Perspective of SGLT2 Inhibition in Treatment of Conditions Connected to Neuronal Loss: Focus on Alzheimer's Disease and Ischemia-Related Brain Injury

Michał Wiciński, Eryk Wódkiewicz, Karol Górski, Maciej Walczak, Bartosz Malinowski, Michał Wiciński, Eryk Wódkiewicz, Karol Górski, Maciej Walczak, Bartosz Malinowski

Abstract

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are oral anti-hyperglycemic agents approved for the treatment of type 2 diabetes mellitus. Some reports suggest their presence in the central nervous system and possible neuroprotective properties. SGLT2 inhibition by empagliflozin has shown to reduce amyloid burden in cortical regions of APP/PS1xd/db mice. The same effect was noticed regarding tau pathology and brain atrophy volume. Empagliflozin presented beneficial effect on cognitive function, which may be connected to an increase in cerebral brain-derived neurotrophic factor. Canagliflozin and dapagliflozin may possess acetylcholinesterase inhibiting activity, resembling in this matter Alzheimer's disease-registered therapies. SGLT2 inhibitors may prove to impact risk factors of atherosclerosis and pathways participating both in acute and late stage of stroke. Their mechanism of action can be related to induction in hepatocyte nuclear factor-1α, vascular endothelial growth factor-A, and proinflammatory factors limitation. Empagliflozin may have a positive effect on preservation of neurovascular unit in diabetic mice, preventing its aberrant remodeling. Canagliflozin seems to present some cytostatic properties by limiting both human and mice endothelial cells proliferation. The paper presents potential mechanisms of SGLT-2 inhibitors in conditions connected with neuronal damage, with special emphasis on Alzheimer's disease and cerebral ischemia.

Keywords: Alzheimer’s disease; cytokines; neurodegeneration; pharmacology; stroke.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Proposed mechanisms of Sodium-glucose co-transporter 2 inhibitors (SGLT2i) activity. ↓—reduction, ↑—increase, GSH—glutathione, MDA—malondialdehyde, ROS—reactive oxygen species, SP—senile plaques, Aβ—amyloid β, HIF1α—hypoxia-inducible factor 1α, BDNF—brain-derived neurotrophic factor, VEGF-A—vascular endothelial growth factor-A, IL-6—interleukin 6, TNFα—tumor necrosis factor α, VCAM-1—vascular cell adhesion protein, MCP-1—monocyte chemotactic protein-1. The differences in colors of Figure 1 have been used for aesthetic purposes only.

References

    1. Nauck M.A. Update on developments with SGLT2 inhibitors in the management of type 2 diabetes. Drug Des. Dev. Ther. 2014;8:1335–1380. doi: 10.2147/DDDT.S50773.
    1. Heise T., Seewaldt-Becker E., Macha S., Hantel S., Pinnetti S., Seman L., Woerle H.J. Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks’ treatment with empagliflozin once daily in patients with type 2 diabetes. Diabetes Obes. Metab. 2013;15:613–621. doi: 10.1111/dom.12073.
    1. Shah K., DeSilva S., Abbruscato T. The Role of Glucose Transporters in Brain Disease: Diabetes and Alzheimer’s Disease. Int. J. Mol. Sci. 2012;13:12629–12655. doi: 10.3390/ijms131012629.
    1. Yu A.S., Hirayama B.A., Timbol G., Liu J., Basarah E., Kepe V., Satyamurthy N., Huang S.-C., Wright E.M., Barrio J.R. Functional expression of SGLTs in rat brain. Am. J. Physiol. Physiol. 2010;299:C1277–C1284. doi: 10.1152/ajpcell.00296.2010.
    1. Yu A.S., Hirayama B.A., Timbol G., Liu J., Diez-Sampedro A., Kepe V., Satyamurthy N., Huang S.-C., Wright E.M., Barrio J.R. Regional distribution of SGLT activity in rat brain in vivo. Am. J. Physiol. Physiol. 2013;304:C240–C247. doi: 10.1152/ajpcell.00317.2012.
    1. Poppe R., Karbach U., Gambaryan S., Wiesinger H., Lutzenburg M., Kraemer M., Witte O.W., Koepsell H. Expression of the Na+-D-glucose cotransporter SGLT1 in neurons. J. Neurochem. 1997;69:84–94. doi: 10.1046/j.1471-4159.1997.69010084.x.
    1. Enerson B.E., Drewes L.R. The Rat Blood—Brain Barrier Transcriptome. Br. J. Pharmacol. 2005;26:959–973. doi: 10.1038/sj.jcbfm.9600249.
    1. Jurcovicova J. Glucose transport in brain—Effect of inflammation. Endocr. Regul. 2014;48:35–48. doi: 10.4149/endo_2014_01_35.
    1. Sa-Nguanmoo P., Tanajak P., Kerdphoo S., Jaiwongkam T., Pratchayasakul W., Chattipakorn N., Chattipakorn S. 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. doi: 10.1016/j.taap.2017.08.005.
    1. Lin B., Koibuchi N., Hasegawa Y., Sueta D., Toyama K., Uekawa K., Ma M., Nakagawa T., Kusaka H., Kim-Mitsuyama S. Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovasc. Diabetol. 2014;13:1–15. doi: 10.1186/s12933-014-0148-1.
    1. Abdelgadir E., Rashid F., Bashier A., Ali R. SGLT-2 Inhibitors and Cardiovascular Protection: Lessons and Gaps in Understanding the Current Outcome Trials and Possible Benefits of Combining SGLT-2 Inhibitors With GLP-1 Agonists. J. Clin. Med. Res. 2018;10:615–625. doi: 10.14740/jocmr3467w.
    1. McMurray J.J., Solomon S.D., Inzucchi S.E., Køber L., Kosiborod M.N., Martinez F.A., Ponikowski P., Sabatine M.S., Anand I.S., Bělohlávek J., et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N. Engl. J. Med. 2019;381:1995–2008. doi: 10.1056/NEJMoa1911303.
    1. Ndefo U.A., Anidiobi N.O., Basheer E., Eaton A.T. Empagliflozin (Jardiance): A Novel SGLT2 Inhibitor for the Treatment of Type-2 Diabetes. Pharm. Ther. 2015;40:364–368.
    1. Monami M., Nardini C., Mannucci E. Efficacy and safety of sodium glucose co-transport-2 inhibitors in type 2 diabetes: A meta-analysis of randomized clinical trials. Diabetes Obes. Metab. 2013;16:457–466. doi: 10.1111/dom.12244.
    1. DeSouza C.V., Gupta N., Patel A. Cardiometabolic Effects of a New Class of Antidiabetic Agents. Clin. Ther. 2015;37:1178–1194. doi: 10.1016/j.clinthera.2015.02.016.
    1. Erondu N., Desai M., Ways K., Meininger G. Diabetic Ketoacidosis and Related Events in the Canagliflozin Type 2 Diabetes Clinical Program. Diabetes Care. 2015;38:1680–1686. doi: 10.2337/dc15-1251.
    1. Hilaire R.S., Costello H. Prescriber beware: Report of adverse effect of sodium-glucose cotransporter 2 inhibitor use in a patient with contraindication. Am. J. Emerg. Med. 2015;33:604. doi: 10.1016/j.ajem.2014.09.039.
    1. Peters A.L., Buschur E.O., Buse J.B., Cohan P., Diner J.C., Hirsch I.B. Euglycemic Diabetic Ketoacidosis: A Potential Complication of Treatment With Sodium–Glucose Cotransporter 2 Inhibition. Diabetes Care. 2015;38:1687–1693. doi: 10.2337/dc15-0843.
    1. Taylor S.I., Blau J.E., Rother K.I. Perspective: SGLT2 inhibitors may predispose to ketoacidosis. J. Clin. Endocrinol. Metab. 2015;100:2849–2852. doi: 10.1210/jc.2015-1884.
    1. Wang Z.H., Kihl-Selstam E., Eriksson J.W. Ketoacidosis occurs in both Type1 and Type2 diabetes a population-based study from Northern Sweden. Diabet. Med. 2008;25:867–870. doi: 10.1111/j.1464-5491.2008.02461.x.
    1. Thakur A.K., Kamboj P., Goswami K., Ahuja K. Pathophysiology and management of alzheimer’s disease: An overview. J. Anal. Pharm. Res. 2018;7:1. doi: 10.15406/japlr.2018.07.00230.
    1. Bird T.D., Miller B.L. Alzheimer’s disease and primary dementias. In: Fauci A.S., Braunwald E., editors. Harrison’s Principles of Internal Medicine. McGraw-Hill; New York, NY, USA: 2008. pp. 2393–2406.
    1. Emedina M., Avila J. The role of extracellular Tau in the spreading of neurofibrillary pathology. Front. Cell. Neurosci. 2014;8:113. doi: 10.3389/fncel.2014.00113.
    1. Holtzman D.M., Morris J.C., Goate A.M. Alzheimer’s Disease: The Challenge of the Second Century. Sci. Transl. Med. 2011;3:77. doi: 10.1126/scitranslmed.3002369.
    1. Hierro-Bujalance C., Infante-Garcia C., Del Marco A., Herrera M., Carranza-Naval M.J., Suarez J., Alves-Martinez P., Lubian-Lopez S., Garcia-Alloza M. Empagliflozin reduces vascular damage and cognitive impairment in a mixed murine model of Alzheimer’s disease and type 2 diabetes. Alzheimer’s Res. Ther. 2020;12:1–13. doi: 10.1186/s13195-020-00607-4.
    1. Holubova M., Hruba L., Popelova A., Bencze M., Prazienkova V., Gengler S., Kratochvílová H., Haluzík M., Železná B., Kuneš J., et al. Liraglutide and a lipidized analog of prolactin-releasing peptide show neuroprotective effects in a mouse model of beta-amyloid pathology. Neuropharmacology. 2019;144:377–387. doi: 10.1016/j.neuropharm.2018.11.002.
    1. Hölscher C. The incretin hormones glucagonlike peptide 1 and glucose-dependent insulinotropic polypeptide are neuroprotective in mouse models of Alzheimer’s disease. Alzheimer’s Dement. 2014;10:S47–S54. doi: 10.1016/j.jalz.2013.12.009.
    1. Infante-Garcia C., Ramos-Rodriguez J.J., Galindo-Gonzalez L., Garcia-Alloza M. Long-term central pathology and cognitive impairment are exacerbated in a mixed model of Alzheimer’s disease and type 2 diabetes. Psychoneuroendocrinology. 2016;65:15–25. doi: 10.1016/j.psyneuen.2015.12.001.
    1. Ma D.-L., Chen F.-Q., Xu W.-J., Yue W.-Z., Yuan G., Yang Y. Early intervention with glucagon-like peptide 1 analog liraglutide prevents tau hyperphosphorylation in diabetic db/db mice. J. Neurochem. 2015;135:301–308. doi: 10.1111/jnc.13248.
    1. Kosaraju J., Holsinger R.M.D., Guo L., Tam K.Y. Linagliptin, a Dipeptidyl Peptidase-4 Inhibitor, Mitigates Cognitive Deficits and Pathology in the 3xTg-AD Mouse Model of Alzheimer’s Disease. Mol. Neurobiol. 2017;54:6074–6084. doi: 10.1007/s12035-016-0125-7.
    1. Bathina S., Das U.N. Brain-derived neurotrophic factor and its clinical implications. Arch. Med. Sci. 2015;6:1164–1178. doi: 10.5114/aoms.2015.56342.
    1. Cunha C., Brambilla R., Thomas K.L. A simple role for BDNF in learning and memory? Front. Mol. Neurosci. 2010;3:1. doi: 10.3389/neuro.02.001.2010.
    1. Salcedo I., Tweedie D., Li Y., Greig N.H. Neuroprotective and neurotrophic actions of glucagon-like peptide-1: An emerging opportunity to treat neurodegenerative and cerebrovascular disorders. Br. J. Pharmacol. 2012;166:1586–1599. doi: 10.1111/j.1476-5381.2012.01971.x.
    1. Wiciński M., Socha M., Malinowski B., Wódkiewicz E., Walczak M., Górski K., Słupski M., Pawlak-Osińska K. Liraglutide and its Neuroprotective Properties—Focus on Possible Biochemical Mechanisms in Alzheimer’s Disease and Cerebral Ischemic Events. Int. J. Mol. Sci. 2019;20:1050. doi: 10.3390/ijms20051050.
    1. Arafa N.M.S., Ali E.H.A., Hassan M.K. Canagliflozin prevents scopolamine-induced memory impairment in rats: Comparison with galantamine hydrobromide action. Chem. Interact. 2017;277:195–203. doi: 10.1016/j.cbi.2017.08.013.
    1. Shaikh S., Rizvi S.M.D., Shakil S., Riyaz S., Biswas D., Jahan R. Forxiga (dapagliflozin): Plausible role in the treatment of diabetes-associated neurological disorders. Biotechnol. Appl. Biochem. 2016;63:145–150. doi: 10.1002/bab.1319.
    1. Wright E.M., Turk E., Martín M.G. Molecular Basis for Glucose-Galactose Malabsorption. Cell Biophys. 2002;36:115–122. doi: 10.1385/CBB:36:2-3:115.
    1. Shakil S. Molecular Interaction of Anti-Diabetic Drugs With Acetylcholinesterase and Sodium Glucose Co-Transporter 2. J. Cell. Biochem. 2017;118:3855–3865. doi: 10.1002/jcb.26036.
    1. Rizvi S., Shakil S., Biswas D., Shakil S., Shaikh S., Bagga P., Kamal M.A. Invokana (Canagliflozin) as a Dual Inhibitor of Acetylcholinesterase and Sodium Glucose Co-Transporter 2: Advancement in Alzheimer’s Disease- Diabetes Type 2 Linkage via an Enzoinformatics Study. CNS Neurol. Disord. Drug Targets. 2014;13:447–451. doi: 10.2174/18715273113126660160.
    1. Katan M., Luft A. Global Burden of Stroke. Semin. Neurol. 2018;38:208–211. doi: 10.1055/s-0038-1649503.
    1. Sanganalmath S.K., Gopal P., Parker J.R., Downs R.K., Parker J.C., Dawn B. Global cerebral ischemia due to circulatory arrest: Insights into cellular pathophysiology and diagnostic modalities. Mol. Cell. Biochem. 2016;426:111–127. doi: 10.1007/s11010-016-2885-9.
    1. Abdel-Latif R.G., Rifaai R.A., Amin E.F. Empagliflozin alleviates neuronal apoptosis induced by cerebral ischemia/reperfusion injury through HIF-1α/VEGF signaling pathway. Arch. Pharmacal Res. 2020;43:514–525. doi: 10.1007/s12272-020-01237-y.
    1. Carmeliet P., Dor Y., Herbert J.-M., Fukumura D., Brusselmans K., Dewerchin M., Neeman M., Bono F., Abramovitch R., Maxwell P.H., et al. Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nat. Cell Biol. 1998;394:485–490. doi: 10.1038/28867.
    1. Xing J., Lu J. HIF-1α Activation Attenuates IL-6 and TNF-α Pathways in Hippocampus of Rats Following Transient Global Ischemia. Cell. Physiol. Biochem. 2016;39:511–520. doi: 10.1159/000445643.
    1. Ayala-Grosso C., Ng G., Roy S., Robertson G.S. Caspase-cleaved amyloid precursor protein in Alzheimer’s disease. Brain Pathol. 2002;12:430–441. doi: 10.1111/j.1750-3639.2002.tb00460.x.
    1. Rissman R.A., Poon W.W., Blurton-Jones M., Oddo S., Torp R., Vitek M.P., LaFerla F.M., Rohn T.T., Cotman C.W. Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology. J. Clin. Investig. 2004;114:121–130. doi: 10.1172/JCI200420640.
    1. Płóciennik A., Prendecki M., Zuba E., Siudzinski M., Dorszewska J. Activated Caspase-3 and Neurodegeneration and Synaptic Plasticity in Alzheimer’s Disease. Adv. Alzheimer’s Dis. 2015;4:63–77. doi: 10.4236/aad.2015.43007.
    1. Freitas H., Schaan B., David-Silva A., Sabino-Silva R., Okamoto M., Alves-Wagner A.B.T., Mori R., Machado U. SLC2A2 gene expression in kidney of diabetic rats is regulated by HNF-1α and HNF-3β. Mol. Cell. Endocrinol. 2009;305:63–70. doi: 10.1016/j.mce.2009.02.014.
    1. Pontoglio M., Prié D., Cheret C., Doyen A., Leroy C., Froguel P., Velho G., Yaniv M., Friedlander G. HNF1α controls renal glucose reabsorption in mouse and man. EMBO Rep. 2000;1:359–365. doi: 10.1093/embo-reports/kvd071.
    1. Freitas H.S., Anhě G.F., Melo K.F.S., Okamoto M.M., Oliveira-Souza M., Bordin S., Machado U.F. Na+-Glucose Transporter-2 Messenger Ribonucleic Acid Expression in Kidney of Diabetic Rats Correlates with Glycemic Levels: Involvement of Hepatocyte Nuclear Factor-1α Expression and Activity. Endocrinology. 2007;149:717–724. doi: 10.1210/en.2007-1088.
    1. Thau-Zuchman O., Shohami E., Alexandrovich A.G., Leker R.R. Vascular Endothelial Growth Factor Increases Neurogenesis after Traumatic Brain Injury. Br. J. Pharmacol. 2010;30:1008–1016. doi: 10.1038/jcbfm.2009.271.
    1. Schoch H.J. Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain. Brain. 2002;125:2549–2557. doi: 10.1093/brain/awf257.
    1. Larson J., Drew K.L., Folkow L.P., Milton S.L., Park T.J. No oxygen? No problem! Intrinsic brain tolerance to hypoxia in vertebrates. J. Exp. Biol. 2014;217:1024–1039. doi: 10.1242/jeb.085381.
    1. Geiseler S.J., Morland C. The Janus Face of VEGF in Stroke. Int. J. Mol. Sci. 2018;19:1362. doi: 10.3390/ijms19051362.
    1. ElAli A. The implication of neurovascular unit signaling in controlling the subtle balance between injury and repair following ischemic stroke. Neural Regen. Res. 2016;11:914–915. doi: 10.4103/1673-5374.184485.
    1. Hayden M.R., Grant D.G., Aroor A.R., Demarco V.G. Ultrastructural Remodeling of the Neurovascular Unit in the Female Diabetic db/db Model–Part II: Microglia and Mitochondria. Neuroglia. 2018;1:21. doi: 10.3390/neuroglia1020021.
    1. Hayden M.R., Grant D.G., Aroor A.R., Demarco V.G. Ultrastructural Remodeling of the Neurovascular Unit in the Female Diabetic db/db Model—Part III: Oligodendrocyte and Myelin. Neuroglia. 2018;1:24. doi: 10.3390/neuroglia1020024.
    1. Sweeney M.D., Ayyadurai S., Zlokovic B.V. Pericytes of the neurovascular unit: Key functions and signaling pathways. Nat. Neurosci. 2016;19:771–783. doi: 10.1038/nn.4288.
    1. Xing C., Hayakawa K., Lok J., Arai K., Lo E.H. Injury and repair in the neurovascular unit. Neurol. Res. 2012;34:325–330. doi: 10.1179/1743132812Y.0000000019.
    1. Cai W., Zhang K., Li P., Zhu L., Xu J., Yang B., Hu X., Lu Z., Chen J. Dysfunction of the neurovascular unit in ischemic stroke and neurodegenerative diseases: An aging effect. Ageing Res. Rev. 2017;34:77–87. doi: 10.1016/j.arr.2016.09.006.
    1. Hayden M.R., Grant D.G., Aroor A.R., Demarco V.G. Empagliflozin Ameliorates Type 2 Diabetes-Induced Ultrastructural Remodeling of the Neurovascular Unit and Neuroglia in the Female db/db Mouse. Brain Sci. 2019;9:57. doi: 10.3390/brainsci9030057.
    1. Bakris G.L., Fonseca V., Sharma K., Wright E.M. Renal sodium–glucose transport: Role in diabetes mellitus and potential clinical implications. Kidney Int. 2009;75:1272–1277. doi: 10.1038/ki.2009.87.
    1. Shimizu F., Kanda T. Disruption of the blood-brain barrier in inflammatory neurological diseases. Brain Nerve. 2013;65:165.
    1. Amin E.F., Rifaai R.A., Abdel-Latif R.G. Empagliflozin attenuates transient cerebral ischemia/reperfusion injury in hyperglycemic rats via repressing oxidative–inflammatory–apoptotic pathway. Fundam. Clin. Pharmacol. 2020;34:548–558. doi: 10.1111/fcp.12548.
    1. Millar P., Pathak N., Parthsarathy V., Bjourson A.J., O’Kane M., Pathak V., Moffett R.C., Flatt P.R., Gault V. Metabolic and neuroprotective effects of dapagliflozin and liraglutide in diabetic mice. J. Endocrinol. 2017;234:255–267. doi: 10.1530/JOE-17-0263.
    1. Gorelick P.B., Sacco R.L., Smith D.B., Alberts M., Mustone-Alexander L., Rader D., Ross J.L., Raps E., Ozer M.N., Brass L.M., et al. Prevention of a First Stroke: A review of guidelines and a multidisciplinary consensus statement from the National Stroke Association. JAMA. 1999;281:1112–1120. doi: 10.1001/jama.281.12.1112.
    1. Libby P. Inflammation in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 2012;32:2045–2051. doi: 10.1161/ATVBAHA.108.179705.
    1. Hansson G.K., Hermansson A. The immune system in atherosclerosis. Nat. Immunol. 2011;12:204–212. doi: 10.1038/ni.2001.
    1. Elwood E., Lim Z., Naveed H., Galea I. The effect of systemic inflammation on human brain barrier function. Brain Behav. Immun. 2017;62:35–40. doi: 10.1016/j.bbi.2016.10.020.
    1. Dziedzic T. Systemic inflammation as a therapeutic target in acute ischemic stroke. Expert Rev. Neurother. 2015;15:523–531. doi: 10.1586/14737175.2015.1035712.
    1. Chitnis T., Weiner H.L. CNS inflammation and neurodegeneration. J. Clin. Investig. 2017;127:3577–3587. doi: 10.1172/JCI90609.
    1. Holmes C. Review: Systemic inflammation and Alzheimer’s disease. Neuropathol. Appl. Neurobiol. 2013;39:51–68. doi: 10.1111/j.1365-2990.2012.01307.x.
    1. Chen W.-W., Zhang X., Huang W.-J. Role of neuroinflammation in neurodegenerative diseases (Review) Mol. Med. Rep. 2016;13:3391–3396. doi: 10.3892/mmr.2016.4948.
    1. Han J.H., Oh T.J., Lee G., Maeng H.J., Lee D.H., Kim K.M., Choi S.H., Jang H.C., Lee H.S., Park K.S., et al. The beneficial effects of empagliflozin, an SGLT2 inhibitor, on atherosclerosis in ApoE−/− mice fed a western diet. Diabetologia. 2017;60:364–376. doi: 10.1007/s00125-016-4158-2.
    1. Intiso D.F., Zarrelli M., Lagioia G., Di Rienzo F., De Ambrosio C.C., Simone P., Tonali P., Cioffi† R.P. Tumor necrosis factor alpha serum levels and inflammatory response in acute ischemic stroke patients. Neurol. Sci. 2004;24:390–396. doi: 10.1007/s10072-003-0194-z.
    1. Waje-Andreassen U., Krakenes J., Ulvestad E., Thomassen L., Myhr K.-M., Aarseth J., Vedeler C.A. IL-6: An early marker for outcome in acute ischemic stroke. Acta Neurol. Scand. 2005;111:360–365. doi: 10.1111/j.1600-0404.2005.00416.x.
    1. McCusker S.M., Curran M.D., Dynan K.B., McCullagh C.D., Urquhart D.D., Middleton D., Patterson C.C., Mcilroy S.P., Passmore A.P. Association between polymorphism in regulatory region of gene encoding tumour necrosis factor α and risk of Alzheimer’s disease and vascular dementia: A case-control study. Lancet. 2001;357:436–439. doi: 10.1016/S0140-6736(00)04008-3.
    1. Skoog T., Dichtl W., Boquist S., Skoglund-Andersson C., Karpe F., Tang R., Bond M., De Faire U., Nilsson J., Eriksson P., et al. Plasma tumour necrosis factor-α and early carotid atherosclerosis in healthy middle-aged men. Eur. Heart J. 2002;23:376–383. doi: 10.1053/euhj.2001.2805.
    1. Cui G., Wang H., Li R., Zhang L., Li Z., Wang Y., Hui R., Ding H., Wang D.W. Polymorphism of tumor necrosis factor alpha (TNF-alpha) gene promoter, circulating TNF-alpha level, and cardiovascular risk factor for ischemic stroke. J. Neuroinflamm. 2012;9:235. doi: 10.1186/1742-2094-9-235.
    1. Jefferis B.J., Whincup P.H., Welsh P., Wannamethee S.G., Rumley A., Lennon L., Thomson A.G., Carson C., Ebrahim S., Lowe G.D. Circulating TNFα levels in older men and women do not show independent prospective relations with MI or stroke. Atherosclerosis. 2009;205:302–308. doi: 10.1016/j.atherosclerosis.2008.12.001.
    1. Pennig J., Scherrer P., Gissler M.C., Anto-Michel N., Hoppe N., Füner L., Härdtner C., Stachon P., Wolf D., Hilgendorf I., et al. Glucose lowering by SGLT2-inhibitor empagliflozin accelerates atherosclerosis regression in hyperglycemic STZ-diabetic mice. Sci. Rep. 2019;9:17937. doi: 10.1038/s41598-019-54224-9.
    1. Dimitriadis G.K., Nasiri-Ansari N., Agrogiannis G., Kostakis I.D., Randeva M.S., Nikiteas N., Patel V.H., Kaltsas G., Papavassiliou A.G., Randeva H.S., et al. Empagliflozin improves primary haemodynamic parameters and attenuates the development of atherosclerosis in high fat diet fed APOE knockout mice. Mol. Cell. Endocrinol. 2019;494:110487. doi: 10.1016/j.mce.2019.110487.
    1. Ganbaatar B., Fukuda D., Shinohara M., Yagi S., Kusunose K., Yamada H., Soeki T., Hirata K.-I., Sata M. Empagliflozin ameliorates endothelial dysfunction and suppresses atherogenesis in diabetic apolipoprotein E-deficient mice. Eur. J. Pharmacol. 2020;875:173040. doi: 10.1016/j.ejphar.2020.173040.
    1. Behnammanesh G., Durante Z.E., Peyton K.J., Martinez-Lemus L.A., Brown S.M., Bender S.B., Durante W. Canagliflozin Inhibits Human Endothelial Cell Proliferation and Tube Formation. Front. Pharmacol. 2019;10:362. doi: 10.3389/fphar.2019.00362.
    1. Obikane H., Abiko Y., Ueno H., Kusumi Y., Esumi M., Mitsumata M. Effect of endothelial cell proliferation on atherogenesis: A role of p21Sdi/Cip/Waf1 in monocyte adhesion to endothelial cells. Atherosclerosis. 2010;212:116–122. doi: 10.1016/j.atherosclerosis.2010.05.029.
    1. Devineni D., Polidori D., Curtin C.R., Murphy J., Wang S.-S., Stieltjes H., Wajs E. Pharmacokinetics and pharmacodynamics of once- and twice-daily multiple-doses of canagliflozin, a selective inhibitor of sodium glucose co-transporter 2, in healthy participants. Int. J. Clin. Pharmacol. Ther. 2015;53:438–446. doi: 10.5414/CP202324.
    1. Kasichayanula S., Chang M., Hasegawa M., Liu X., Yamahira N., LaCreta F.P., Imai Y., Boulton D.W. Pharmacokinetics and pharmacodynamics of dapagliflozin, a novel selective inhibitor of sodium-glucose co-transporter type 2, in Japanese subjects without and with type 2 diabetes mellitus. Diabetes Obes. Metab. 2011;13:357–365. doi: 10.1111/j.1463-1326.2011.01359.x.
    1. Brand T., Macha S., Mattheus M., Pinnetti S., Woerle H.J. Pharmacokinetics of Empagliflozin, a Sodium Glucose Cotransporter-2 (SGLT-2) Inhibitor, Coadministered with Sitagliptin in Healthy Volunteers. Adv. Ther. 2012;29:889–899. doi: 10.1007/s12325-012-0055-3.
    1. Del Rio D., Stewart A.J., Pellegrini N. A review of recent studies on malondialdehyde as toxic molecule and biological marker of oxidative stress. Nutr. Metab. Cardiovasc. Dis. 2005;15:316–328. doi: 10.1016/j.numecd.2005.05.003.
    1. Tehrani H.S., Moosavi-Movahedi A.A. Catalase and its mysteries. Prog. Biophys. Mol. Biol. 2018;140:5–12. doi: 10.1016/j.pbiomolbio.2018.03.001.
    1. Hines M., Blum J. Bend propagation in flagella. II. Incorporation of dynein cross-bridge kinetics into the equations of motion. Biophys. J. 1979;25:421–441. doi: 10.1016/S0006-3495(79)85313-8.
    1. Zinman B., Wanner C., Lachin J.M., Fitchett D.H., Bluhmki E., Hantel S., Mattheus M., Devins T., Johansen O.E., Woerle H.J., et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. New Engl. J. Med. 2015;373:2117–2128. doi: 10.1056/NEJMoa1504720.
    1. Imprialos K.P., Boutari C., Stavropoulos K., Doumas M., Karagiannis A. Stroke paradox with SGLT-2 inhibitors: A play of chance or a viscosity-mediated reality? J. Neurol. Neurosurg. Psychiatry. 2016;88:249–253. doi: 10.1136/jnnp-2016-314704.
    1. Neal B., Perkovic V., Mahaffey K.W., De Zeeuw D., Fulcher G., Erondu N., Shaw W., Law G., Desai M., Matthews D.R. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N. Engl. J. Med. 2017;377:644–657. doi: 10.1056/NEJMoa1611925.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa