Gliflozins as remedies for correction of neurological complications of non-alcoholic fatty liver disease. Part 1


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

Prikhodko V.A., Okovityi S.V.

1) Saint Petersburg State Chemical and Pharmaceutical University of the Ministry of Healthcare of Russia; 2) Saint Petersburg State University
Abstract. Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have a number of risk factors which are common to those of central nervous system lesions, and also act as an independent cause of the development of cerebrovascular, neurodegenerative, cognitive and mental disorders. The development of drugs applicable not only for the treatment of NAFLD itself, but also for the correction of its psychoneurological complications is an urgent task of modern experimental biomedicine and pharmacology. A promising group of compounds that have shown high therapeutic potential in patients with NAFLD, as well as having a wide range of pleiotropic effects, are sodium-glucose cotransporter inhibitors (gliflozins). Current review represents data concerning the mechanisms of gliflozins’ neuroprotective efficacy, which are of greatest interest in light of the possibility of correcting the neurological complications of NAFLD.

Literature


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.


About the Autors


Veronika A. Prikhodko, PhD (Biology), senior lecturer of the Department of pharmacology and clinical pharmacology, Saint Petersburg State Chemical and Pharmaceutical University of the Ministry of Healthcare of Russia. Address: 197022, Saint Petersburg, 14, lit. A Professora Popova St.
E-mail: veronika.prihodko@pharminnotech.com
ORCID: https://orcid.org/0000-0002-4690-1811
Sergey V. Okovityi, MD, Dr. Sci. (Medicine), professor, head of the Department of pharmacology and clinical pharmacology of the Saint Petersburg State Chemical and Pharmaceutical University of the Ministry of Healthcare of Russia, professor of the scientific, clinical and educational center for gastroenterology and hepatology, Saint Petersburg State University. Address: 197022, Saint Petersburg, 14, lit. A Professora Popova St.
E-mail: sergey.okovity@pharminnotech.com
ORCID: https://orcid.org/0000-0003-4294-5531


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