Metformin: A Growing Journey from Glycemic Control to the Treatment of Alzheimer’s Disease and Depression

Mohamed       El Massry; Lynn    M.    Alaeddine; Leen       Ali; Celine       Saad; Assaad    A.    Eid
doi:10.2174/0929867327666200908114902
Abstract

Metabolic stress, transduced as an altered cellular redox and energy status, presents as the main culprit in many diseases, including diabetes. However, its role in the pathology of neurological disorders is still not fully elucidated. Metformin, a biguanide compound, is an FDA approved antidiabetic drug generally used for the treatment of type 2 diabetes. The recently described wide spectrum of action executed by this drug suggests a potential therapeutic benefit in a panoply of disorders. Current studies imply that metformin could play a neuroprotective role by reversing hallmarks of brain injury (metabolic dysfunction, neuronal dystrophy and cellular loss), in addition to cognitive and behavioral alterations that accompany the onset of certain brain diseases such as Alzheimer’s disease (AD) and depression. However, the mechanisms by which metformin exerts its protective effect in neurodegenerative disorders are not yet fully elucidated. The aim of this review is to reexamine the mechanisms through which metformin performs its function while concentrating on its effect on reestablishing homeostasis in a metabolically disturbed milieu. We will also highlight the importance of metabolic stress, not only as a component of many neurological disorders, but also as a primary driving force for neural insult. Of interest, we will explore the involvement of metabolic stress in the pathobiology of AD and depression. The derangement in major metabolic pathways, including AMPK, insulin and glucose transporters, will be explored and the potential therapeutic effects of metformin administration on the reversal of brain injury in such metabolism dependent diseases will be exposed.
Keywords: Metabolic Stress, Metformin, Alzheimer's Disease, Depression, AMPK Pathway, Insulin, Glucose Transporters.
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[1] 
Chen, Y.; Zhao, X.; Wu, H. Metabolic stress and cardiovascular disease in diabetes mellitus: the role of protein o-glcnac modification. Arterioscler. Thromb. Vasc. Biol.,  2019, 39(10), 1911-1924.
[http://dx.doi.org/10.1161/ATVBAHA.119.312192] [PMID: 31462094] 
[2] 
Singh, H. Islet compensation in metabolic stress: lessons from animal models. Curr. Diabetes Rev.,  2016, 12(4), 315-321.
[http://dx.doi.org/10.2174/1573399811666150617161915] [PMID: 26081679] 
[3] 
Wellen, K.E.; Thompson, C.B. Cellular metabolic stress: considering how cells respond to nutrient excess. Mol. Cell,  2010, 40(2), 323-332.
[http://dx.doi.org/10.1016/j.molcel.2010.10.004] [PMID: 20965425] 
[4] 
Nolan, C.J.; Ruderman, N.B.; Kahn, S.E.; Pedersen, O.; Prentki, M. Insulin resistance as a physiological defense against metabolic stress: implications for the management of subsets of type 2 diabetes. Diabetes,  2015, 64(3), 673-686.
[http://dx.doi.org/10.2337/db14-0694] [PMID: 25713189] 
[5] 
Giannarelli, R.; Aragona, M.; Coppelli, A.; Del Prato, S. educing insulin resistance with metformin: the evidence today Diabetes Metab.,  2003, 29(4 pt. 2), 6S28-26S35.
[http://dx.doi.org/10.1016/S1262-3636(03)72785-2] [PMID: 14502098] 
[6] 
Camandola, S.; Mattson, M.P. Brain metabolism in health, aging, and neurodegeneration. EMBO J.,  2017, 36(11), 1474-1492.
[http://dx.doi.org/10.15252/embj.201695810] [PMID: 28438892] 
[7] 
De Felice, F.G.; Lourenco, M.V. Brain metabolic stress and neuroinflammation at the basis of cognitive impairment in Alzheimer’s disease. Front. Aging Neurosci.,  2015, 7, 94.
[http://dx.doi.org/10.3389/fnagi.2015.00094] [PMID: 26042036] 
[8] 
Hryhorczuk, C.; Sharma, S.; Fulton, S.E. Metabolic disturbances connecting obesity and depression. Front. Neurosci.,  2013, 7, 177.
[http://dx.doi.org/10.3389/fnins.2013.00177] [PMID: 24109426] 
[9] 
De Felice, F.G. Alzheimer’s disease and insulin resistance: translating basic science into clinical applications. J. Clin. Invest.,  2013, 123(2), 531-539.
[http://dx.doi.org/10.1172/JCI64595] [PMID: 23485579] 
[10] 
Moulton, C.D.; Pickup, J.C.; Ismail, K. The link between depression and diabetes: the search for shared mechanisms. Lancet Diabetes Endocrinol.,  2015, 3(6), 461-471.
[http://dx.doi.org/10.1016/S2213-8587(15)00134-5] [PMID: 25995124] 
[11] 
Vial, G.; Detaille, D.; Guigas, B. Role of mitochondria in the mechanism (s) of action of metformin. Front. Endocrinol. (Lausanne),  2019, 10, 294.
[http://dx.doi.org/10.3389/fendo.2019.00294] [PMID: 31133988] 
[12] 
Zhou, G.; Myers, R.; Li, Y.; Chen, Y.; Shen, X.; Fenyk-Melody, J.; Wu, M.; Ventre, J.; Doebber, T.; Fujii, N.; Musi, N.; Hirshman, M.F.; Goodyear, L.J.; Moller, D.E. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest.,  2001, 108(8), 1167-1174.
[http://dx.doi.org/10.1172/JCI13505] [PMID: 11602624] 
[13] 
Eid, A.A.; Ford, B.M.; Block, K.; Kasinath, B.S.; Gorin, Y.; Ghosh-Choudhury, G.; Barnes, J.L.; Abboud, H.E. AMP-activated protein kinase (AMPK) negatively regulates Nox4-dependent activation of p53 and epithelial cell apoptosis in diabetes. J. Biol. Chem.,  2010, 285(48), 37503-37512.
[http://dx.doi.org/10.1074/jbc.M110.136796] [PMID: 20861022] 
[14] 
Anwar, M.A.; Kheir, W.A.; Eid, S.; Fares, J.; Liu, X.; Eid, A.H.; Eid, A.A. Colorectal and prostate cancer risk in diabetes: metformin, an actor behind the scene. J. Cancer,  2014, 5(9), 736-744.
[http://dx.doi.org/10.7150/jca.9726] [PMID: 25368673] 
[15] 
Foretz, M.; Taleux, N.; Guigas, B.; Horman, S.; Beauloye, C.; Andreelli, F.; Bertrand, L.; Viollet, B. [Regulation of energy
metabolism by AMPK: a novel therapeutic approach
for the treatment of metabolic and cardiovascular diseases]. Med. Sci. (Paris),  2006, 22(4), 381-388.
[http://dx.doi.org/10.1051/medsci/2006224381] [PMID: 16597407] 
[16] 
Mroueh, F.M.; Noureldein, M.; Zeidan, Y.H.; Boutary, S.; Irani, S.A.M.; Eid, S.; Haddad, M.; Barakat, R.; Harb, F.; Costantine, J.; Kanj, R.; Sauleau, E.A.; Ouhtit, A.; Azar, S.T.; Eid, A.H.; Eid, A.A. Unmasking the interplay between mTOR and Nox4: novel insights into the mechanism connecting diabetes and cancer. FASEB J.,  2019, 33(12), 14051-14066.
[http://dx.doi.org/10.1096/fj.201900396RR] [PMID: 31661292] 
[17] 
Geagea, A.G.; Rizzo, M.; Jurjus, A.; Cappello, F.; Leone, A.; Tomasello, G.; Gracia, C.; Al Kattar, S.; Massaad-Massade, L.; Eid, A. A novel therapeutic approach to colorectal cancer in diabetes: role of metformin and rapamycin. Oncotarget,  2019, 10(13), 1284-1305.
[http://dx.doi.org/10.18632/oncotarget.26641] [PMID: 30863490] 
[18] 
Emerling, B.M.; Weinberg, F.; Snyder, C.; Burgess, Z.; Mutlu, G.M.; Viollet, B.; Budinger, G.R.; Chandel, N.S. Hypoxic activation of AMPK is dependent on mitochondrial ROS but independent of an increase in AMP/ATP ratio. Free Radic. Biol. Med.,  2009, 46(10), 1386-1391.
[http://dx.doi.org/10.1016/j.freeradbiomed.2009.02.019] [PMID: 19268526] 
[19] 
Hardie, D.G.; Carling, D. The AMP-activated protein kinase--fuel gauge of the mammalian cell? Eur. J. Biochem.,  1997, 246(2), 259-273.
[http://dx.doi.org/10.1111/j.1432-1033.1997.00259.x] [PMID: 9208914] 
[20] 
Mitchelhill, K.I.; Stapleton, D.; Gao, G.; House, C.; Michell, B.; Katsis, F.; Witters, L.A.; Kemp, B.E. Mammalian AMP-activated protein kinase shares structural and functional homology with the catalytic domain of yeast Snf1 protein kinase. J. Biol. Chem.,  1994, 269(4), 2361-2364.
[PMID: 7905477] 
[21] 
Chowdhury, S.K.R.; Dobrowsky, R.T.; Fernyhough, P. Nutrient excess and altered mitochondrial proteome and function contribute to neurodegeneration in diabetes. Mitochondrion,  2011, 11(6), 845-854.
[http://dx.doi.org/10.1016/j.mito.2011.06.007] [PMID: 21742060] 
[22] 
Herzig, S.; Shaw, R.J. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol.,  2018, 19(2), 121-135.
[http://dx.doi.org/10.1038/nrm.2017.95] [PMID: 28974774] 
[23] 
Smiley, D.; Umpierrez, G. Metformin/rosiglitazone combination pill (Avandamet) for the treatment of patients with Type 2 diabetes. Expert Opin. Pharmacother.,  2007, 8(9), 1353-1364.
[http://dx.doi.org/10.1517/14656566.8.9.1353] [PMID: 17563269] 
[24] 
Rena, G.; Hardie, D.G.; Pearson, E.R. The mechanisms of action of metformin. Diabetologia,  2017, 60(9), 1577-1585.
[http://dx.doi.org/10.1007/s00125-017-4342-z] [PMID: 28776086] 
[25] 
Hundal, R.S.; Krssak, M.; Dufour, S.; Laurent, D.; Lebon, V.; Chandramouli, V.; Inzucchi, S.E.; Schumann, W.C.; Petersen, K.F.; Landau, B.R.; Shulman, G.I. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes,  2000, 49(12), 2063-2069.
[http://dx.doi.org/10.2337/diabetes.49.12.2063] [PMID: 11118008] 
[26] 
Gunton, J.E.; Delhanty, P.J.; Takahashi, S.; Baxter, R.C. Metformin rapidly increases insulin receptor activation in human liver and signals preferentially through insulin-receptor substrate-2. J. Clin. Endocrinol. Metab.,  2003, 88(3), 1323-1332.
[http://dx.doi.org/10.1210/jc.2002-021394] [PMID: 12629126] 
[27] 
Cusi, K.; Defronzo, R.A. Metformin: a review of its metabolic effects. Diabetes Rev. (Alex.),  1998, 6(2), 89-131.
[28] 
Johnson, A.B.; Webster, J.M.; Sum, C-F.; Heseltine, L.; Argyraki, M.; Cooper, B.G.; Taylor, R. The impact of metformin therapy on hepatic glucose production and skeletal muscle glycogen synthase activity in overweight type II diabetic patients. Metabolism,  1993, 42(9), 1217-1222.
[http://dx.doi.org/10.1016/0026-0495(93)90284-U] [PMID: 8412779] 
[29] 
Klip, A.; Leiter, L.A. Cellular mechanism of action of metformin. Diabetes Care,  1990, 13(6), 696-704.
[http://dx.doi.org/10.2337/diacare.13.6.696] [PMID: 2162756] 
[30] 
Rossetti, L.; DeFronzo, R.A.; Gherzi, R.; Stein, P.; Andraghetti, G.; Falzetti, G.; Shulman, G.I.; Klein-Robbenhaar, E.; Cordera, R. Effect of metformin treatment on insulin action in diabetic rats: in vivo and in vitro correlations. Metabolism,  1990, 39(4), 425-435.
[http://dx.doi.org/10.1016/0026-0495(90)90259-F] [PMID: 2157941] 
[31] 
Muntoni, S.; Reaven, G.M. Metformin and fatty acids. Diabetes Care,  1999, 22(1), 179-180.
[http://dx.doi.org/10.2337/diacare.22.1.179] [PMID: 10333929] 
[32] 
Perriello, G.; Misericordia, P.; Volpi, E.; Santucci, A.; Santucci, C.; Ferrannini, E.; Ventura, M.M.; Santeusanio, F.; Brunetti, P.; Bolli, G.B. Acute antihyperglycemic mechanisms of metformin in NIDDM. Evidence for suppression of lipid oxidation and hepatic glucose production. Diabetes,  1994, 43(7), 920-928.
[http://dx.doi.org/10.2337/diab.43.7.920] [PMID: 8013758] 
[33] 
Patanè, G.; Piro, S.; Rabuazzo, A.M.; Anello, M.; Vigneri, R.; Purrello, F. Metformin restores insulin secretion altered by chronic exposure to free fatty acids or high glucose: a direct metformin effect on pancreatic beta-cells. Diabetes,  2000, 49(5), 735-740.
[http://dx.doi.org/10.2337/diabetes.49.5.735] [PMID: 10905481] 
[34] 
Vancura, A.; Bu, P.; Bhagwat, M.; Zeng, J.; Vancurova, I. Metformin as an anticancer agent. Trends Pharmacol. Sci.,  2018, 39(10), 867-878.
[http://dx.doi.org/10.1016/j.tips.2018.07.006] [PMID: 30150001] 
[35] 
Eid, A.A.; Ford, B.M.; Bhandary, B.; de Cassia Cavaglieri, R.; Block, K.; Barnes, J.L.; Gorin, Y.; Choudhury, G.G.; Abboud, H.E. Mammalian target of rapamycin regulates Nox4-mediated podocyte depletion in diabetic renal injury. Diabetes,  2013, 62(8), 2935-2947.
[http://dx.doi.org/10.2337/db12-1504] [PMID: 23557706] 
[36] 
Kelly, B.; Tannahill, G.M.; Murphy, M.P.; O’Neill, L.A. Metformin inhibits the production of reactive oxygen species from NADH: ubiquinone oxidoreductase to limit induction of interleukin-1β (IL-1β) and boosts interleukin-10 (IL-10) in lipopolysaccharide (LPS)-activated macrophages. J. Biol. Chem.,  2015, 290(33), 20348-20359.
[http://dx.doi.org/10.1074/jbc.M115.662114] [PMID: 26152715] 
[37] 
Feigin, V.L.; Nichols, E.; Alam, T.; Bannick, M.S.; Beghi, E.; Blake, N.; Culpepper, W.J.; Dorsey, E.R.; Elbaz, A.; Ellenbogen, R.G. GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol.,  2019, 18(5), 459-480.
[http://dx.doi.org/10.1016/S1474-4422(18)30499-X] [PMID: 30879893] 
[38] 
Willians, L.; Wilkins. Professional Guide to Diseases.,  9th Ed.; Wolters Kluwer, Netherlands, 2009.
[39] 
Mattson, M.P.; Duan, W.; Chan, S.L.; Camandola, S. Par-4: an emerging pivotal player in neuronal apoptosis and neurodegenerative disorders. J. Mol. Neurosci.,  1999, 13(1-2), 17-30.
[http://dx.doi.org/10.1385/JMN:13:1-2:17] [PMID: 10691289] 
[40] 
Domise, M. Vingtdeux, V. AMPK in neurodegenerative
diseases. In: AMP-activated Protein Kinase,  Cordero, M.;
Viollet, B. Eds.; Springer, New York, 2016, Vol. 107, pp.
153-177.
[http://dx.doi.org/10.1007/978-3-319-43589-3_7] 
[41] 
Pérez Ortiz J.M.; Orr, H.T. Spinocerebellar ataxia type 1:
molecular mechanisms of neurodegeneration and preclinical
studies. In: Polyglutamine Disorders. Advances in Experimental
Medicine and Biology,  Nóbrega, C.; Pereira de
Almeida, L. Eds.; Springer,: New York, 2018, 1049, pp.135-
145.
[http://dx.doi.org/10.1007/978-3-319-71779-1_6] 
[42] 
Domise, M.; Didier, S.; Marinangeli, C.; Zhao, H.; Chandakkar, P.; Buée, L.; Viollet, B.; Davies, P.; Marambaud, P.; Vingtdeux, V. AMP-activated protein kinase modulates tau phosphorylation and tau pathology in vivo. Sci. Rep.,  2016, 6, 26758.
[http://dx.doi.org/10.1038/srep26758] [PMID: 27230293] 
[43] 
Jiang, P.; Gan, M.; Ebrahim, A.S.; Castanedes-Casey, M.; Dickson, D.W.; Yen, S-H.C. Adenosine monophosphate-activated protein kinase overactivation leads to accumulation of α-synuclein oligomers and decrease of neurites. Neurobiol. Aging,  2013, 34(5), 1504-1515.
[http://dx.doi.org/10.1016/j.neurobiolaging.2012.11.001] [PMID: 23200460] 
[44] 
Ju, T-C.; Chen, H-M.; Lin, J-T.; Chang, C-P.; Chang, W-C.; Kang, J-J.; Sun, C-P.; Tao, M-H.; Tu, P-H.; Chang, C.; Dickson, D.W.; Chern, Y. Nuclear translocation of AMPK-α1 potentiates striatal neurodegeneration in Huntington’s disease. J. Cell Biol.,  2011, 194(2), 209-227.
[http://dx.doi.org/10.1083/jcb.201105010] [PMID: 21768291] 
[45] 
Yuan, S.Y.; Liu, J.; Zhou, J.; Lu, W.; Zhou, H.Y.; Long, L.H.; Hu, Z.L.; Ni, L.; Wang, Y.; Chen, J.G.; Wang, F. AMPK Mediates Glucocorticoids Stress-Induced Downregulation of the Glucocorticoid Receptor in Cultured Rat Prefrontal Cortical Astrocytes. PLoS One,  2016, 11(8)e0159513
[http://dx.doi.org/10.1371/journal.pone.0159513] [PMID: 27513844] 
[46] 
Alzheimer’s Association. 2016 Alzheimer’s disease facts and figures. Alzheimers Dement.,  2016, 12(4), 459-509.
[http://dx.doi.org/10.1016/j.jalz.2016.03.001] [PMID: 27570871] 
[47] 
Bekris, L.M.; Yu, C-E.; Bird, T.D.; Tsuang, D.W. Genetics of Alzheimer disease. J. Geriatr. Psychiatry Neurol.,  2010, 23(4), 213-227.
[http://dx.doi.org/10.1177/0891988710383571] [PMID: 21045163] 
[48] 
de la Monte, S.M.; Tong, M. Brain metabolic dysfunction at the core of Alzheimer’s disease. Biochem. Pharmacol.,  2014, 88(4), 548-559.
[http://dx.doi.org/10.1016/j.bcp.2013.12.012] [PMID: 24380887] 
[49] 
Zhang, C.; Fang, X.; Yao, P.; Mao, Y.; Cai, J.; Zhang, Y.; Chen, M.; Fan, W.; Tang, W.; Song, L. Metabolic adverse effects of olanzapine on cognitive dysfunction: A possible relationship between BDNF and TNF-alpha. Psychoneuroendocrinology,  2017, 81, 138-143.
[http://dx.doi.org/10.1016/j.psyneuen.2017.04.014] [PMID: 28477447] 
[50] 
Hoyer, S. Brain glucose and energy metabolism abnormalities in sporadic Alzheimer disease. Causes and consequences: an update. Exp. Gerontol.,  2000, 35(9-10), 1363-1372.
[http://dx.doi.org/10.1016/S0531-5565(00)00156-X] [PMID: 11113614] 
[51] 
Lester-Coll, N.; Rivera, E.J.; Soscia, S.J.; Doiron, K.; Wands, J.R.; de la Monte, S.M. Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer’s disease. J. Alzheimers Dis.,  2006, 9(1), 13-33.
[http://dx.doi.org/10.3233/JAD-2006-9102] [PMID: 16627931] 
[52] 
Weinstock, M.; Shoham, S. Rat models of dementia based on reductions in regional glucose metabolism, cerebral blood flow and cytochrome oxidase activity. J. Neural Transm. (Vienna),  2004, 111(3), 347-366.
[http://dx.doi.org/10.1007/s00702-003-0058-y] [PMID: 14991459] 
[53] 
Hoyer, S.; Lannert, H.; Nöldner, M.; Chatterjee, S.S. Damaged neuronal energy metabolism and behavior are improved by Ginkgo biloba extract (EGb 761). J. Neural Transm. (Vienna),  1999, 106(11-12), 1171-1188.
[http://dx.doi.org/10.1007/s007020050232] [PMID: 10651112] 
[54] 
Frölich, L.; Blum-Degen, D.; Bernstein, H-G.; Engelsberger, S.; Humrich, J.; Laufer, S.; Muschner, D.; Thalheimer, A.; Türk, A.; Hoyer, S.; Zöchling, R.; Boissl, K.W.; Jellinger, K.; Riederer, P. Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease. J. Neural Transm. (Vienna),  1998, 105(4-5), 423-438.
[http://dx.doi.org/10.1007/s007020050068] [PMID: 9720972] 
[55] 
Frölich, L.; Blum-Degen, D.; Riederer, P.; Hoyer, S. A disturbance in the neuronal insulin receptor signal transduction in sporadic Alzheimer’s disease. Ann. N. Y. Acad. Sci.,  1999, 893(1), 290-293.
[http://dx.doi.org/10.1111/j.1749-6632.1999.tb07839.x] [PMID: 10672251] 
[56] 
Abbott, M-A.; Wells, D.G.; Fallon, J.R. The insulin receptor tyrosine kinase substrate p58/53 and the insulin receptor are components of CNS synapses. J. Neurosci.,  1999, 19(17), 7300-7308.
[http://dx.doi.org/10.1523/JNEUROSCI.19-17-07300.1999] [PMID: 10460236] 
[57] 
Furst, A.J.; Lal, R.A. Amyloid-β and glucose metabolism in Alzheimer’s disease. J. Alzheimers Dis.,  2011, 26(s3)(Suppl. 3), 105-116.
[http://dx.doi.org/10.3233/JAD-2011-0066] [PMID: 21971455] 
[58] 
Gasparini, L.; Gouras, G.K.; Wang, R.; Gross, R.S.; Beal, M.F.; Greengard, P.; Xu, H. Stimulation of β-amyloid precursor protein trafficking by insulin reduces intraneuronal β-amyloid and requires mitogen-activated protein kinase signaling. J. Neurosci.,  2001, 21(8), 2561-2570.
[http://dx.doi.org/10.1523/JNEUROSCI.21-08-02561.2001] [PMID: 11306609] 
[59] 
Bhat, R.V.; Budd Haeberlein, S.L.; Avila, J. Glycogen synthase kinase 3: a drug target for CNS therapies. J. Neurochem.,  2004, 89(6), 1313-1317.
[http://dx.doi.org/10.1111/j.1471-4159.2004.02422.x] [PMID: 15189333] 
[60] 
Schubert, M.; Brazil, D.P.; Burks, D.J.; Kushner, J.A.; Ye, J.; Flint, C.L.; Farhang-Fallah, J.; Dikkes, P.; Warot, X.M.; Rio, C.; Corfas, G.; White, M.F. Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. J. Neurosci.,  2003, 23(18), 7084-7092.
[http://dx.doi.org/10.1523/JNEUROSCI.23-18-07084.2003] [PMID: 12904469] 
[61] 
de la Monte, S.M.; Wands, J.R. Alzheimer’s disease is type 3 diabetes-evidence reviewed. J. Diabetes Sci. Technol.,  2008, 2(6), 1101-1113.
[http://dx.doi.org/10.1177/193229680800200619] [PMID: 19885299] 
[62] 
de la Monte, S.M.; Wands, J.R. Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer’s disease. J. Alzheimers Dis.,  2006, 9(2), 167-181.
[http://dx.doi.org/10.3233/JAD-2006-9209] [PMID: 16873964] 
[63] 
Jurcovicova, J. Glucose transport in brain - effect of inflammation. Endocr. Regul.,  2014, 48(1), 35-48.
[http://dx.doi.org/10.4149/endo_2014_01_35] [PMID: 24524374] 
[64] 
Apelt, J.; Mehlhorn, G.; Schliebs, R. Insulin-sensitive GLUT4 glucose transporters are colocalized with GLUT3-expressing cells and demonstrate a chemically distinct neuron-specific localization in rat brain. J. Neurosci. Res.,  1999, 57(5), 693-705.
[http://dx.doi.org/10.1002/(SICI)1097-4547(19990901)57:5<693::AID-JNR11>3.0.CO;2-X] [PMID: 10462693] 
[65] 
Pearson-Leary, J.; McNay, E.C. Novel Roles for the Insulin-Regulated Glucose Transporter-4 in Hippocampally Dependent Memory. J. Neurosci.,  2016, 36(47), 11851-11864.
[http://dx.doi.org/10.1523/JNEUROSCI.1700-16.2016] [PMID: 27881773] 
[66] 
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(10), 12629-12655.
[http://dx.doi.org/10.3390/ijms131012629] [PMID: 23202918] 
[67] 
Harr, S.D.; Simonian, N.A.; Hyman, B.T. Functional alterations in Alzheimer’s disease: decreased glucose transporter 3 immunoreactivity in the perforant pathway terminal zone. J. Neuropathol. Exp. Neurol.,  1995, 54(1), 38-41.
[http://dx.doi.org/10.1097/00005072-199501000-00005] [PMID: 7815078] 
[68] 
Simpson, I.A.; Chundu, K.R.; Davies-Hill, T.; Honer, W.G.; Davies, P. Decreased concentrations of GLUT1 and GLUT3 glucose transporters in the brains of patients with Alzheimer’s disease. Ann. Neurol.,  1994, 35(5), 546-551.
[http://dx.doi.org/10.1002/ana.410350507] [PMID: 8179300] 
[69] 
Johnson, A.B.; Blum, N.R. Nucleoside phosphatase activities associated with the tangles and plaques of alzheimer’s disease: a histochemical study of natural and experimental neurofibrillary tangles. J. Neuropathol. Exp. Neurol.,  1970, 29(3), 463-478.
[http://dx.doi.org/10.1097/00005072-197007000-00009] [PMID: 4317450] 
[70] 
Wiśniewski, H.; Terry, R.D.; Hirano, A. Neurofibrillary pathology. J. Neuropathol. Exp. Neurol.,  1970, 29(2), 163-176.
[http://dx.doi.org/10.1097/00005072-197004000-00001] [PMID: 5435819] 
[71] 
Hirai, K.; Aliev, G.; Nunomura, A.; Fujioka, H.; Russell, R.L.; Atwood, C.S.; Johnson, A.B.; Kress, Y.; Vinters, H.V.; Tabaton, M.; Shimohama, S.; Cash, A.D.; Siedlak, S.L.; Harris, P.L.; Jones, P.K.; Petersen, R.B.; Perry, G.; Smith, M.A. Mitochondrial abnormalities in Alzheimer’s disease. J. Neurosci.,  2001, 21(9), 3017-3023.
[http://dx.doi.org/10.1523/JNEUROSCI.21-09-03017.2001] [PMID: 11312286] 
[72] 
Baloyannis, S.J. Mitochondrial alterations in Alzheimer’s disease. J. Alzheimers Dis.,  2006, 9(2), 119-126.
[http://dx.doi.org/10.3233/JAD-2006-9204] [PMID: 16873959] 
[73] 
Maurer, I.; Zierz, S.; Möller, H.J. A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients. Neurobiol. Aging,  2000, 21(3), 455-462.
[http://dx.doi.org/10.1016/S0197-4580(00)00112-3] [PMID: 10858595] 
[74] 
Gibson, G.E.; Starkov, A.; Blass, J.P.; Ratan, R.R.; Beal, M.F. Cause and consequence: mitochondrial dysfunction initiates and propagates neuronal dysfunction, neuronal death and behavioral abnormalities in age-associated neurodegenerative diseases. Biochim. Biophys. Acta,  2010, 1802(1), 122-134.
[http://dx.doi.org/10.1016/j.bbadis.2009.08.010] [PMID: 19715758] 
[75] 
Swerdlow, R.H. Mitochondria and mitochondrial cascades in Alzheimer’s disease. J. Alzheimers Dis.,  2018, 62(3), 1403-1416.
[http://dx.doi.org/10.3233/JAD-170585] [PMID: 29036828] 
[76] 
Webster, M-T.; Pearce, B.R.; Bowen, D.M.; Francis, P.T. The effects of perturbed energy metabolism on the processing of amyloid precursor protein in PC12 cells. J. Neural Transm. (Vienna),  1998, 105(8-9), 839-853.
[http://dx.doi.org/10.1007/s007020050098] [PMID: 9869322] 
[77] 
Fukui, H.; Diaz, F.; Garcia, S.; Moraes, C.T. Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA,  2007, 104(35), 14163-14168.
[http://dx.doi.org/10.1073/pnas.0705738104] [PMID: 17715058] 
[78] 
Cardoso, S.M.; Santos, S.; Swerdlow, R.H.; Oliveira, C.R. Functional mitochondria are required for amyloid β-mediated neurotoxicity. FASEB J.,  2001, 15(8), 1439-1441.
[http://dx.doi.org/10.1096/fj.00-0561fje] [PMID: 11387250] 
[79] 
Lustbader, J.W.; Cirilli, M.; Lin, C.; Xu, H.W.; Takuma, K.; Wang, N.; Caspersen, C.; Chen, X.; Pollak, S.; Chaney, M.; Trinchese, F.; Liu, S.; Gunn-Moore, F.; Lue, L.F.; Walker, D.G.; Kuppusamy, P.; Zewier, Z.L.; Arancio, O.; Stern, D.; Yan, S.S.; Wu, H. ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science,  2004, 304(5669), 448-452.
[http://dx.doi.org/10.1126/science.1091230] [PMID: 15087549] 
[80] 
Du, H.; Guo, L.; Fang, F.; Chen, D.; Sosunov, A.A.; McKhann, G.M.; Yan, Y.; Wang, C.; Zhang, H.; Molkentin, J.D.; Gunn-Moore, F.J.; Vonsattel, J.P.; Arancio, O.; Chen, J.X.; Yan, S.D. Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat. Med.,  2008, 14(10), 1097-1105.
[http://dx.doi.org/10.1038/nm.1868] [PMID: 18806802] 
[81] 
Reddy, P.H. Abnormal tau, mitochondrial dysfunction, impaired axonal transport of mitochondria, and synaptic deprivation in Alzheimer’s disease. Brain Res.,  2011, 1415, 136-148.
[http://dx.doi.org/10.1016/j.brainres.2011.07.052] [PMID: 21872849] 
[82] 
Du, X.; Wang, X.; Geng, M. Alzheimer’s disease hypothesis and related therapies. Transl. Neurodegener.,  2018, 7, 2.
[http://dx.doi.org/10.1186/s40035-018-0107-y] [PMID: 29423193] 
[83] 
Daulatzai, M.A. Cerebral hypoperfusion and glucose hypometabolism: Key pathophysiological modulators promote neurodegeneration, cognitive impairment, and Alzheimer’s disease. J. Neurosci. Res.,  2017, 95(4), 943-972.
[http://dx.doi.org/10.1002/jnr.23777] [PMID: 27350397] 
[84] 
de la Monte, S.M. The Full Spectrum of Alzheimer’s Disease Is Rooted in Metabolic Derangements That Drive Type 3 Diabetes. Adv. Exp. Med. Biol.,  2019, 1128, 45-83.
[http://dx.doi.org/10.1007/978-981-13-3540-2_4] [PMID: 31062325] 
[85] 
Yarchoan, M.; Arnold, S.E. Repurposing diabetes drugs for brain insulin resistance in Alzheimer disease. Diabetes,  2014, 63(7), 2253-2261.
[http://dx.doi.org/10.2337/db14-0287] [PMID: 24931035] 
[86] 
Imfeld, P.; Bodmer, M.; Jick, S.S.; Meier, C.R. Metformin, other antidiabetic drugs, and risk of Alzheimer’s disease: a population-based case-control study. J. Am. Geriatr. Soc.,  2012, 60(5), 916-921.
[http://dx.doi.org/10.1111/j.1532-5415.2012.03916.x] [PMID: 22458300] 
[87] 
Moore, E.M.; Mander, A.G.; Ames, D.; Kotowicz, M.A.; Carne, R.P.; Brodaty, H.; Woodward, M.; Boundy, K.; Ellis, K.A.; Bush, A.I.; Faux, N.G.; Martins, R.; Szoeke, C.; Rowe, C.; Watters, D.A. AIBL Investigators. Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care,  2013, 36(10), 2981-2987.
[http://dx.doi.org/10.2337/dc13-0229] [PMID: 24009301] 
[88] 
Weinstein, G.; Davis-Plourde, K.L.; Conner, S.; Himali, J.J.; Beiser, A.S.; Lee, A.; Rawlings, A.M.; Sedaghat, S.; Ding, J.; Moshier, E.; van Duijn, C.M.; Beeri, M.S.; Selvin, E.; Ikram, M.A.; Launer, L.J.; Haan, M.N.; Seshadri, S. Association of metformin, sulfonylurea and insulin use with brain structure and function and risk of dementia and Alzheimer’s disease: Pooled analysis from 5 cohorts. PLoS One,  2019, 14(2)e0212293
[http://dx.doi.org/10.1371/journal.pone.0212293] [PMID: 30768625] 
[89] 
Hsu, C.C.; Wahlqvist, M.L.; Lee, M.S.; Tsai, H.N. Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin. J. Alzheimers Dis.,  2011, 24(3), 485-493.
[http://dx.doi.org/10.3233/JAD-2011-101524] [PMID: 21297276] 
[90] 
Chin-Hsiao, T. Metformin and the Risk of Dementia in Type 2 Diabetes Patients. Aging Dis.,  2019, 10(1), 37-48.
[http://dx.doi.org/10.14336/AD.2017.1202] [PMID: 30705766] 
[91] 
Cheng, C.; Lin, C.H.; Tsai, Y.W.; Tsai, C.J.; Chou, P.H.; Lan, T.H. Type 2 diabetes and antidiabetic medications in relation to dementia diagnosis. J. Gerontol. A Biol. Sci. Med. Sci.,  2014, 69(10), 1299-1305.
[http://dx.doi.org/10.1093/gerona/glu073] [PMID: 24899525] 
[92] 
Orkaby, A.R.; Cho, K.; Cormack, J.; Gagnon, D.R.; Driver, J.A. Metformin vs sulfonylurea use and risk of dementia in US veterans aged ≥65 years with diabetes. Neurology,  2017, 89(18), 1877-1885.
[http://dx.doi.org/10.1212/WNL.0000000000004586] [PMID: 28954880] 
[93] 
Luchsinger, J.A.; Perez, T.; Chang, H.; Mehta, P.; Steffener, J.; Pradabhan, G.; Ichise, M.; Manly, J.; Devanand, D.P.; Bagiella, E. Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial. J. Alzheimers Dis.,  2016, 51(2), 501-514.
[http://dx.doi.org/10.3233/JAD-150493] [PMID: 26890736] 
[94] 
Koenig, A.M.; Mechanic-Hamilton, D.; Xie, S.X.; Combs, M.F.; Cappola, A.R.; Xie, L.; Detre, J.A.; Wolk, D.A.; Arnold, S.E. Effects of the Insulin Sensitizer Metformin in Alzheimer Disease: Pilot Data From a Randomized Placebo-controlled Crossover Study. Alzheimer Dis. Assoc. Disord.,  2017, 31(2), 107-113.
[http://dx.doi.org/10.1097/WAD.0000000000000202] [PMID: 28538088] 
[95] 
Chen, Y.; Zhou, K.; Wang, R.; Liu, Y.; Kwak, Y.D.; Ma, T.; Thompson, R.C.; Zhao, Y.; Smith, L.; Gasparini, L.; Luo, Z.; Xu, H.; Liao, F.F. Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer’s amyloid peptides via up-regulating BACE1 transcription. Proc. Natl. Acad. Sci. USA,  2009, 106(10), 3907-3912.
[http://dx.doi.org/10.1073/pnas.0807991106] [PMID: 19237574] 
[96] 
Correia, S.; Carvalho, C.; Santos, M.S.; Proença, T.; Nunes, E.; Duarte, A.I.; Monteiro, P.; Seiça, R.; Oliveira, C.R.; Moreira, P.I. Metformin protects the brain against the oxidative imbalance promoted by type 2 diabetes. Med. Chem.,  2008, 4(4), 358-364.
[http://dx.doi.org/10.2174/157340608784872299] [PMID: 18673148] 
[97] 
Gupta, A.; Bisht, B.; Dey, C.S. Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer’s-like changes. Neuropharmacology,  2011, 60(6), 910-920.
[http://dx.doi.org/10.1016/j.neuropharm.2011.01.033] [PMID: 21277873] 
[98] 
Chen, B.; Teng, Y.; Zhang, X.; Lv, X.; Yin, Y. Metformin Alleviated Aβ-Induced Apoptosis via the Suppression of JNK MAPK Signaling Pathway in Cultured Hippocampal Neurons. BioMed Res. Int.,  2016, 20161421430
[http://dx.doi.org/10.1155/2016/1421430] [PMID: 27403417] 
[99] 
Picone, P.; Nuzzo, D.; Caruana, L.; Messina, E.; Barera, A.; Vasto, S.; Di Carlo, M. Metformin increases APP expression and processing via oxidative stress, mitochondrial dysfunction and NF-κB activation: Use of insulin to attenuate metformin’s effect. Biochim. Biophys. Acta,  2015, 1853(5), 1046-1059.
[http://dx.doi.org/10.1016/j.bbamcr.2015.01.017] [PMID: 25667085] 
[100] 
Li, J.; Deng, J.; Sheng, W.; Zuo, Z. Metformin attenuates Alzheimer’s disease-like neuropathology in obese, leptin-resistant mice. Pharmacol. Biochem. Behav.,  2012, 101(4), 564-574.
[http://dx.doi.org/10.1016/j.pbb.2012.03.002] [PMID: 22425595] 
[101] 
Hettich, M.M.; Matthes, F.; Ryan, D.P.; Griesche, N.; Schröder, S.; Dorn, S.; Krauβ, S.; Ehninger, D. The anti-diabetic drug metformin reduces BACE1 protein level by interfering with the MID1 complex. PLoS One,  2014, 9(7)e102420
[http://dx.doi.org/10.1371/journal.pone.0102420] [PMID: 25025689] 
[102] 
Kickstein, E.; Krauss, S.; Thornhill, P.; Rutschow, D.; Zeller, R.; Sharkey, J.; Williamson, R.; Fuchs, M.; Köhler, A.; Glossmann, H.; Schneider, R.; Sutherland, C.; Schweiger, S. Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proc. Natl. Acad. Sci. USA,  2010, 107(50), 21830-21835.
[http://dx.doi.org/10.1073/pnas.0912793107] [PMID: 21098287] 
[103] 
Esmaeili, M.H.; Rastak, S. Metforminimproves learning and memory in streptozotocin-induced diabetic rats. International Journal of Advanced Biotechnology and Research,  2017, 8(1), 234-243.
[104] 
Farr, S.A.; Roesler, E.; Niehoff, M.L.; Roby, D.A.; McKee, A.; Morley, J.E. Metformin Improves Learning and Memory in the SAMP8 Mouse Model of Alzheimer’s Disease. J. Alzheimers Dis.,  2019, 68(4), 1699-1710.
[http://dx.doi.org/10.3233/JAD-181240] [PMID: 30958364] 
[105] 
Barini, E.; Antico, O.; Zhao, Y.; Asta, F.; Tucci, V.; Catelani, T.; Marotta, R.; Xu, H.; Gasparini, L. Metformin promotes tau aggregation and exacerbates abnormal behavior in a mouse model of tauopathy. Mol. Neurodegener.,  2016, 11, 16.
[http://dx.doi.org/10.1186/s13024-016-0082-7] [PMID: 26858121] 
[106] 
Mostafa, D.K.; Ismail, C.A.; Ghareeb, D.A. Differential metformin dose-dependent effects on cognition in rats: role of Akt. Psychopharmacology (Berl.),  2016, 233(13), 2513-2524.
[http://dx.doi.org/10.1007/s00213-016-4301-2] [PMID: 27113224] 
[107] 
Teo, E.; Ravi, S.; Barardo, D.; Kim, H.S.; Fong, S.; Cazenave-Gassiot, A.; Tan, T.Y.; Ching, J.; Kovalik, J.P.; Wenk, M.R.; Gunawan, R.; Moore, P.K.; Halliwell, B.; Tolwinski, N.; Gruber, J. Metabolic stress is a primary pathogenic event in transgenic Caenorhabditis elegans expressing pan-neuronal human amyloid beta. eLife,  2019, 8, e50069.
[http://dx.doi.org/10.7554/eLife.50069] [PMID: 31610847] 
[108] 
Rotermund, C.; Machetanz, G.; Fitzgerald, J.C. The Therapeutic Potential of Metformin in Neurodegenerative Diseases. Front. Endocrinol. (Lausanne),  2018, 9, 400.
[http://dx.doi.org/10.3389/fendo.2018.00400] [PMID: 30072954] 
[109] 
Chiang, M.C.; Cheng, Y.C.; Chen, S.J.; Yen, C.H.; Huang, R.N. Metformin activation of AMPK-dependent pathways is neuroprotective in human neural stem cells against Amyloid-beta-induced mitochondrial dysfunction. Exp. Cell Res.,  2016, 347(2), 322-331.
[http://dx.doi.org/10.1016/j.yexcr.2016.08.013] [PMID: 27554603] 
[110] 
Ronnett, G.V.; Ramamurthy, S.; Kleman, A.M.; Landree, L.E.; Aja, S. AMPK in the brain: its roles in energy balance and neuroprotection. J. Neurochem.,  2009, 109(Suppl. 1), 17-23.
[http://dx.doi.org/10.1111/j.1471-4159.2009.05916.x] [PMID: 19393004] 
[111] 
Wang, J.; Gallagher, D.; DeVito, L.M.; Cancino, G.I.; Tsui, D.; He, L.; Keller, G.M.; Frankland, P.W.; Kaplan, D.R.; Miller, F.D. Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. Cell Stem Cell,  2012, 11(1), 23-35.
[http://dx.doi.org/10.1016/j.stem.2012.03.016] [PMID: 22770240] 
[112] 
Ou, Z.; Kong, X.; Sun, X.; He, X.; Zhang, L.; Gong, Z.; Huang, J.; Xu, B.; Long, D.; Li, J.; Li, Q.; Xu, L.; Xuan, A. Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice. Brain Behav. Immun.,  2018, 69, 351-363.
[http://dx.doi.org/10.1016/j.bbi.2017.12.009] [PMID: 29253574] 
[113] 
DiTacchio, K.A.; Heinemann, S.F.; Dziewczapolski, G. Metformin treatment alters memory function in a mouse model of Alzheimer’s disease. J. Alzheimers Dis.,  2015, 44(1), 43-48.
[http://dx.doi.org/10.3233/JAD-141332] [PMID: 25190626] 
[114] 
Kitabchi, A.E.; Temprosa, M.; Knowler, W.C.; Kahn, S.E.; Fowler, S.E.; Haffner, S.M.; Andres, R.; Saudek, C.; Edelstein, S.L.; Arakaki, R.; Murphy, M.B.; Shamoon, H. Diabetes Prevention Program Research Group. Role of insulin secretion and sensitivity in the evolution of type 2 diabetes in the diabetes prevention program: effects of lifestyle intervention and metformin. Diabetes,  2005, 54(8), 2404-2414.
[http://dx.doi.org/10.2337/diabetes.54.8.2404] [PMID: 16046308] 
[115] 
Haffner, S.; Temprosa, M.; Crandall, J.; Fowler, S.; Goldberg, R.; Horton, E.; Marcovina, S.; Mather, K.; Orchard, T.; Ratner, R.; Barrett-Connor, E. Diabetes Prevention Program Research Group. Intensive lifestyle intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance. Diabetes,  2005, 54(5), 1566-1572.
[http://dx.doi.org/10.2337/diabetes.54.5.1566] [PMID: 15855347] 
[116] 
Arnold, S.E.; Arvanitakis, Z.; Macauley-Rambach, S.L.; Koenig, A.M.; Wang, H.Y.; Ahima, R.S.; Craft, S.; Gandy, S.; Buettner, C.; Stoeckel, L.E.; Holtzman, D.M.; Nathan, D.M. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat. Rev. Neurol.,  2018, 14(3), 168-181.
[http://dx.doi.org/10.1038/nrneurol.2017.185] [PMID: 29377010] 
[117] 
Ding, F.; Yao, J.; Rettberg, J.R.; Chen, S.; Brinton, R.D. Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer’s mouse brain: implication for bioenergetic intervention. PLoS One,  2013, 8(11)e79977
[http://dx.doi.org/10.1371/journal.pone.0079977] [PMID: 24244584] 
[118] 
Hundal, H.S.; Ramlal, T.; Reyes, R.; Leiter, L.A.; Klip, A. Cellular mechanism of metformin action involves glucose transporter translocation from an intracellular pool to the plasma membrane in L6 muscle cells. Endocrinology,  1992, 131(3), 1165-1173.
[http://dx.doi.org/10.1210/endo.131.3.1505458] [PMID: 1505458] 
[119] 
Cooper, A.C.; Fleming, I.N.; Phyu, S.M.; Smith, T.A. Changes in [18F]Fluoro-2-deoxy-D-glucose incorporation induced by doxorubicin and anti-HER antibodies by breast cancer cells modulated by co-treatment with metformin and its effects on intracellular signalling. J. Cancer Res. Clin. Oncol.,  2015, 141(9), 1523-1532.
[http://dx.doi.org/10.1007/s00432-015-1909-2] [PMID: 25579456] 
[120] 
Niccoli, T.; Cabecinha, M.; Tillmann, A.; Kerr, F.; Wong, C.T.; Cardenes, D.; Vincent, A.J.; Bettedi, L.; Li, L.; Grönke, S.; Dols, J.; Partridge, L. Increased Glucose Transport into Neurons Rescues Aβ Toxicity in Drosophila. Curr. Biol.,  2016, 26(17), 2291-2300.
[http://dx.doi.org/10.1016/j.cub.2016.07.017] [PMID: 27524482] 
[121] 
Pittenger, C.; Duman, R.S. Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology,  2008, 33(1), 88-109.
[http://dx.doi.org/10.1038/sj.npp.1301574] [PMID: 17851537] 
[122] 
Schmidt, H.D.; Duman, R.S. The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior. Behav. Pharmacol.,  2007, 18(5-6), 391-418.
[http://dx.doi.org/10.1097/FBP.0b013e3282ee2aa8] [PMID: 17762509] 
[123] 
Phillips, O.R.; Onopa, A.K.; Zaiko, Y.V.; Singh, M.K. Insulin resistance is associated with smaller brain volumes in a preliminary study of depressed and obese children. Pediatr. Diabetes,  2018, 19(5), 892-897.
[http://dx.doi.org/10.1111/pedi.12672] [PMID: 29569318] 
[124] 
Kennedy, S.H.; Rizvi, S.; Fulton, K.; Rasmussen, J. A double-blind comparison of sexual functioning, antidepressant efficacy, and tolerability between agomelatine and venlafaxine XR. J. Clin. Psychopharmacol.,  2008, 28(3), 329-333.
[http://dx.doi.org/10.1097/JCP.0b013e318172b48c] [PMID: 18480691] 
[125] 
Trivedi, M.H.; Rush, A.J.; Wisniewski, S.R.; Nierenberg, A.A.; Warden, D.; Ritz, L.; Norquist, G.; Howland, R.H.; Lebowitz, B.; McGrath, P.J.; Shores-Wilson, K.; Biggs, M.M.; Balasubramani, G.K.; Fava, M. STAR*D Study Team. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am. J. Psychiatry,  2006, 163(1), 28-40.
[http://dx.doi.org/10.1176/appi.ajp.163.1.28] [PMID: 16390886] 
[126] 
Masi, G.; Brovedani, P. The hippocampus, neurotrophic factors and depression: possible implications for the pharmacotherapy of depression. CNS Drugs,  2011, 25(11), 913-931.
[http://dx.doi.org/10.2165/11595900-000000000-00000] [PMID: 22054117] 
[127] 
Markowicz-Piasecka, M.; Sikora, J.; Szydłowska, A.; Skupień, A.; Mikiciuk-Olasik, E.; Huttunen, K.M. Metformin–a future therapy for neurodegenerative diseases. Pharm. Res.,  2017, 34(12), 2614-2627.
[http://dx.doi.org/10.1007/s11095-017-2199-y] [PMID: 28589443] 
[128] 
Gold, P.W.; Machado-Vieira, R.; Pavlatou, M.G. Clinical and biochemical manifestations of depression: relation to the neurobiology of stress Neural Plast.,  2015, 2015, 581976.
[http://dx.doi.org/10.1155/2015/581976] [PMID: 25878903] 
[129] 
McIntyre, R.S.; Soczynska, J.K.; Konarski, J.Z.; Woldeyohannes, H.O.; Law, C.W.; Miranda, A.; Fulgosi, D.; Kennedy, S.H. Should depressive syndromes be reclassified as “metabolic syndrome type II”? Ann. Clin. Psychiatry,  2007, 19(4), 257-264.
[http://dx.doi.org/10.1080/10401230701653377] [PMID: 18058283] 
[130] 
Hung, Y.J.; Hsieh, C.H.; Chen, Y.J.; Pei, D.; Kuo, S.W.; Shen, D.C.; Sheu, W.H.H.; Chen, Y.C. Insulin sensitivity, proinflammatory markers and adiponectin in young males with different subtypes of depressive disorder. Clin. Endocrinol. (Oxf.),  2007, 67(5), 784-789.
[http://dx.doi.org/10.1111/j.1365-2265.2007.02963.x] [PMID: 17697007] 
[131] 
Leonard, B.L.; Watson, R.N.; Loomes, K.M.; Phillips, A.R.; Cooper, G.J. Insulin resistance in the Zucker diabetic fatty rat: a metabolic characterisation of obese and lean phenotypes. Acta Diabetol.,  2005, 42(4), 162-170.
[http://dx.doi.org/10.1007/s00592-005-0197-8] [PMID: 16382303] 
[132] 
Zou, X.H.; Sun, L.H.; Yang, W.; Li, B.J.; Cui, R.J. Potential role of insulin on the pathogenesis of depression. Cell Prolif.,  2020, 53(5), e12806-e12806.
[http://dx.doi.org/10.1111/cpr.12806] [PMID: 32281722] 
[133] 
Hamer, J.A.; Testani, D.; Mansur, R.B.; Lee, Y.; Subramaniapillai, M.; McIntyre, R.S. Brain insulin resistance: A treatment target for cognitive impairment and anhedonia in depression. Exp. Neurol.,  2019, 315, 1-8.
[http://dx.doi.org/10.1016/j.expneurol.2019.01.016] [PMID: 30695707] 
[134] 
Głombik, K.; Detka, J.; Góralska, J.; Kurek, A.; Solnica, B.; Budziszewska, B. Brain Metabolic Alterations in Rats Showing Depression-Like and Obesity Phenotypes. Neurotox. Res.,  2020, 37(2), 406-424.
[http://dx.doi.org/10.1007/s12640-019-00131-w] [PMID: 31782099] 
[135] 
Kahl, K.G.; Kerling, A.; Tegtbur, U.; Gützlaff, E.; Herrmann, J.; Borchert, L.; Ates, Z.; Westhoff-Bleck, M.; Hueper, K.; Hartung, D. Effects of additional exercise training on epicardial, intra-abdominal and subcutaneous adipose tissue in major depressive disorder: A randomized pilot study. J. Affect. Disord.,  2016, 192, 91-97.
[http://dx.doi.org/10.1016/j.jad.2015.12.015] [PMID: 26707353] 
[136] 
Detka, J.; Kurek, A.; Kucharczyk, M.; Głombik, K.; Basta-Kaim, A.; Kubera, M.; Lasoń, W.; Budziszewska, B. Brain glucose metabolism in an animal model of depression. Neuroscience,  2015, 295, 198-208.
[http://dx.doi.org/10.1016/j.neuroscience.2015.03.046] [PMID: 25819664] 
[137] 
Culmsee, C.; Michels, S.; Scheu, S.; Arolt, V.; Dannlowski, U.; Alferink, J. Mitochondria, Microglia, and the Immune System-How Are They Linked in Affective Disorders? Front. Psychiatry,  2019, 9, 739.
[http://dx.doi.org/10.3389/fpsyt.2018.00739] [PMID: 30687139] 
[138] 
Kambe, Y.; Miyata, A. Potential involvement of the mitochondrial unfolded protein response in depressive-like symptoms in mice. Neurosci. Lett.,  2015, 588, 166-171.
[http://dx.doi.org/10.1016/j.neulet.2015.01.006] [PMID: 25576703] 
[139] 
Martins-de-Souza, D.; Guest, P.C.; Harris, L.W.; Vanattou-Saifoudine, N.; Webster, M.J.; Rahmoune, H.; Bahn, S. Identification of proteomic signatures associated with depression and psychotic depression in post-mortem brains from major depression patients. Transl. Psychiatry,  2012, 2(3), e87-e87.
[http://dx.doi.org/10.1038/tp.2012.13] [PMID: 22832852] 
[140] 
Scaini, G.; Santos, P.M.; Benedet, J.; Rochi, N.; Gomes, L.M.; Borges, L.S.; Rezin, G.T.; Pezente, D.P.; Quevedo, J.; Streck, E.L. Evaluation of Krebs cycle enzymes in the brain of rats after chronic administration of antidepressants. Brain Res. Bull.,  2010, 82(3-4), 224-227.
[http://dx.doi.org/10.1016/j.brainresbull.2010.03.006] [PMID: 20347017] 
[141] 
Allen, J.; Romay-Tallon, R.; Brymer, K.J.; Caruncho, H.J.; Kalynchuk, L.E. Mitochondria and mood: mitochondrial dysfunction as a key player in the manifestation of depression. Front. Neurosci.,  2018, 12, 386.
[http://dx.doi.org/10.3389/fnins.2018.00386] [PMID: 29928190] 
[142] 
Gong, Y.; Chai, Y.; Ding, J-H.; Sun, X-L.; Hu, G. Chronic mild stress damages mitochondrial ultrastructure and function in mouse brain. Neurosci. Lett.,  2011, 488(1), 76-80.
[http://dx.doi.org/10.1016/j.neulet.2010.11.006] [PMID: 21070835] 
[143] 
Gamaro, G.D.; Streck, E.L.; Matté, C.; Prediger, M.E.; Wyse, A.T.; Dalmaz, C. Reduction of hippocampal Na+, K+-ATPase activity in rats subjected to an experimental model of depression. Neurochem. Res.,  2003, 28(9), 1339-1344.
[http://dx.doi.org/10.1023/A:1024988113978] [PMID: 12938855] 
[144] 
Dunbar, J.A.; Reddy, P.; Davis-Lameloise, N.; Philpot, B.; Laatikainen, T.; Kilkkinen, A.; Bunker, S.J.; Best, J.D.; Vartiainen, E.; Kai Lo, S.; Janus, E.D. Depression: an important comorbidity with metabolic syndrome in a general population. Diabetes Care,  2008, 31(12), 2368-2373.
[http://dx.doi.org/10.2337/dc08-0175] [PMID: 18835951] 
[145] 
Holtzheimer, P.E., III; Nemeroff, C.B. Future prospects in depression research. Dialogues Clin. Neurosci.,  2006, 8(2), 175-189.
[PMID: 16889104] 
[146] 
Nemeroff, C.B. Prevalence and management of treatment-resistant depression. J. Clin. Psychiatry,  2007, 68(8)(Suppl. 8), 17-25.
[PMID: 17640154] 
[147] 
Sharma, A.N.; Ligade, S.S.; Sharma, J.N.; Shukla, P.; Elased, K.M.; Lucot, J.B. GLP-1 receptor agonist liraglutide reverses long-term atypical antipsychotic treatment associated behavioral depression and metabolic abnormalities in rats. Metab. Brain Dis.,  2015, 30(2), 519-527.
[http://dx.doi.org/10.1007/s11011-014-9591-7] [PMID: 25023888] 
[148] 
Fang, W.; Zhang, J.; Hong, L.; Huang, W.; Dai, X.; Ye, Q.; Chen, X. Metformin ameliorates stress-induced depression-like behaviors via enhancing the expression of BDNF by activating AMPK/CREB-mediated histone acetylation. J. Affect. Disord.,  2020, 260, 302-313.
[http://dx.doi.org/10.1016/j.jad.2019.09.013] [PMID: 31521867] 
[149] 
Grigolon, R.B.; Brietzke, E.; Mansur, R.B.; Idzikowski, M.A.; Gerchman, F.; De Felice, F.G.; McIntyre, R.S. Association between diabetes and mood disorders and the potential use of anti-hyperglycemic agents as antidepressants. Prog. Neuropsychopharmacol. Biol. Psychiatry,  2019, 95109720
[http://dx.doi.org/10.1016/j.pnpbp.2019.109720] [PMID: 31352032] 
[150] 
Ai, H.; Fang, W.; Hu, H.; Hu, X.; Lu, W. Antidiabetic Drug Metformin Ameliorates Depressive-Like Behavior in Mice with Chronic Restraint Stress via Activation of AMP-Activated Protein Kinase. Aging Dis.,  2020, 11(1), 31-43.
[http://dx.doi.org/10.14336/AD.2019.0403] [PMID: 32010479] 
[151] 
Moulton, C.D.; Hopkins, C.W.P.; Ismail, K.; Stahl, D. Repositioning of diabetes treatments for depressive symptoms: A systematic review and meta-analysis of clinical trials. Psychoneuroendocrinology,  2018, 94, 91-103.
[http://dx.doi.org/10.1016/j.psyneuen.2018.05.010] [PMID: 29775878] 
[152] 
Wang, C.P.; Lorenzo, C.; Habib, S.L.; Jo, B.; Espinoza, S.E. Differential effects of metformin on age related comorbidities in older men with type 2 diabetes. J. Diabetes Complications,  2017, 31(4), 679-686.
[http://dx.doi.org/10.1016/j.jdiacomp.2017.01.013] [PMID: 28190681] 
[153] 
Guo, M.; Mi, J.; Jiang, Q-M.; Xu, J-M.; Tang, Y-Y.; Tian, G.; Wang, B. Metformin may produce antidepressant effects through improvement of cognitive function among depressed patients with diabetes mellitus. Clin. Exp. Pharmacol. Physiol.,  2014, 41(9), 650-656.
[http://dx.doi.org/10.1111/1440-1681.12265] [PMID: 24862430] 
[154] 
Chen, F.; Wei, G.; Wang, Y.; Liu, T.; Huang, T.; Wei, Q.; Ma, G.; Wang, D. Risk factors for depression in elderly diabetic patients and the effect of metformin on the condition. BMC Public Health,  2019, 19(1), 1063.
[http://dx.doi.org/10.1186/s12889-019-7392-y] [PMID: 31391021] 
[155] 
Shivavedi, N.; Kumar, M.; Tej, G.N.V.C.; Nayak, P.K. Metformin and ascorbic acid combination therapy ameliorates type 2 diabetes mellitus and comorbid depression in rats. Brain Res.,  2017, 1674, 1-9.
[http://dx.doi.org/10.1016/j.brainres.2017.08.019] [PMID: 28827076] 
[156] 
Keshavarzi, S.; Kermanshahi, S.; Karami, L.; Motaghinejad, M.; Motevalian, M.; Sadr, S. Protective role of metformin against methamphetamine induced anxiety, depression, cognition impairment and neurodegeneration in rat: The role of CREB/BDNF and Akt/GSK3 signaling pathways. Neurotoxicology,  2019, 72, 74-84.
[http://dx.doi.org/10.1016/j.neuro.2019.02.004] [PMID: 30742852] 
[157] 
Yang, S.; Chen, X.; Xu, Y.; Hao, Y.; Meng, X. Effects of metformin on lipopolysaccharide-induced depressive-like behavior in mice and its mechanisms. Neuroreport,  2020, 31(4), 305-310.
[http://dx.doi.org/10.1097/WNR.0000000000001401] [PMID: 31977586] 
[158] 
Soliman, E.; Essmat, N.; Mahmoud, M.F.; Mahmoud, A.A.A. Impact of some oral hypoglycemic agents on type 2 diabetes-associated depression and reserpine-induced depression in rats: the role of brain oxidative stress and inflammation. Naunyn Schmiedebergs Arch. Pharmacol.,  2020, 393(8), 1391-1404.
[http://dx.doi.org/10.1007/s00210-020-01838-w] [PMID: 32077986] 
[159] 
Poggini, S.; Golia, M.T.; Alboni, S.; Milior, G.; Sciarria, L.P.; Viglione, A.; Matte Bon, G.; Brunello, N.; Puglisi-Allegra, S.; Limatola, C.; Maggi, L.; Branchi, I. Combined Fluoxetine and Metformin Treatment Potentiates Antidepressant Efficacy Increasing IGF2 Expression in the Dorsal Hippocampus. Neural Plast.,  2019, 20194651031
[http://dx.doi.org/10.1155/2019/4651031] [PMID: 30804991] 
[160] 
Erensoy, H.; Niafar, M.; Ghafarzadeh, S.; Aghamohammadzadeh, N.; Nader, N.D. A pilot trial of metformin for insulin resistance and mood disturbances in adolescent and adult women with polycystic ovary syndrome. Gynecol. Endocrinol.,  2019, 35(1), 72-75.
[http://dx.doi.org/10.1080/09513590.2018.1498476] [PMID: 30182764] 
[161] 
Zemdegs, J.; Martin, H.; Pintana, H.; Bullich, S.; Manta, S.; Marqués, M.A.; Moro, C.; Layé, S.; Ducrocq, F.; Chattipakorn, N.; Chattipakorn, S.C.; Rampon, C.; Pénicaud, L.; Fioramonti, X.; Guiard, B.P. Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids. J. Neurosci.,  2019, 39(30), 5935-5948.
[http://dx.doi.org/10.1523/JNEUROSCI.2904-18.2019] [PMID: 31160539] 
[162] 
Liu, W.; Liu, J.; Huang, Z.; Cui, Z.; Li, L.; Liu, W.; Qi, Z. Possible role of GLP-1 in antidepressant effects of metformin and exercise in CUMS mice. J. Affect. Disord.,  2019, 246, 486-497.
[http://dx.doi.org/10.1016/j.jad.2018.12.112] [PMID: 30599373] 
[163] 
Łabuzek, K.; Suchy, D.; Gabryel, B.; Bielecka, A.; Liber, S.; Okopień, B. Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide. Pharmacol. Rep.,  2010, 62(5), 956-965.
[http://dx.doi.org/10.1016/S1734-1140(10)70357-1] [PMID: 21098880] 
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DOI https://dx.doi.org/10.2174/0929867327666200908114902	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X
Current Medicinal Chemistry

Metformin: A Growing Journey from Glycemic Control to the Treatment of Alzheimer’s Disease and Depression

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