Neuroprotective Effects of Sodium‑Glucose Cotransporter‑2 (SGLT2) Inhibitors (Gliflozins) on Diabetes‑Induced Neurodegeneration and Neurotoxicity: A Graphical Review

Mina Gholami, Natalie Coleman‑Fuller, Mahsa Salehirad, Sepideh Darbeheshti, Majid Motaghinejad

Abstract


Diabetes is a chronic endocrine disorder that negatively affects various body systems, including the nervous system. Diabetes can cause or exacerbate various neurological disorders, and diabetes‑induced neurodegeneration can involve several mechanisms such as mitochondrial dysfunction, activation of oxidative stress, neuronal inflammation, and cell death. In recent years, the management of diabetes‑induced neurodegeneration has relied on several types of drugs, including sodium‑glucose cotransporter‑2 (SGLT2) inhibitors, also called gliflozins. In addition to exerting powerful effects in reducing blood glucose, gliflozins have strong anti‑neuro‑inflammatory characteristics that function by inhibiting oxidative stress and cell death in the nervous system in diabetic subjects. This review presents the molecular pathways involved in diabetes‑induced neurodegeneration and evaluates the clinical and laboratory studies investigating the neuroprotective effects of gliflozins against diabetes‑induced neurodegeneration, with discussion about the contributing roles of diverse molecular pathways, such as mitochondrial dysfunction, oxidative stress, neuro‑inflammation, and cell death. Several databases—including Web of Science, Scopus, PubMed, Google Scholar, and various publishers, such as Springer, Wiley, and Elsevier—were searched for keywords regarding the neuroprotective effects of gliflozins against diabetes‑triggered neurodegenerative events. Additionally, anti‑neuro‑inflammatory, anti‑oxidative stress, and anti‑cell death keywords were applied to evaluate potential neuronal protection mechanisms of gliflozins in diabetes subjects. The search period considered valid peer‑reviewed studies published from January 2000 to July 2023. The current body of literature suggests that gliflozins can exert neuroprotective effects against diabetes‑induced neurodegenerative events and neuronal dysfunction, and these effects are mediated via activation of mitochondrial function and prevention of cell death processes, oxidative stress, and inflammation in neurons affected by diabetes. Gliflozins can confer neuroprotective properties in diabetes‑triggered neurodegeneration, and these effects are mediated by inhibiting oxidative stress, inflammation, and cell death.

Keywords


Diabetes; gliflozins; neurodegeneration; neurotoxicity

Full Text:

PDF

References


Umegaki H. Neurodegeneration in diabetes mellitus.

Neurodegener Dis 2012:258‑65.

Lieth E, Gardner TW, Barber AJ, Antonetti DA. Retinal

neurodegeneration: Early pathology in diabetes. Clin Exp

Ophthalmol 2000;28:3‑8.

Moran C, Beare R, Phan TG, Bruce DG, Callisaya ML,

Srikanth V. Type 2 diabetes mellitus and biomarkers of

neurodegeneration. Neurology 2015;85:1123‑30.

Pessina AC. Target organs of individuals with diabetes caught

between arterial stiffness and damage to the microcirculation.

J Hypertension 2007;25:S13‑8.

Mohamed J, Nafizah AN, Zariyantey A, Budin S. Mechanisms of

diabetes‑induced liver damage: The role of oxidative stress and

inflammation. Sultan Qaboos Univ Med J 2016;16:e132‑41.

Levey AS, Astor BC, Stevens LA, Coresh J. Chronic kidney

disease, diabetes, and hypertension: What’s in a name? Kidney

Int 2010;78:19‑22.

Bree AJ, Puente EC, Daphna‑Iken D, Fisher SJ. Diabetes

increases brain damage caused by severe hypoglycemia. Am J

Physiol Endocrinol Metab 2009;297:E194‑201.

Kennedy JM, Zochodne DW. Impaired peripheral nerve

regeneration in diabetes mellitus. J Peripher Nerv Syst

;10:144‑57.

Obrosova IG. Diabetes and the peripheral nerve. Biochim

Biophys Acta 2009;1792:931‑40.

Adler A. Obesity and target organ damage: Diabetes. Int J Obes

;26:S11‑4.

Lynch SK, Abràmoff MD. Diabetic retinopathy is a

neurodegenerative disorder. Vis Res 2017;139:101‑7.

Tesfaye S. Neuropathy in diabetes. Medicine 2010;38:649‑55.

Omidi G, Karimi SA, Rezvani‑Kamran A, Monsef A, Shahidi S,

Komaki A. Effect of coenzyme Q10 supplementation on

diabetes induced memory deficits in rats. Metab Brain Dis

;34:833‑40.

Zhou X, Gan T, Fang G, Wang S, Mao Y, Ying C. Zeaxanthin

improved diabetes‑induced anxiety and depression through

inhibiting inflammation in hippocampus. Metab Brain Dis

;33:705‑11.

Aswar U, Chepurwar S, Shintre S, Aswar M. Telmisartan

attenuates diabetes induced depression in rats. Pharmacol Rep

;69:358‑64.

Muriach M, Flores‑Bellver M, Romero FJ, Barcia JM.

Diabetes and the brain: Oxidative stress, inflammation,

and autophagy. Oxid Med Cell Longev 2014;2014:102158.

doi: 10.1155/2014/102158.

Kahya MC, Nazıroğlu M, Övey İS. Modulation of

diabetes‑induced oxidative stress, apoptosis, and Ca2+entry

through TRPM2 and TRPV1 channels in dorsal root ganglion

and hippocampus of diabetic rats by melatonin and selenium.

Mol Neurobiol 2017;54:2345‑60.

Chung SS, Ho EC, Lam KS, Chung SK. Contribution of polyol

pathway to diabetes‑induced oxidative stress. J Am Soc Nephrol

;14(Suppl 3):S233‑6.

Jangra A, Datusalia AK, Khandwe S, Sharma SS. Amelioration

of diabetes‑induced neurobehavioral and neurochemical changes

by melatonin and nicotinamide: Implication of oxidative stress–

PARP pathway. Pharmacol Biochem Behav 2013;114:43‑51.

Cinteza M. Gliflozins–a new border stone. Maedica 2019;14:3‑4.

Lee KA, Jin HY, Lee NY, Kim YJ, Park TS. Effect of

empagliflozin, a selective sodium‑glucose cotransporter 2 inhibitor,

on kidney and peripheral nerves in streptozotocin‑induced

diabetic rats. Diabetes Metab J 2018;42:338.

Jakubiak GK. Antidiabetic Drugs from Group of Gliflozins and

their Role in Pharmacotherapy of Diabetes. Medycyna Rodzinna;

;3,146-51.

Millar P, Pathak N, Parthsarathy V, Bjourson AJ, O’Kane M,

Pathak V, et al. Metabolic and neuroprotective effects of

dapagliflozin and liraglutide in diabetic mice. J Endocrinol 2017;234:255‑67.

Lee YH, Kim SH, Kang JM, Heo JH, Kim D‑J, Park SH, et al.

Empagliflozin attenuates diabetic tubulopathy by improving

mitochondrial fragmentation and autophagy. Am J Physiol Renal

Physiol 2019;317:F767‑80.

Keles R, Hazar‑Yavuz AN, Yildiz S, Cam ME, Sener G.

Dapagliflozin attenuates anxiolytic‑like behavior of rats in open

field test. Eur J Pharmacol 2019;29:201‑2.

Khan T, Khan S, Akhtar M, Ali J, Najmi AK. Empagliflozin

nanoparticles attenuates type 2 diabetes induced cognitive

impairment via oxidative stress and inflammatory pathway in

high fructose diet induced hyperglycemic mice. Neurochemistry

Int 2021;150:105158. doi: 10.1016/j.neuint. 2021.105158.

Heimke M, Lenz F, Rickert U, Lucius R, Cossais F.

Anti‑inflammatory properties of the SGLT2 inhibitor

empagliflozin in activated primary microglia. Cells 2022;11:3107.

doi: 10.3390/cells11193107.

Motawi TK, Al‑Kady RH, Abdelraouf SM, Senousy MA.

Empagliflozin alleviates endoplasmic reticulum stress and

augments autophagy in rotenone‑induced Parkinson’s disease

in rats: Targeting the GRP78/PERK/eIF2α/CHOP pathway

and miR‑211‑5p. Chem Biol Interact 2022;362:110002.

doi: 10.1016/j.cbi. 2022.110002.

De A, Chattopadhyay P, Singh M. In‑vitro antioxidant activity

and free radical scavenging potential of phlorizin derived

sodium glucose cotransporter 2 inhibitor. J Drug Deliv Ther

;257‑64.

Ala M, Khoshdel MRF, Dehpour AR. Empagliflozin enhances

autophagy, mitochondrial biogenesis, and antioxidant

defense and ameliorates renal ischemia/reperfusion in

nondiabetic rats. Oxid Med Cell Longev 2022;2022:1197061.

doi: 10.1155/2022/1197061.

Secker PF, Beneke S, Schlichenmaier N, Delp J, Gutbier S,

Leist M, et al. Canagliflozin mediated dual inhibition of

mitochondrial glutamate dehydrogenase and complex I:

An off‑target adverse effect. Cell Death Dis 2018;9:1‑13.

doi: 10.1038/s41419‑018‑0273‑y.

Bendotti G, Montefusco L, Pastore I, Lazzaroni E, Lunati M,

Fiorina P. The anti‑inflammatory and immunological properties

of SGLT‑2 inhibitors. J Endocrinol Invest 2023;46:2445‑52.

Lee N, Heo YJ, Choi S‑E, Jeon JY, Han SJ, Kim DJ, et al.

Anti‑inflammatory effects of empagliflozin and gemigliptin

on LPS‑stimulated macrophage via the IKK/NF‑κB,

MKK7/JNK, and JAK2/STAT1 signalling pathways. J Immunol

Res 2021;2021:9944880. doi: 10.1155/2021/9944880.

Sasaki M, Ozawa Y, Kurihara T, Kubota S, Yuki K, Noda K,

et al. Neurodegenerative influence of oxidative stress in the retina

of a murine model of diabetes. Diabetologia 2010;53:971‑9.

Silva KC, Rosales MA, Biswas SK, Lopes de Faria JB, Lopes

de Faria JM. Diabetic retinal neurodegeneration is associated

with mitochondrial oxidative stress and is improved by an

angiotensin receptor blocker in a model combining hypertension

and diabetes. Diabetes 2009;58:1382‑90.

Pop-Busui R, Sima A, Stevens M. Diabetic neuropathy and

oxidative stress. Diabetes Metab Res Rev 2006;22:257‑73.

Sandireddy R, Yerra VG, Areti A, Komirishetty P, Kumar A.

Neuroinflammation and oxidative stress in diabetic neuropathy:

Futuristic strategies based on these targets. Int J Endocrinol

;2014:674987. doi: 10.1155/2014/674987.

Du Y, Veenstra A, Palczewski K, Kern TS. Photoreceptor

cells are major contributors to diabetes‑induced oxidative

stress and local inflammation in the retina. Proc Natl Acad Sci

;110:16586‑91.

Yang H, Jin X, Lam CWK, Yan S‑K. Oxidative stress and

diabetes mellitus. Clin Chem Lab Med 2011;49:1773‑82.

Gandhi S, Abramov AY. Mechanism of oxidative stress in

neurodegeneration. Oxid Med Cell Longev 2012;2012:428010.

doi: 10.1155/2012/428010.

Cohen G, Riahi Y, Sunda V, Deplano S, Chatgilialoglu C,

Ferreri C, et al. Signaling properties of 4‑hydroxyalkenals

formed by lipid peroxidation in diabetes. Free Radic Biol Med

;65:978‑87.

Kumawat M, Singh N, Singh S. Status of antioxidant enzymes

and lipid peroxidation in type 2 diabetes mellitus with

neuropathy. Ann Neurosci 2010;12:49‑52.

Vincent AM, Russell JW, Low P, Feldman EL. Oxidative

stress in the pathogenesis of diabetic neuropathy. Endocr Rev

;25:612‑28.

Kowluru RA, Chan P‑S. Oxidative stress and diabetic retinopathy.

Exp Diabetes Res 2007;2007:43603. doi: 10.1155/2007/43603.

Calderon G, Juarez O, Hernandez G, Punzo S, De la Cruz Z.

Oxidative stress and diabetic retinopathy: Development and

treatment. Eye 2017;31:1122‑30.

Barber AJ. A new view of diabetic retinopathy:

A neurodegenerative disease of the eye. Prog

Neuropsychopharmacol Biol Psychiatry 2003;27:283‑90.

Asmat U, Abad K, Ismail K. Diabetes mellitus and oxidative

stress—A concise review. Saudi Pharm J 2016;24:547‑53.

Hosseini A, Abdollahi M. Diabetic neuropathy and oxidative

stress: Therapeutic perspectives. Oxid Med Cell Longev

;2013:168039. doi: 10.1155/2013/168039.

Kasznicki J, Kosmalski M, Sliwinska A, Mrowicka M,

Stanczyk M, Majsterek I, et al. Evaluation of oxidative stress

markers in pathogenesis of diabetic neuropathy. Mol Biol Rep

;39:8669‑78.

Pan H‑Z, Zhang H, Chang D, Li H, Sui H. The change of

oxidative stress products in diabetes mellitus and diabetic

retinopathy. Br J Ophthalmol 2008;92:548‑51.

Abcouwer SF, Gardner TW. Diabetic retinopathy: Loss of

neuroretinal adaptation to the diabetic metabolic environment.

Ann N Y Acad Sci 2014;1311:174‑90.

Behl T, Kaur I, Kotwani A. Implication of oxidative stress

in progression of diabetic retinopathy. Surv Ophthalmol

;61:187‑96.

West IC. Radicals and oxidative stress in diabetes. Diabet Med

;17:171‑80.

Turk Z. Glycotoxines, carbonyl stress and relevance to diabetes

and its complications. Physiological Res 2010;59:147‑56.

Naudi A, Jove M, Ayala V, Cassanye A, Serrano J, Gonzalo H,

et al. Cellular dysfunction in diabetes as maladaptive

response to mitochondrial oxidative stress. Exp Diabetes Res

;2012:696215. doi: 10.1155/2012/696215.

Mule NK, Singh JN. Diabetes mellitus to neurodegenerative

disorders: Is oxidative stress fueling the flame? CNS Neurol

Disord Drug Targets 2018;17:644‑53.

Rosales‑Corral S, Tan D‑X, Manchester L, Reiter RJ. Diabetes

and alzheimer disease, two overlapping pathologies with the

same background: Oxidative stress. Oxid Med Cell Longev

;2015:985845. doi: 10.1155/2015/985845.

Niedowicz DM, Daleke DL. The role of oxidative stress in

diabetic complications. Cell Biochem Biophys 2005;43:289‑330.

Hassan A, Kandel RS, Mishra R, Gautam J, Alaref A,

Jahan N. Diabetes mellitus and Parkinson’s disease: Shared

pathophysiological links and possible therapeutic implications.

Cureus 2020;12:e9853. doi: 10.7759/cureus. 9853.

Domínguez R, Pagano M, Marschoff E, González S, Repetto M, Serra J. Alzheimer disease and cognitive impairment associated

with diabetes mellitus type 2: Associations and a hypothesis.

Neurología (English Edition) 2014;29:567‑72.

Magyari M, Sorensen PS. Comorbidity in multiple sclerosis.

Front Neurol 2020;11:851.

Chen R, Ovbiagele B, Feng W. Diabetes and stroke:

Epidemiology, pathophysiology, pharmaceuticals and outcomes.

Am J Med Sci 2016;351:380‑6.

Luscher TF, Creager MA, Beckman JA, Cosentino F. Diabetes

and vascular disease: Pathophysiology, clinical consequences,

and medical therapy: Part II. Circulation 2003;108:1655‑61.

Song Y, Ding W, Bei Y, Xiao Y, Tong H‑D, Wang L‑B, et al.

Insulin is a potential antioxidant for diabetes‑associated cognitive

decline via regulating Nrf2 dependent antioxidant enzymes.

Biomed Pharmacother 2018;104:474‑84.

Ceretta LB, Réus GZ, Abelaira HM, Ribeiro KF, Zappellini G,

Felisbino FF, et al. Increased oxidative stress and imbalance in

antioxidant enzymes in the brains of alloxan‑induced diabetic rats.

Exp Diabetes Res 2012;2012:302682. doi: 10.1155/2012/302682.

Kowluru RA, Kennedy A. Therapeutic potential of anti‑oxidants

and diabetic retinopathy. Expert Opin Investig Drugs

;10:1665‑76.

Zhong Q, Kowluru RA. Epigenetic changes in mitochondrial

superoxide dismutase in the retina and the development of

diabetic retinopathy. Diabetes 2011;60:1304‑13.

Younus H. Therapeutic potentials of superoxide dismutase. Int J

Health Sci 2018;12:88.

Yorek MA. The role of oxidative stress in diabetic vascular and

neural disease. Free Radic Res 2003;37:471‑80.

Schmeichel AM, Schmelzer JD, Low PA. Oxidative injury and

apoptosis of dorsal root ganglion neurons in chronic experimental

diabetic neuropathy. Diabetes 2003;52:165‑71.

Iranzo O. Manganese complexes displaying superoxide dismutase

activity: A balance between different factors. Bioorganic Chem

;39:73‑87.

Shanmugam KR, Mallikarjuna K, Kesireddy N, Reddy KS.

Neuroprotective effect of ginger on anti‑oxidant enzymes

in streptozotocin‑induced diabetic rats. Food Chem Toxicol

;49:893‑7.

Alipour M, Salehi I, Soufi FG. Effect of exercise on

diabetes‑induced oxidative stress in the rat hippocampus. Iran

Red Crescent Med J 2012;14:222‑8.

Madsen‑Bouterse SA, Zhong Q, Mohammad G, Ho Y‑S,

Kowluru RA. Oxidative damage of mitochondrial DNA in

diabetes and its protection by manganese superoxide dismutase.

Free Radic Res 2010;44:313‑21.

Sytze van Dam P. Oxidative stress and diabetic neuropathy:

Pathophysiological mechanisms and treatment perspectives.

Diabetes Metab Res Rev 2002;18:176‑84.

Obrosova IG. Update on the pathogenesis of diabetic neuropathy.

Curr Diab Rep 2003;3:439‑45.

Fernyhough P. Mitochondrial dysfunction in diabetic neuropathy:

A series of unfortunate metabolic events. Curr Diab Rep

;15:1‑10.

Shamsul Ola M, S Alhomida A. Neurodegeneration in diabetic

retina and its potential drug targets. Curr Neuropharmacol

;12:380‑6.

Simó R, Hernández C. Neurodegeneration in the diabetic eye:

New insights and therapeutic perspectives. Trends Endocrinol

Metab 2014;25:23‑33.

Clausen A, Doctrow S, Baudry M. Prevention of cognitive deficits

and brain oxidative stress with superoxide dismutase/catalase

mimetics in aged mice. Neurobiol Aging 2010;31:425‑33.

Infante‑Garcia C, Garcia‑Alloza M. Review of the effect of

natural compounds and extracts on neurodegeneration in animal

models of diabetes mellitus. Int J Mol Sci 2019;20:2533.

doi: 10.3390/ijms20102533.

Sofic E, Salkovic‑Petrisic M, Tahirovic I, Sapcanin A, Mandel S,

Youdim M, et al. Brain catalase in the streptozotocin‑rat

model of sporadic Alzheimer’s disease treated with the iron

chelator–monoamine oxidase inhibitor, M30. J Neural Transm

;122:559‑64.

Giordano CR, Roberts R, Krentz KA, Bissig D, Talreja D,

Kumar A, et al. Catalase therapy corrects oxidative

stress‑induced pathophysiology in incipient diabetic retinopathy.

Invest Ophthalmol Vis Sci 2015;56:3095‑102.

Kwong‑Han K, Zunaina E, Hanizasurana H, Che‑Badariah AA,

Che‑Maraina CH. Comparison of catalase, glutathione peroxidase

and malondialdehyde levels in tears among diabetic patients

with and without diabetic retinopathy. J Diabetes Metab Disord

;21:681‑8.

Djordjević GM, Djurić SS, Djordjević VB, Apostolski S,

Zivkovic M. The role of oxidative stress in pathogenesis of

diabetic neuropathy: Erythrocyte superoxide dismutase, catalase

and glutathione peroxidase level in relation to peripheral nerve

conduction in diabetic neuropathy patients. Role of the Adipocyte

in Development of Type. Vol. 2. 2011. p. 153‑72.

Tiwari BK, Pandey KB, Abidi A, Rizvi SI. Markers of

oxidative stress during diabetes mellitus. J Biomark 2013;2013.

doi: 10.1155/2013/378790.

Figueroa‑Romero C, Sadidi M, Feldman EL. Mechanisms of

disease: The oxidative stress theory of diabetic neuropathy. Rev

Endocr Metab Disord 2008;9:301‑14.

Sims‑Robinson C, Kim B, Rosko A, Feldman EL. How does

diabetes accelerate Alzheimer disease pathology? Nat Rev

Neurol 2010;6:551‑9.

Chowdhury SKR, Smith DR, Fernyhough P. The role of aberrant

mitochondrial bioenergetics in diabetic neuropathy. Neurobiol

Dis 2013;51:56‑65.

Srinivasan S, Stevens M, Wiley JW. Diabetic peripheral

neuropathy: Evidence for apoptosis and associated mitochondrial

dysfunction. Diabetes 2000;49:1932‑8.

Piotrowski P, Wierzbicka K, Smialek M. Neuronal death in the

rat hippocampus in experimental diabetes and cerebral ischaemia

treated with antioxidants. Folia Neuropathol 2001;39:147‑54.

Kempuraj D, Thangavel R, Natteru P, Selvakumar G, Saeed D,

Zahoor H, et al. Neuroinflammation induces neurodegeneration.

J Neurol Neurosurg Spine 2016;1:7267. doi: 10.3390/

ijms23137267.

Srodulski S, Sharma S, Bachstetter AB, Brelsfoard JM,

Pascual C, Xie XS, et al. Neuroinflammation and neurologic

deficits in diabetes linked to brain accumulation of amylin. Mol

Neurodegener 2014;9:1‑12. doi: 10.1186/1750‑1326‑9‑30.

Fletcher EL, Phipps JA, Ward MM, Puthussery T,

Wilkinson‑Berka JL. Neuronal and glial cell abnormality as

predictors of progression of diabetic retinopathy. Curr Pharm

Design 2007;13:2699‑712.

Nagayach A, Patro N, Patro I. Experimentally induced diabetes

causes glial activation, glutamate toxicity and cellular damage

leading to changes in motor function. Front Cell Neurosci

;8:355. doi: 10.3389/fncel. 2014.00355.

Zeng H‑Y, Green WR, Tso MO. Microglial activation in human

diabetic retinopathy. Arch Ophthalmol 2008;126:227‑32.

Zhang T‑T, Xue R, Fan S‑Y, Fan Q‑Y, An L, Li J, et al.

Ammoxetine attenuates diabetic neuropathic pain through

inhibiting microglial activation and neuroinflammation in the spinal cord. J Neuroinflammation 2018;15:1‑13. doi: 10.1186/

s12974‑018‑1216‑3.

Krady JK, Basu A, Allen CM, Xu Y, LaNoue KF, Gardner TW,

et al. Minocycline reduces proinflammatory cytokine expression,

microglial activation, and caspase‑3 activation in a rodent model

of diabetic retinopathy. Diabetes 2005;54:1559‑65.

Skundric DS, Lisak RP. Role of neuropoietic cytokines in

development and progression of diabetic polyneuropathy: From

glucose metabolism to neurodegeneration. Exp Diabesity Res

;4:303‑12.

Cheung CMG, Vania M, Ang M, Chee SP, Li J. Comparison

of aqueous humor cytokine and chemokine levels in diabetic

patients with and without retinopathy. Mol Vis 2012;18:830‑7.

Chatzigeorgiou A, Harokopos V, Mylona‑Karagianni C,

Tsouvalas E, Aidinis V, Kamper E. The pattern of inflammatory/

anti‑inflammatory cytokines and chemokines in type 1 diabetic

patients over time. Ann Med 2010;42:426‑38.

King GL. The role of inflammatory cytokines in diabetes and its

complications. J Periodontol 2008;79:1527‑34.

Saleh A, Smith DR, Balakrishnan S, Dunn L, Martens C,

Tweed CW, et al. Tumor necrosis factor‑α elevates neurite

outgrowth through an NF‑κB‑dependent pathway in cultured

adult sensory neurons: Diminished expression in diabetes may

contribute to sensory neuropathy. Brain Res 2011;1423:87‑95.

Purwata TE. High TNF‑alpha plasma levels and macrophages

iNOS and TNF‑alpha expression as risk factors for painful

diabetic neuropathy. J Pain Res 2011;4:169‑75.

Mendiola AS, Cardona AE. The IL‑1β phenomena in

neuroinflammatory diseases. J Neural Transm 2018;125:781‑95.

Andriambeloson E, Baillet C, Vitte PA, Garotta G, Dreano M,

Callizot N. Interleukin-6 attenuates the development of

experimental diabetes-related neuropathy. Neuropathology

;26:32‑42.

Herder C, Carstensen M, Ouwens D. Anti-inflammatory

cytokines and risk of type 2 diabetes. Diabetes Obes Metab

;15:39‑50.

Zhang W, Liu H, Rojas M, Caldwell RW, Caldwell RB.

Anti‑inflammatory therapy for diabetic retinopathy.

Immunotherapy 2011;3:609‑28.

Carbonetto P, Stephens M. Integrated enrichment analysis of

variants and pathways in genome‑wide association studies

indicates central role for IL‑2 signaling genes in type 1 diabetes,

and cytokine signaling genes in Crohn’s disease. PLoS Genet

;9:e1003770. doi: 10.1371/journal.pgen.1003770.

Creusot RJ, Chang P, Healey DG, Tcherepanova IY,

Nicolette CA, Fathman CG. A short pulse of IL‑4 delivered

by DCs electroporated with modified mRNA can both prevent

and treat autoimmune diabetes in NOD mice. Mol Ther

;18:2112‑20.

Akbari M, Hassan‑Zadeh V. IL‑6 signalling pathways and

the development of type 2 diabetes. Inflammopharmacology

;26:685‑98.

Rodrigues KF, Pietrani NT, Bosco AA, Campos FMF,

Sandrim VC, Gomes KB. IL‑6, TNF‑α, and IL‑10 levels/

polymorphisms and their association with type 2 diabetes

mellitus and obesity in Brazilian individuals. Arch Endocrinol

Metab 2017;61:438‑46.

Hanifi‐Moghaddam P, Kappler S, Seissler J, MüllerScholze S, Martin S, Roep B, et al. Altered chemokine levels

in individuals at risk of type 1 diabetes mellitus. Diabetic Med

;23:156‑63.

Herder C, Haastert B, Müller‑Scholze S, Koenig W, Thorand B,

Holle R, et al. Association of systemic chemokine concentrations

with impaired glucose tolerance and type 2 diabetes: Results

from the cooperative health research in the Region of Augsburg

Survey S4 (KORA S4). Diabetes 2005;54(Suppl 2):S11‑7.

Lontchi‑Yimagou E, Sobngwi E, Matsha TE, Kengne AP.

Diabetes mellitus and inflammation. Curr Diabs Rep

;13:435‑44.

Laaksonen D, Niskanen L, Nyyssönen K, Punnonen K,

Tuomainen T‑P, Valkonen V‑P, et al. C‑reactive protein and

the development of the metabolic syndrome and diabetes in

middle‑aged men. Diabetologia 2004;47:1403‑10.

Chase HP, Cooper S, Osberg I, Stene LC, Barriga K, Norris J,

et al. Elevated C‑reactive protein levels in the development of

type 1 diabetes. Diabetes 2004;53:2569‑73.

Pugazhenthi S, Qin L, Reddy PH. Common neurodegenerative

pathways in obesity, diabetes, and Alzheimer’s disease. Biochim

Biophys Acta Mol Basis Dis 2017;1863:1037‑45.

De Felice FG, Ferreira ST. Inflammation, defective insulin

signaling, and mitochondrial dysfunction as common molecular

denominators connecting type 2 diabetes to Alzheimer disease.

Diabetes 2014;63:2262‑72.

Rübsam A, Parikh S, Fort PE. Role of inflammation in

diabetic retinopathy. Int J Mol Sci 2018;19:942. doi: 10.3390/

ijms19040942.

Yu Y, Chen H, Su SB. Neuroinflammatory responses in diabetic

retinopathy. J Neuroinflammation 2015;12:1‑15. doi: 10.1186/

s12974‑015‑0368‑7.

Debnath M, Agrawal S. Diabetic neuropathy: Oxidative stress

and neuroinflammation. Med Res 2016;3:237‑41.

Madonna R, Giovannelli G, Confalone P, Renna FV, Geng

Y‑J, De Caterina R. High glucose‑induced hyperosmolarity

contributes to COX‑2 expression and angiogenesis: Implications

for diabetic retinopathy. Cardiovasc Diabetol 2016;18:15.

doi: 10.1186/s12933‑016‑0342‑4.

Wong WT, Tian XY, Huang Y. Endothelial dysfunction in

diabetes and hypertension: Cross talk in RAS, BMP4, and

ROS‑dependent COX‑2–derived prostanoids. J Cardiovasc

Pharmacol 2013;61:204‑14.

Mastrocola R, Restivo F, Vercellinatto I, Danni O,

Brignardello E, Aragno M, et al. Oxidative and nitrosative

stress in brain mitochondria of diabetic rats. J Endocrinol

;187:37‑44.

Costagliola C, Romano V, De Tollis M, Aceto F, Romano MR,

Pedicino C, et al. TNF‑alpha levels in tears: A novel biomarker

to assess the degree of diabetic retinopathy. Mediators Inflamm

;2013:629529. doi: 10.1155/2013/629529.

Serasanambati M, Chilakapati SR. Function of nuclear factor

kappa B (NF‑kB) in human diseases‑A review. South Indian J

Biol Sci. 2016;2:368‑87.

Ghanaatfar F, Ghanaatfar A, Isapour P, Farokhi N,

Bozorgniahosseini S, Javadi M, et al. Is lithium neuroprotective?

An updated mechanistic illustrated review. Fundamental &

clinical pharmacology. 2023;37:4-30.

Patel S, Santani D. Role of NF‑κB in the pathogenesis of

diabetes and its associated complications. Pharmacol Rep

;61:595‑603.

Li J, Tang Y, Cai D. IKKβ/NF‑κB disrupts adult hypothalamic

neural stem cells to mediate a neurodegenerative mechanism

of dietary obesity and pre‑diabetes. Nat Cell Biol

;14:999‑1012.

Granic I, Dolga AM, Nijholt IM, van Dijk G, Eisel UL.

Inflammation and NF‑κB in Alzheimer’s disease and diabetes.

J Alzheimer’s Dis 2009;16:809‑21.

Yun JH, Lee DH, Jeong HS, Kim HS, Ye SK, Cho CH. STAT3 activation in microglia exacerbates hippocampal neuronal

apoptosis in diabetic brains. J Cell Physiol 2021;236:7058‑70.

Chowdhury SR, Saleh A, Akude E, Smith DR, Morrow D,

Tessler L, et al. Ciliary neurotrophic factor reverses aberrant

mitochondrial bioenergetics through the JAK/STAT pathway in

cultured sensory neurons derived from streptozotocin‑induced

diabetic rodents. Cell Mol Neurobiol 2014;34:643‑9.

Cho C‑H, Roh K‑H, Lim N‑Y, Park SJ, Park S, Kim HW. Role

of the JAK/STAT pathway in a streptozotocin‑induced diabetic

retinopathy mouse model. Graefes Arch Clin Exp Ophthalmol

;260:3553‑63.

Abdul Y, Abdelsaid M, Li W, Webb RC, Sullivan JC, Dong G,

et al. Inhibition of toll‑like receptor‑4 (TLR‑4) improves

neurobehavioral outcomes after acute ischemic stroke in

diabetic rats: Possible role of vascular endothelial TLR‑4. Mol

Neurobiol 2019;56:1607‑17.

Dasu MR, Ramirez S, Isseroff RR. Toll‑like receptors and

diabetes: A therapeutic perspective. Clin Sci 2012;122:203‑14.

Wong FS, Wen L. Toll-like receptors and diabetes. Ann N Y

Acad Sci 2008;1150:123‑32.

Vincent AM, Brownlee M, Russell JW. Oxidative stress and

programmed cell death in diabetic neuropathy. Ann N Y Acad

Sci 2002;959:368‑83.

Muranyi M, Fujioka M, He Q, Han A, Yong G, Csiszar K,

et al. Diabetes activates cell death pathway after transient focal

cerebral ischemia. Diabetes 2003;52:481‑6.

Martin PM, Roon P, Van Ells TK, Ganapathy V, Smith SB.

Death of retinal neurons in streptozotocin‑induced diabetic

mice. Invest Ophthalmol Vis Sci 2004;45:3330‑6.

Li Z‑G, Zhang W, Grunberger G, Sima AA. Hippocampal

neuronal apoptosis in type 1 diabetes. Brain Res

;946:221‑31.

Barber AJ, Gardner TW, Abcouwer SF. The significance of

vascular and neural apoptosis to the pathology of diabetic

retinopathy. Invest Ophthalmol Vis Sci 2011;52:1156‑63.

Sadeghi A, Hami J, Razavi S, Esfandiary E, Hejazi Z. The

effect of diabetes mellitus on apoptosis in hippocampus:

Cellular and molecular aspects. Int J Prev Med 2016;7:57. doi:

4103/2008‑7802.178531.

Kong F‑J, Ma L‑L, Guo J‑J, Xu L‑H, Li Y, Qu S. Endoplasmic

reticulum stress/autophagy pathway is involved in

diabetes‑induced neuronal apoptosis and cognitive decline in

mice. Clin Sci 2018;132:111‑25.

Liu Y‑P, Shao S‑J, Guo H‑D. Schwann cells apoptosis is

induced by high glucose in diabetic peripheral neuropathy. Life

Sci 2020;248:117459. doi: 10.1016/j.lfs. 2020.117459.

Hengartner MO. The biochemistry of apoptosis. Nature

;407:770‑6.

Cheng H, Gang X, Liu Y, Wang G, Zhao X, Wang G.

Mitochondrial dysfunction plays a key role in the development

of neurodegenerative diseases in diabetes. Am J Physiol

Endocrinol Metab 2020;318:E750‑E64.

Nazarnezhad S, Rahmati M, Shayannia A, Abbasi Z, Salehi M,

Khaksari M. Nesfatin‑1 protects PC12 cells against high

glucose‑induced cytotoxicity via inhibiting oxidative stress,

autophagy and apoptosis. Neurotoxicology 2019;74:196‑202.

Bhattacharya D, Mukhopadhyay M, Bhattacharyya M,

Karmakar P. Is autophagy associated with diabetes mellitus and

its complications? A review. EXCLI J 2018;17:709‑20.

Wang X, Zhang B, Xia R, Jia Q. Inflammation, apoptosis and

autophagy as critical players in vascular dementia. Eur Rev

Med Pharmacol Sci 2020;24:9601‑14.

Schubert M, Gautam D, Surjo D, Ueki K, Baudler S, Schubert D,

et al. Role for neuronal insulin resistance in neurodegenerative

diseases. Proc Natl Acad Sci 2004;101:3100‑5.

Liu J, Liu L, Han YS, Yi J, Guo C, Zhao HQ, et al. The

molecular mechanism underlying mitophagy‐mediated

hippocampal neuron apoptosis in diabetes‐related depression.

J Cell Mol Med 2021;25:7342‑53.

Zhang X, Xu L, He D, Ling S. Endoplasmic reticulum

stress‑mediated hippocampal neuron apoptosis involved

in diabetic cognitive impairment. Biomed Res Int

;2013:924327. doi: 10.1155/2013/924327.

Lavrik IN. Systems biology of apoptosis signaling networks.

Curr Opin Biotechnol 2010;21:551‑5.

Yu P, Zhang X, Liu N, Tang L, Peng C, Chen X. Pyroptosis:

Mechanisms and diseases. Signal Transduct Target Ther

;6:1‑21. doi: 10.1038/s41392‑021‑00507‑5.

Bergsbaken T, Fink SL, Cookson BT. Pyroptosis: Host cell

death and inflammation. Nat Rev Microbiol 2009;7:99‑109.

Zhang X, Wang N, Barile GR, Bao S, Gillies M. Diabetic

retinopathy: Neuron protection as a therapeutic target. Int J

Biochem Cell Biol 2013;45:1525‑9.

Chen X, Famurewa AC, Tang J, Olatunde OO, Olatunji OJ.

Hyperoside attenuates neuroinflammation, cognitive

impairment and oxidative stress via suppressing TNF‑α/NF‑κB/

caspase‑3 signaling in type 2 diabetes rats. Nutr Neurosci

;25:1774‑84.

Park S‑H, Park J‑W, Park S‑J, Kim K‑Y, Chung J‑W,

Chun M‑H, et al. Apoptotic death of photoreceptors in the

streptozotocin‑induced diabetic rat retina. Diabetologia

;46:1260‑8.

Shamsaei N, Abdi H, Shamsi M. The Effect of a continuous

training on necrosis and apoptosis changes in the hippocampus

of diabetic rats. J Ilam Univ Med Sci 2017;25:1. doi: ‎10.29252/

sjimu. 25.1.1.

Yang J‑S, Lu C‑C, Kuo S‑C, Hsu Y‑M, Tsai S‑C, Chen S‑Y,

et al. Autophagy and its link to type II diabetes mellitus.

Biomedicine 2017;7:8. doi: 10.1051/bmdcn/2017070201.

Kimura N. Diabetes mellitus induces Alzheimer’s disease

pathology: Histopathological evidence from animal models. Int

J Mol Sci 2016;17:503.

Martins IJ. Nutritional and genotoxic stress contributes to

diabetes and neurodegenerative diseases such as Parkinson’s and

Alzheimer’s diseases. Front Endocrinol (Lausanne) 2018;9:196.

doi: 10.3389/fendo.2018.00196.

Pagano G, Polychronis S, Wilson H, Giordano B, Ferrara N,

Niccolini F, et al. Diabetes mellitus and Parkinson disease.

Neurology 2018;90:e1654‑62.

Ogawa W, Sakaguchi K. Euglycemic diabetic ketoacidosis

induced by SGLT2 inhibitors: Possible mechanism and

contributing factors. J Diabetes Investig 2016;7:135‑8.

Sha W, Wen S, Chen L, Xu B, Lei T, Zhou L. The role of

SGLT2 inhibitor on the treatment of diabetic retinopathy.

J Diabetes Res 2020;2020:8867875. doi: 10.1155/2020/8867875.

Karami F, Jamaati H, Coleman‑Fuller N, Zeini MS, Hayes AW,

Gholami M, et al. Is metformin neuroprotective against diabetes

mellitus‑induced neurodegeneration? An updated graphical

review of molecular basis. Pharmacol Rep 2023;75:511‑43.

Hsia DS, Grove O, Cefalu WT. An update on SGLT2 inhibitors

for the treatment of diabetes mellitus. Curr Opin Endocrinol

Diabetes Obes 2017;24:73.

Dong D, Lou P, Wang J, Zhang P, Sun J, Chang G, et al.

Interaction of sleep quality and anxiety on quality of life in

individuals with type 2 diabetes mellitus. Health Qual Life

Outcomes. 2020;18:1‑7.

Shinkov A, Borissova A‑M, Kovatcheva R, Vlahov J,

Dakovska L, Atanassova I, et al. Increased prevalence of

depression and anxiety among subjects with metabolic syndrome

and known type 2 diabetes mellitus–A population‑based study.

Postgrad Med 2018;130:251‑7.

Muscatello M, Troili GM, Pandolfo G, Mento C, Gallo G,

Lanza G, et al. Depression, anxiety and anger in patients with

type 1 diabetes mellitus. Recenti Prog Med 2017;108:77‑82.

Amiri S, Behnezhad S. Diabetes and anxiety symptoms:

A systematic review and meta‑analysis. Int J Psychiatry Med

:0091217419837407. doi: 10.1177/0091217419837407.

Tang Y, Yu C, Wu J, Chen H, Zeng Y, Wang X, et al. Lychee

seed extract protects against neuronal injury and improves

cognitive function in rats with type II diabetes mellitus with

cognitive impairment. Int J Mol Med 2018;41:251‑63.

Li W, Huang E, Gao S. Type 1 diabetes mellitus and

cognitive impairments: A systematic review. J Alzheimer’s Dis

;57:29‑36.

Clar C, Gill JA, Waugh N. Systematic review of SGLT2 receptor

inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open

;2:e001007. doi: 10.1136/bmjopen‑2012‑001007.

Herat LY, Matthews VB, Rakoczy PE, Carnagarin R,

Schlaich M. Focusing on sodium glucose cotransporter‑2

and the sympathetic nervous system: Potential impact in

diabetic retinopathy. Int J Endocrinol. 2018;2018:9254126.

doi: 10.1155/2018/9254126.

Hemmingsen B, Krogh J, Metzendorf MI, Richter B. Sodiumglucose cotransporter (SGLT) 2 inhibitors for prevention or

delay of type 2 diabetes mellitus and its associated complications

in people at risk for the development of type 2 diabetes

mellitus. Cochrane Database Syst Rev 2016;4:CD012106. doi:

1002/14651858.CD012106.pub2.

Ferrannini E, Solini A. SGLT2 inhibition in diabetes mellitus:

Rationale and clinical prospects. Nat Rev Endocrinol

;8:495‑502.

Chao EC, Henry RR. SGLT2 inhibition — A novel strategy for

diabetes treatment. Nat Rev Drug Discov 2010;9:551‑9.

Filippas‑Ntekouan S, Filippatos TD, Elisaf MS. SGLT2

inhibitors: Are they safe? Postgrad Med 2018;130:72‑82.

Feinkohl I, Price JF, Strachan MW, Frier BM. The impact of

diabetes on cognitive decline: Potential vascular, metabolic, and

psychosocial risk factors. Alzheimers Res Ther 2015;7:1‑22.

Oelze M, Kröller‑Schön S, Welschof P, Jansen T, Hausding M,

Mikhed Y, et al. The sodium‑glucose co‑transporter 2 inhibitor

empagliflozin improves diabetes‑induced vascular dysfunction

in the streptozotocin diabetes rat model by interfering with

oxidative stress and glucotoxicity. PloS One 2014;9:e112394.

doi: 10.1371/journal.pone.0112394.

Lin B, Koibuchi N, Hasegawa Y, Sueta D, Toyama K,

Uekawa K, et al. 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.

Amin EF, Rifaai RA, Abdel‐latif RG. Empagliflozin attenuates

transient cerebral ischemia/reperfusion injury in hyperglycemic

rats via repressing oxidative–inflammatory–apoptotic pathway.

Fundam Clin Pharmacol 2020;34:548‑58.

Sa‑Nguanmoo P, Tanajak P, Kerdphoo S, Jaiwongkam T,

Pratchayasakul W, Chattipakorn N, 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

;333:43‑50.

Chen C, Turnbull DM, Reeve AK. Mitochondrial dysfunction in

Parkinson’s disease—cause or consequence? Biology 2019;8:38.

Arab HH, Safar MM, Shahin NN. Targeting ROS‑dependent

AKT/GSK‑3β/NF‑κB and DJ‑1/Nrf2 pathways by dapagliflozin

attenuates neuronal injury and motor dysfunction in

rotenone‑induced Parkinson’s disease rat model. ACS Chem

Neurosci 2021;12:689‑703.

El Mouhayyar C, Riachy R, Khalil AB, Eid A, Azar S. SGLT2

inhibitors, GLP‑1 agonists, and DPP‑4 inhibitors in diabetes

and microvascular complications: A review. Int J Endocrinol

;2020:1762164. doi: 10.1155/2020/1762164.

Lin K‑J, Wang T‑J, Chen S‑D, Lin K‑L, Liou C‑W,

Lan M‑Y, et al. Two birds one stone: The neuroprotective

effect of antidiabetic agents on Parkinson disease—focus on

sodium‑glucose cotransporter 2 (SGLT2) inhibitors. Antioxidants

;10:1935. doi: 10.3390/antiox10121935.

Rizzo MR, Di Meo I, Polito R, Auriemma MC, Gambardella A,

di Mauro G, et al. Cognitive impairment and type 2 diabetes

mellitus: Focus of SGLT2 inhibitors treatment. Pharmacol Res

;176:106062. doi: 10.1016/j.phrs.2022.106062.

Theofilis P, Sagris M, Oikonomou E, Antonopoulos AS,

Siasos G, Tsioufis K, et al. The impact of SGLT2 inhibitors

on inflammation: A systematic review and meta‑analysis of

studies in rodents. Int Immunopharmacol 2022;111:109080.

doi: 10.1016/j.intimp.2022.109080.

Naznin F, Sakoda H, Okada T, Tsubouchi H, Waise TZ,

Arakawa K, et al. Canagliflozin, a sodium glucose cotransporter

inhibitor, attenuates obesity‑induced inflammation in the

nodose ganglion, hypothalamus, and skeletal muscle of mice.

Eur J Pharmacol 2017;794:37‑44.

Steven S, Oelze M, Hanf A, Kröller‑Schön S, Kashani F,

Roohani S, et al. The SGLT2 inhibitor empagliflozin improves

the primary diabetic complications in ZDF rats. Redox Biol

;13:370‑85.

Pirklbauer M, Sallaberger S, Staudinger P, Corazza U, Leierer J,

Mayer G, et al. Empagliflozin inhibits IL‑1β‑mediated

inflammatory response in human proximal tubular cells. Int J

Mol Sci 2021;22:5089. doi: 10.3390/ijms22105089.

Muhammad RN, Ahmed LA, Abdul Salam RM, Ahmed KA,

Attia AS. Crosstalk among NLRP3 inflammasome, ET BR

signaling, and miRNAs in stress‑induced depression‑like

behavior: A modulatory role for SGLT2 inhibitors.

Neurotherapeutics 2021;18:2664‑2681.

Wiciński M, Wódkiewicz E, Górski K, Walczak M,

Malinowski B. Perspective of SGLT2 inhibition in treatment

of conditions connected to neuronal loss: Focus on Alzheimer’s

disease and ischemia‑related brain injury. Pharmaceuticals

;13:379. doi: 10.3390/ph 13110379.

Pawlos A, Broncel M, Woźniak E, Gorzelak‑Pabiś P.

Neuroprotective effect of SGLT2 inhibitors. Molecules

;26:7213. doi: 10.3390/molecules26237213.

Hierro‑Bujalance C, Infante‑Garcia C, Del Marco A, Herrera M,

Carranza‑Naval MJ, Suarez J, et al. Empagliflozin reduces

vascular damage and cognitive impairment in a mixed murine

model of Alzheimer’s disease and type 2 diabetes. Alzheimers

Res Ther 2020;12:1‑13.

Abdel‑Latif RG, Rifaai RA, Amin EF. Empagliflozin alleviates

neuronal apoptosis induced by cerebral ischemia/reperfusion

injury through HIF‑1α/VEGF signaling pathway. Arch Pharm

Res 2020;43:514‑25.

Freeman LR, Haley‑Zitlin V, Rosenberger DS, Granholm A‑C.

Damaging effects of a high‑fat diet to the brain and cognition: A review of proposed mechanisms. Nutr Neurosci

;17:241‑51.

Palaiodimou L, Lioutas V‑A, Lambadiari V, Paraskevas GP,

Voumvourakis K, Tsivgoulis G. Glycemia management in acute

ischemic stroke: Current concepts and novel therapeutic targets.

Postgrad Med 2019;131:423‑37.

El‑Sahar AE, Rastanawi AA, El‑Yamany MF, Saad MA.

Dapagliflozin improves behavioral dysfunction of Huntington’s

disease in rats via inhibiting apoptosis‑related glycolysis. Life

Sci 2020;257:118076.

Ibrahim WW, Kamel AS, Wahid A, Abdelkader NF.

Dapagliflozin as an autophagic enhancer via LKB1/AMPK/

SIRT1 pathway in ovariectomized/d‑galactose Alzheimer’s rat

model. Inflammopharmacology 2022;30:2505‑20.

Madhusudhanan J, Suresh G, Devanathan V. Neurodegeneration

in type 2 diabetes: Alzheimer’s as a case study. Brain Behav

;10:e01577. doi: 10.1002/brb3.1577.

Panahi Y, Khalili N, Sahebi E, Namazi S, Karimian MS,

Majeed M, et al. Antioxidant effects of curcuminoids in patients

with type 2 diabetes mellitus: A randomized controlled trial.

Inflammopharmacology 2017;25:25‑31.

Hamed SA. Brain injury with diabetes mellitus: Evidence,

mechanisms and treatment implications. Expert Rev Clin

Pharmacol 2017;10:409‑28.

Dobi A, Rosanaly S, Devin A, Baret P, Meilhac O, Harry GJ,

et al. Advanced glycation end‑products disrupt brain

microvascular endothelial cell barrier: The role of mitochondria

and oxidative stress. Microvasc Res 2021;133:104098.

doi: 10.1016/j.mvr. 2020.104098.

Venkat P, Chopp M, Chen J. Blood–brain barrier disruption,

vascular impairment, and ischemia/reperfusion damage

in diabetic stroke. J Am Heart Assoc 2017;6:e005819.

doi: 10.1161/JAHA.117.005819.

Hasan R, Lasker S, Hasan A, Zerin F, Zamila M, Parvez F,

et al. Canagliflozin ameliorates renal oxidative stress and

inflammation by stimulating AMPK–Akt–eNOS pathway

in the isoprenaline‑induced oxidative stress model. Sci Rep

;10:14659. doi: 10.1038/s41598‑020‑71599‑2.

Zhong Y, Zhu Y, He T, Li W, Li Q, Miao Y. Brain‑derived

neurotrophic factor inhibits hyperglycemia‑induced apoptosis

and downregulation of synaptic plasticity‑related proteins in

hippocampal neurons via the PI3K/Akt pathway. Int J Mol Med

;43:294‑304.

Moreira PI, Santos MS, Seiça R, Oliveira CR. Brain

mitochondrial dysfunction as a link between Alzheimer’s

disease and diabetes. J Neurol Sci 2007;257:206‑14.

Shibusawa R, Yamada E, Okada S, Nakajima Y, Bastie CC,

Maeshima A, et al. Dapagliflozin rescues endoplasmic reticulum

stress‑mediated cell death. Sci Rep 2019;9:9887.

Faridvand Y, Kazemzadeh H, Vahedian V, Mirzajanzadeh P,

Nejabati HR, Safaie N, et al. Dapagliflozin attenuates high

glucose-induced endothelial cell apoptosis and inflammation

through AMPK/SIRT1 activation. Clin Exp Pharmacol Physiol

;49:643‑51.

Avgerinos KI, Mullins RJ, Vreones M, Mustapic M,

Chen Q, Melvin D, et al. Empagliflozin induced ketosis,

upregulated IGF‑1/insulin receptors and the canonical insulin

signaling pathway in neurons, and decreased the excitatory

neurotransmitter glutamate in the brain of non‑diabetics. Cells

;11:3372. doi: 10.3390/cells11213372.

Larsen EL, Andersen A, Kjær LK, Eickhoff MK,

Frimodt‑Møller M, Persson F, et al. Effects of two‑and

twelve‑weeks sodium‑glucose cotransporter 2 inhibition on

DNA and RNA oxidation: Two randomized, placebo‑controlled

trials. Free Radic Res 2023;57:140‑51.

Guerrero‑Castillo AP, Sigfrido Benitez‑Renteria A,

Cuevas‑Ramos D, López‑Carrasco G, Silva A, Brito GX,

et al. 885‑P: Impact on glycaemic variability in newly onset

T2DM patients initiating dapagliflozin plus metformin vs.

metformin alone, a randomized open label clinical study—The

MAGNNIFY trial. Diabetes 2023;72(Suppl 1). doi: 10.2337/

db23‑885‑P