikhodko V.A., Okovityi S.V., Kulikov A.N. Gliflozins in non-alcoholic fatty liver disease: Perspectives of use outside diabetes, cardiac and nephroprotection. Terapiya = Therapy. 2023; 9(7): 130–141 (In Russ.)).


https://doi.org/10.18565/therapy.2023.7.130–141. EDN: CACFYZ.


16. Jin Z., Yuan Y., Zheng C. et al. Effects of sodium-glucose co-transporter 2 inhibitors on liver fibrosis in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus: An updated meta-analysis of randomized controlled trials. J Diabetes Complications. 2023; 37(8): 108558.


https://doi.org/10.1016/j.jdiacomp.2023.108558. PMID: 37499274.


17. Nakhal M.M., Aburuz S., Sadek B., Akour A. Repurposing SGLT2 inhibitors for neurological disorders: A focus on the autism spectrum disorder. Molecules. 2022; 27(21): 7174.


https://doi.org/10.3390/molecules27217174. PMID: 36364000. PMCID: PMC9653623.


18. Tharmaraja T., Ho J.S.Y., Sia C.H. et al. Sodium-glucose cotransporter 2 inhibitors and neurological disorders: A scoping review. Ther Adv Chronic Dis. 2022; 13: 20406223221086996.


https://doi.org/10.1177/20406223221086996. PMID: 35432846. PMCID: PMC9006360.


19. Hadjihambi A. Cerebrovascular alterations in NAFLD: Is it increasing our risk of Alzheimer’s disease? Anal Biochem. 2022; 636: 114387.


https://doi.org/10.1016/j.ab.2021.114387. PMID: 34537182.


20. Yoshikawa S., Taniguchi K., Sawamura H. et al. Metabolic associated fatty liver disease as a risk factor for the development of central nervous system disorders. Livers. 2023; 3(1): 21−32.


https://doi.org/10.3390/livers3010002.


21. Tahara A., Takasu T., Yokono M. et al. Characterization and comparison of sodium-glucose cotransporter 2 inhibitors in pharmacokinetics, pharmacodynamics, and pharmacologic effects. J Pharmacol Sci. 2016; 130(3): 159−69.


https://doi.org/10.1016/j.jphs.2016.02.003. PMID: 26970780.


22. Pawlos A., Broncel M., Wozniak E., Gorzelak-Pabis P. Neuroprotective effect of SGLT2 inhibitors. Molecules. 2021; 26(23): 7213.


https://doi.org/10.3390/molecules26237213. PMID: 34885795. PMCID: PMC8659196.


23. Terami N., Ogawa D., Tachibana H. et al. Long-term treatment with the sodium glucose cotransporter 2 inhibitor, dapagliflozin, ameliorates glucose homeostasis and diabetic nephropathy in db/db mice. PLoS One. 2014; 9(6): e100777.


https://doi.org/10.1371/journal.pone.0100777. PMID: 24960177. PMCID: PMC4069074.


24. Cheon S.Y., Song J. Novel insights into non-alcoholic fatty liver disease and dementia: Insulin resistance, hyperammonemia, gut dysbiosis, vascular impairment, and inflammation. Cell Biosci. 2022; 12(1): 99.


https://doi.org/10.1186/s13578-022-00836-0. PMID: 35765060. PMCID: PMC9237975.


25. Dong M., Wen S., Zhou L. The relationship between the blood-brain-barrier and the central effects of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors. Diabetes Metab Syndr Obes. 2022; 15: 2583−97.


https://doi.org/10.2147/DMSO.S375559. PMID: 36035518. PMCID: PMC9417299.


26. Fonseca-Correa J.I., Correa-Rotter R. Sodium-glucose cotransporter 2 inhibitors mechanisms of action: A review. Front Med (Lausanne). 2021; 8: 777861.


https://doi.org/10.3389/fmed.2021.777861. PMID: 34988095. PMCID: PMC8720766.


27. Zheng Z., Chen X., Zhang Y. et al. Canagliflozin ameliorates neuronal injury after cerebral ischemia reperfusion by targeting SGLT1 and AMPK-dependent apoptosis. Neurotherapeutics. 2024; 21(2): e00305.


https://doi.org/10.1016/j.neurot.2023.11.002.


28. Yamazaki Y., Ogihara S., Harada S., Tokuyama S. Activation of cerebral sodium-glucose transporter type 1 function mediated by post-ischemic hyperglycemia exacerbates the development of cerebral ischemia. Neuroscience. 2015; 310: 674−85.


https://doi.org/10.1016/j.neuroscience.2015.10.005. PMID: 26454021.


29. Yamazaki Y., Harada S., Tokuyama S. Post-ischemic hyperglycemia exacerbates the development of cerebral ischemic neuronal damage through the cerebral sodium-glucose transporter. Brain Res. 2012; 1489: 113−20.


https://doi.org/10.1016/j.brainres.2012.10.020. PMID: 23078759.


30. Ishida N., Saito M., Sato S. et al. Mizagliflozin, a selective SGLT1 inhibitor, improves vascular cognitive impairment in a mouse model of small vessel disease. Pharmacol Res Perspect. 2021; 9(5): e00869.


https://doi.org/10.1002/prp2.869. PMID: 34586752. PMCID: PMC8480397.


31. Pang B., Zhang L.L., Li B. et al. The sodium glucose co-transporter 2 inhibitor ertugliflozin for Alzheimer’s disease: Inhibition of brain insulin signaling disruption-induced tau hyperphosphorylation. Physiol Behav. 2023; 263: 114134.


https://doi.org/10.1016/j.physbeh.2023.114134. PMID: 36809844.


32. Hanaguri J., Yokota H., Kushiyama A. et al. The effect of sodium-dependent glucose cotransporter 2 inhibitor tofogliflozin on neurovascular coupling in the retina in type 2 diabetic mice. Int J Mol Sci. 2022; 23(3): 1362.


https://doi.org/10.3390/ijms23031362. PMID: 35163285. PMCID: PMC8835894.


33. Lombardi R., Fargion S., Fracanzani A.L. Brain involvement in non-alcoholic fatty liver disease (NAFLD): A systematic review. Dig Liver Dis. 2019; 51(9): 1214−22.


https://doi.org/10.1016/j.dld.2019.05.015. PMID: 31176631.


34. Kuchay M.S., Farooqui K.J., Mishra S.K., Mithal A. Glucose lowering efficacy and pleiotropic effects of sodium-glucose cotransporter 2 inhibitors. Adv Exp Med Biol. 2021; 1307: 213−30.


https://doi.org/10.1007/5584_2020_479. PMID: 32006266.


35. Kasper P., Martin A., Lang S. et al. NAFLD and cardiovascular diseases: A clinical review. Clin Res Cardiol. 2021; 110(7): 921−37.


https://doi.org/10.1007/s00392-020-01709-7. PMID: 32696080. PMCID: PMC8238775.


36. Lockwood A.H., Yap E.W., Rhoades H.M., Wong W.H. Altered cerebral blood flow and glucose metabolism in patients with liver disease and minimal encephalopathy. J Cereb Blood Flow Metab. 1991; 11(2): 331−36.


https://doi.org/10.1038/jcbfm.1991.66. PMID: 1997505.


37. Wang S., Tang C., Liu Y. et al. Impact of impaired cerebral blood flow autoregulation on cognitive impairment. Front Aging. 2022; 3: 1077302.


https://doi.org/10.3389/fragi.2022.1077302. PMID: 36531742. PMCID: PMC9755178.


38. Sweeney M.D., Kisler K., Montagne A. et al. The role of brain vasculature in neurodegenerative disorders. Nat Neurosci. 2018; 21(10): 1318−31.


https://doi.org/10.1038/s41593-018-0234-x. PMID: 30250261. PMCID: PMC6198802.


39. Liu M., He E., Fu X. et al. Cerebral blood flow self-regulation in depression. J Affect Disord. 2022; 302: 324−31.


https://doi.org/10.1016/j.jad.2022.01.057. PMID: 35032508.


40. Li L., Yang Y., Bai J. et al. Impaired vascular endothelial function is associated with peripheral neuropathy in patients with type 2 diabetes. Diabetes Metab Syndr Obes. 2022; 15: 1437−49.


https://doi.org/10.2147/DMSO.S352316. PMID: 35573865. PMCID: PMC9091688.


41. Damluji A.A., Alfaraidhy M., AlHajri N. et al. Sarcopenia and cardiovascular diseases. Circulation. 2023; 147(20): 1534−53.


https://doi.org/10.1161/CIRCULATIONAHA.123.064071. PMID: 37186680. PMCID: PMC10180053.


42. Lopaschuk G.D., Verma S. Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: A state-of-the-art review. JACC Basic Transl Sci. 2020; 5(6): 632−44.


https://doi.org/10.1016/j.jacbts.2020.02.004. PMID: 32613148. PMCID: PMC7315190.


43. Adam C.A., Anghel R., Marcu D.T.M. et al. Impact of sodium-glucose cotransporter 2 (SGLT2) inhibitors on arterial stiffness and vascular aging – what do we know so far? (A narrative review). Life (Basel). 2022; 12(6): 803.


https://doi.org/10.3390/life12060803. PMID: 35743834. PMCID: PMC9224553.


44. McGuire D.K., Shih W.J., Cosentino F. et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: A meta-analysis. JAMA Cardiol. 2021; 6(2): 148−58.


https://doi.org/10.1001/jamacardio.2020.4511. PMID: 33031522. PMCID: PMC7542529.


45. Treewaree S., Kulthamrongsri N., Owattanapanich W., Krittayaphong R. Is it time for class I recommendation for sodium-glucose cotransporter-2 inhibitors in heart failure with mildly reduced or preserved ejection fraction?: An updated systematic review and meta-analysis. Front Cardiovasc Med. 2023; 10: 1046194.


https://doi.org/10.3389/fcvm.2023.1046194. PMID: 36824458. PMCID: PMC9941559.


46. Mavrakanas T.A., Tsoukas M.A., Brophy J.M. et al. SGLT-2 inhibitors improve cardiovascular and renal outcomes in patients with CKD: A systematic review and meta-analysis. Sci Rep. 2023; 13(1): 15922.


https://doi.org/10.1038/s41598-023-42989-z. PMID: 37741858. PMCID: PMC10517929.


47. Adori M., Bhat S., Gramignoli R. et al. Hepatic innervations and nonalcoholic fatty liver disease. Semin Liver Dis. 2023; 43(2): 149−62.


https://doi.org/10.1055/s-0043-57237. PMID: 37156523. PMCID: PMC10348844.


48. Targher G., Mantovani A., Grander C. et al. Association between non-alcoholic fatty liver disease and impaired cardiac sympathetic/parasympathetic balance in subjects with and without type 2 diabetes-The Cooperative Health Research in South Tyrol (CHRIS)-NAFLD sub-study. Nutr Metab Cardiovasc Dis. 2021; 31(12): 3464−73. https://doi.org/10.1016/j.numecd.2021.08.037. PMID: 34627696.


49. Hart E.C. Human hypertension, sympathetic activity and the selfish brain. Exp Physiol. 2016; 101(12): 1451–62.


https://doi.org/10.1113/EP085775. PMID: 27519960.


50. Lee R.H, Couto E Silva A., Lerner F.M. et al. Interruption of perivascular sympathetic nerves of cerebral arteries offers neuroprotection against ischemia. Am J Physiol Heart Circ Physiol. 2017; 312(1): H182−H188.


https://doi.org/10.1152/ajpheart.00482.2016. PMID: 27864234.


51. Sano M. Sodium glucose cotransporter (SGLT)-2 inhibitors alleviate the renal stress responsible for sympathetic activation. Ther Adv Cardiovasc Dis. 2020; 14: 1753944720939383.


https://doi.org/10.1177/1753944720939383. PMID: 32715944. PMCID: PMC7385812.


52. Nguyen T., Wen S., Gong M. et al. Dapagliflozin activates neurons in the central nervous system and regulates cardiovascular activity by inhibiting SGLT-2 in mice. Diabetes Metab Syndr Obes. 2020; 13: 2781−99.


https://doi.org/10.2147/DMSO.S258593. PMID: 32848437. PMCID: PMC7425107.


53. Оковитый С.В., Радько С.В. Митохондриальная дисфункция в патогенезе различных поражений печени. Доктор.Ру. 2015; (12): 30–33. (Okovityi S.V., Radko S.V. Mitochondrial dysfunctions’ role in pathogenesis of different liver disorders. Doctor.Ru. 2015; (12): 30–33 (In Russ.)). EDN: UNJRTL.


54. Niknahad H., Jamshidzadeh A., Heidari R. et al. Ammonia-induced mitochondrial dysfunction and energy metabolism disturbances in isolated brain and liver mitochondria, and the effect of taurine administration: Relevance to hepatic encephalopathy treatment. Clin Exp Hepatol. 2017; 3(3): 141−51.


https://doi.org/10.5114/ceh.2017.68833. PMID: 29062904. PMCID: PMC5649485.


55. Sa-Nguanmoo P., Tanajak P., Kerdphoo S. et al. SGLT2-inhibitor and DPP-4 inhibitor improve brain function via attenuating mitochondrial dysfunction, insulin resistance, inflammation, and apoptosis in HFD-induced obese rats. Toxicol Appl Pharmacol. 2017; 333: 43−50.


https://doi.org/10.1016/j.taap.2017.08.005. PMID: 28807765.


56. Takashima M., Nakamura K., Kiyohara T. et al. Low-dose sodium-glucose cotransporter 2 inhibitor ameliorates ischemic brain injury in mice through pericyte protection without glucose-lowering effects. Commun Biol. 2022; 5(1): 653.


https://doi.org/10.1038/s42003-022-03605-4. PMID: 35780235. PMCID: PMC9250510.


57. Yaribeygi H., Maleki M., Butler A.E. et al. Sodium-glucose cotransporter 2 inhibitors and mitochondrial functions: State of the art. EXCLI J. 2023; 22: 53–66.


https://doi.org/10.17179/excli2022-5482. PMID: 36814854. PMCID: PMC9939776.


58. Steven S., Oelze M., Hanf A. et al. The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats. Redox Biol. 2017; 13: 370−85.


https://doi.org/10.1016/j.redox.2017.06.009. PMID: 28667906. PMCID: PMC5491464.


59. Iannantuoni F., de Maranon A.M., Diaz-Morales N. et al. The SGLT2 inhibitor empagliflozin ameliorates the inflammatory profile in type 2 diabetic patients and promotes an antioxidant response in leukocytes. J Clin Med. 2019; 8(11): 1814.


https://doi.org/10.3390/jcm8111814. PMID: 31683785. PMCID: PMC6912454.


60. Tsai K.F., Chen Y.L., Chiou T.T. et al. Emergence of SGLT2 inhibitors as powerful antioxidants in human diseases. Antioxidants (Basel). 2021; 10(8): 1166.


https://doi.org/10.3390/antiox10081166. PMID: 34439414. PMCID: PMC8388972.


Об авторах / Для корреспонденции


Вероника Александровна Приходько, к. биол. н., старший преподаватель кафедры фармакологии и клинической фармакологии ФГБОУ ВО «Санкт-Петербургский государственный химико-фармацевтический университет» Минздрава России. Адрес: 197022, г. Санкт-Петербург, ул. Профессора Попова, д. 14, лит. А.
E-mail: veronika.prihodko@pharminnotech.com
ORCID: https://orcid.org/0000-0002-4690-1811
Сергей Владимирович Оковитый, д. м. н., профессор, заведующий кафедрой фармакологии и клинической фармакологии ФГБОУ ВО «Санкт-Петербургский государственный химико-фармацевтический университет» Минздрава России, профессор Научно-клинического и образовательного центра гастроэнтерологии и гепатологии ФГБОУ ВО «Санкт-Петербургский государственный университет». Адрес: 197022, г. Санкт-Петербург,
ул. Профессора Попова, д. 14, лит. А.
E-mail: sergey.okovity@pharminnotech.com
ORCID: https://orcid.org/0000-0003-4294-5531


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