A Link Between Brain Insulin Resistance and Cognitive Dysfunctions: Targeting Ca2+/cAMP Signalling

Author(s): Leandro B. Bergantin*

Journal Name: Central Nervous System Agents in Medicinal Chemistry
Formerly Current Medicinal Chemistry - Central Nervous System Agents

Volume 20 , Issue 2 , 2020


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Graphical Abstract:


Abstract:

Background: A correlation between cognitive dysfunctions and brain insulin resistance has been established by several clinical and experimental studies. Consistent data support that people diagnosed with brain insulin resistance, resulted from diabetes, have shown an increased risk of presenting cognitive dysfunctions, clinical signs of dementia and depression, then speculating a role of dysregulations related to insulin signalling in these diseases. Furthermore, it is currently discussed that Ca2+ signalling, and its dysregulations, may be a factor which could correlate with brain insulin resistance and cognitive dysfunctions.

Objective: Following this, revealing this interplay between these diseases may provide novel insights into the pathogenesis of such diseases.

Methods: Publications covering topics such as Ca2+ signalling, diabetes, depression and dementia (alone or combined) were collected by searching PubMed and EMBASE.

Results: The controlling of both neurotransmitters/hormones release and neuronal death could be achieved through modulating Ca2+ and cAMP signalling pathways (Ca2+/cAMP signalling).

Conclusion: Taking into account our previous reports on Ca2+/cAMP signalling, and considering a limited discussion in the literature on the role of Ca2+/cAMP signalling in the link between cognitive dysfunctions and brain insulin resistance, this article has comprehensively discussed the role of these signalling pathways in this link (between cognitive dysfunctions and brain insulin resistance).

Keywords: Diabetes, dementia, depression, Ca2+/cAMP signalling, Ca2+ channel blockers, pharmacotherapy, neurodegeneration.

[1]
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]
[2]
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]
[3]
Bergantin, L.B. Hypertension, diabetes and neurodegenerative diseases: Is there a Clinical Link through the Ca2+/cAMP Signalling Interaction? Curr. Hypertens. Rev., 2019, 15(1), 32-39.
[http://dx.doi.org/10.2174/1573402114666180817113242 ] [PMID: 30117399]
[4]
Bergantin, L.B.; Caricati-Neto, A. Challenges for the pharmacological treatment of neurological and psychiatric disorders: Implications of the Ca(2+)/cAMP intracellular signalling interaction. Eur. J. Pharmacol., 2016, 788, 255-260.
[http://dx.doi.org/10.1016/j.ejphar.2016.06.034] [PMID: 27349146]
[5]
Bergantin, L.B. Debating the “bidirectional link” between diabetes and depression through the Ca2+/cAMP signalling: Off-label effects of Ca2+ channel blockers. Pharmacol. Res., 2019, 141, 298-302.
[http://dx.doi.org/10.1016/j.phrs.2019.01.008] [PMID: 30639385]
[6]
Wu, C.L.; Wen, S.H. A 10-year follow-up study of the association between calcium channel blocker use and the risk of dementia in elderly hypertensive patients. Medicine (Baltimore), 2016, 95(32) e4593
[http://dx.doi.org/10.1097/MD.0000000000004593] [PMID: 27512890]
[7]
Tully, P.J.; Peters, R.; Pérès, K.; Anstey, K.J.; Tzourio, C. Effect of SSRI and calcium channel blockers on depression symptoms and cognitive function in elderly persons treated for hypertension: three city cohort study. Int. Psychogeriatr., 2018, 30(9), 1345-1354.
[http://dx.doi.org/10.1017/S1041610217002903] [PMID: 29559030]
[8]
Khodneva, Y.; Shalev, A.; Frank, S.J.; Carson, A.P.; Safford, M.M. Calcium channel blocker use is associated with lower fasting serum glucose among adults with diabetes from the REGARDS study. Diabetes Res. Clin. Pract., 2016, 115, 115-121.
[http://dx.doi.org/10.1016/j.diabres.2016.01.021] [PMID: 26818894]
[9]
Xu, G.; Chen, J.; Jing, G.; Shalev, A. Preventing β-cell loss and diabetes with calcium channel blockers. Diabetes, 2012, 61(4), 848-856.
[http://dx.doi.org/10.2337/db11-0955] [PMID: 22442301]
[10]
Bergantin, L.B.; Souza, C.F.; Ferreira, R.M.; Smaili, S.S.; Jurkiewicz, N.H.; Caricati-Neto, A.; Jurkiewicz, A. Novel model for “calcium paradox” in sympathetic transmission of smooth muscles: role of cyclic AMP pathway. Cell Calcium, 2013, 54(3), 202-212.
[http://dx.doi.org/10.1016/j.ceca.2013.06.004] [PMID: 23849429]
[11]
Caricati-Neto, A.; García, A.G.; Bergantin, L.B. Pharmacological implications of the Ca(2+)/cAMP signaling interaction: from risk for antihypertensive therapy to potential beneficial for neurological and psychiatric disorders. Pharmacol. Res. Perspect., 2015, 3(5) e00181
[http://dx.doi.org/10.1002/prp2.181] [PMID: 26516591]
[12]
McCrimmon, R.J.; Ryan, C.M.; Frier, B.M. Diabetes and cognitive dysfunction. Lancet, 2012, 379(9833), 2291-2299.
[http://dx.doi.org/10.1016/S0140-6736(12)60360-2] [PMID: 22683129]
[13]
Munshi, M.; Grande, L.; Hayes, M.; Ayres, D.; Suhl, E.; Capelson, R.; Lin, S.; Milberg, W.; Weinger, K. Cognitive dysfunction is associated with poor diabetes control in older adults. Diabetes Care, 2006, 29(8), 1794-1799.
[http://dx.doi.org/10.2337/dc06-0506] [PMID: 16873782]
[14]
Sinclair, A.J.; Girling, A.J.; Bayer, A.J. Cognitive dysfunction in older subjects with diabetes mellitus: Impact on diabetes self-management and use of care services. All Wales Research into Elderly (AWARE) Study. Diabetes Res. Clin. Pract., 2000, 50(3), 203-212.
[http://dx.doi.org/10.1016/S0168-8227(00)00195-9] [PMID: 11106835]
[15]
Alencar, R.C.; Cobas, R.A.; Gomes, M.B. Assessment of cognitive status in patients with type 2 diabetes through the Mini-Mental Status Examination: a cross-sectional study. Diabetol. Metab. Syndr., 2010, 2(1), 10.
[http://dx.doi.org/10.1186/1758-5996-2-10] [PMID: 20205826]
[16]
Wessels, A.M.; Lane, K.A.; Gao, S.; Hall, K.S.; Unverzagt, F.W.; Hendrie, H.C. Diabetes and cognitive decline in elderly African Americans: A 15-year follow-up study. Alzheimers Dement., 2011, 7(4), 418-424.
[http://dx.doi.org/10.1016/j.jalz.2010.07.003] [PMID: 21784353]
[17]
Feinkohl, I.; Keller, M.; Robertson, C.M.; Morling, J.R.; Williamson, R.M.; Nee, L.D.; McLachlan, S.; Sattar, N.; Welsh, P.; Reynolds, R.M.; Russ, T.C.; Deary, I.J.; Strachan, M.W.; Price, J.F. Clinical and subclinical macrovascular disease as predictors of cognitive decline in older patients with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabetes Care, 2013, 36(9), 2779-2786.
[http://dx.doi.org/10.2337/dc12-2241] [PMID: 23579182]
[18]
Zhao, Q.; Roberts, R.O.; Ding, D.; Cha, R.; Guo, Q.; Meng, H.; Luo, J.; Machulda, M.M.; Shane Pankratz, V.; Wang, B.; Christianson, T.J.; Aakre, J.A.; Knopman, D.S.; Boeve, B.F.; Hong, Z.; Petersen, R.C. Diabetes is associated with worse executive function in both Eastern and Western populations: Shanghai aging study and mayo clinic study of aging. J. Alzheimers Dis., 2015, 47(1), 167-176.
[http://dx.doi.org/10.3233/JAD-150073] [PMID: 26402765]
[19]
Qiu, C.; Sigurdsson, S.; Zhang, Q.; Jonsdottir, M.K.; Kjartansson, O.; Eiriksdottir, G.; Garcia, M.E.; Harris, T.B.; van Buchem, M.A.; Gudnason, V.; Launer, L.J. Diabetes, markers of brain pathology and cognitive function: the Age, Gene/Environment Susceptibility-Reykjavik Study. Ann. Neurol., 2014, 75(1), 138-146.
[http://dx.doi.org/10.1002/ana.24063] [PMID: 24243491]
[20]
Moran, C.; Phan, T.G.; Chen, J.; Blizzard, L.; Beare, R.; Venn, A.; Münch, G.; Wood, A.G.; Forbes, J.; Greenaway, T.M.; Pearson, S.; Srikanth, V. Brain atrophy in type 2 diabetes: regional distribution and influence on cognition. Diabetes Care, 2013, 36(12), 4036-4042.
[http://dx.doi.org/10.2337/dc13-0143] [PMID: 23939539]
[21]
Kooistra, M.; Geerlings, M.I.; van der Graaf, Y.; Mali, W.P.; Vincken, K.L.; Kappelle, L.J.; Muller, M.; Biessels, G.J. Vascular brain lesions, brain atrophy, and cognitive decline. The Second Manifestations of ARTerial disease--Magnetic Resonance (SMART-MR) study. Neurobiol. Aging, 2014, 35(1), 35-41.
[http://dx.doi.org/10.1016/j.neurobiolaging.2013.07.004] [PMID: 23932882]
[22]
van Elderen, S.G.; de Roos, A.; de Craen, A.J.; Westendorp, R.G.; Blauw, G.J.; Jukema, J.W.; Bollen, E.L.; Middelkoop, H.A.; van Buchem, M.A.; van der Grond, J. Progression of brain atrophy and cognitive decline in diabetes mellitus: A 3-year follow-up. Neurology, 2010, 75(11), 997-1002.
[http://dx.doi.org/10.1212/WNL.0b013e3181f25f06] [PMID: 20837967]
[23]
Whitmer, R.A. Type 2 diabetes and risk of cognitive impairment and dementia. Curr. Neurol. Neurosci. Rep., 2007, 7(5), 373-380.
[http://dx.doi.org/10.1007/s11910-007-0058-7] [PMID: 17764626]
[24]
Guariguata, L.; Whiting, D.R.; Hambleton, I.; Beagley, J.; Linnenkamp, U.; Shaw, J.E. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res. Clin. Pract., 2014, 103(2), 137-149.
[http://dx.doi.org/10.1016/j.diabres.2013.11.002] [PMID: 24630390]
[25]
Albai, O.; Roman, D.; Frandes, M. Hypertriglyceridemia, an important and independent risk factor for acute pancreatitis in patients with type 2 diabetes mellitus. Ther. Clin. Risk Manag., 2017, 13, 515-522.
[http://dx.doi.org/10.2147/TCRM.S134560] [PMID: 28450786]
[26]
Bruce, D.G.; Casey, G.P.; Grange, V.; Clarnette, R.C.; Almeida, O.P.; Foster, J.K.; Ives, F.J.; Davis, T.M. Cognitive impairment, physical disability and depressive symptoms in older diabetic patients: the Fremantle Cognition in Diabetes Study. Diabetes Res. Clin. Pract., 2003, 61(1), 59-67.
[http://dx.doi.org/10.1016/S0168-8227(03)00084-6] [PMID: 12849924]
[27]
Watson, G.S.; Craft, S. The role of insulin resistance in the pathogenesis of Alzheimer’s disease: Implications for treatment. CNS Drugs, 2003, 17(1), 27-45.
[http://dx.doi.org/10.2165/00023210-200317010-00003] [PMID: 12467491]
[28]
Yaffe, K.; Blackwell, T.; Whitmer, R.A.; Krueger, K.; Barrett Connor, E. Glycosylated hemoglobin level and development of mild cognitive impairment or dementia in older women. J. Nutr. Health Aging, 2006, 10(4), 293-295.
[PMID: 16886099]
[29]
Kodl, C.T.; Seaquist, E.R. Cognitive dysfunction and diabetes mellitus. Endocr. Rev., 2008, 29(4), 494-511.
[http://dx.doi.org/10.1210/er.2007-0034] [PMID: 18436709]
[30]
Cunnane, S.; Nugent, S.; Roy, M.; Courchesne-Loyer, A.; Croteau, E.; Tremblay, S.; Castellano, A.; Pifferi, F.; Bocti, C.; Paquet, N.; Begdouri, H.; Bentourkia, M.; Turcotte, E.; Allard, M.; Barberger-Gateau, P.; Fulop, T.; Rapoport, S.I. Brain fuel metabolism, aging, and Alzheimer’s disease. Nutrition, 2011, 27(1), 3-20.
[http://dx.doi.org/10.1016/j.nut.2010.07.021] [PMID: 21035308]
[31]
Cunnane, S.C.; Plourde, M.; Pifferi, F.; Bégin, M.; Féart, C.; Barberger-Gateau, P. Fish, docosahexaenoic acid and Alzheimer’s disease. Prog. Lipid Res., 2009, 48(5), 239-256.
[http://dx.doi.org/10.1016/j.plipres.2009.04.001] [PMID: 19362576]
[32]
Yassine, H.N.; Croteau, E.; Rawat, V.; Hibbeln, J.R.; Rapoport, S.I.; Cunnane, S.C.; Umhau, J.C. DHA brain uptake and APOE4 status: a PET study with [1-11C]-DHA. Alzheimers Res. Ther., 2017, 9(1), 23.
[http://dx.doi.org/10.1186/s13195-017-0250-1] [PMID: 28335828]
[33]
Croteau, E.; Castellano, C.A.; Richard, M.A.; Fortier, M.; Nugent, S.; Lepage, M.; Duchesne, S.; Whittingstall, K.; Turcotte, É.E.; Bocti, C.; Fülöp, T.; Cunnane, S.C. Ketogenic medium chain triglycerides increase brain energy metabolism in Alzheimer’s disease. J. Alzheimers Dis., 2018, 64(2), 551-561.
[http://dx.doi.org/10.3233/JAD-180202] [PMID: 29914035]
[34]
Aliev, G.; Shahida, K.; Gan, S.H.; Firoz, C.; Khan, A.; Abuzenadah, A.M.; Kamal, W.; Kamal, M.A.; Tan, Y.; Qu, X.; Reale, M. Alzheimer disease and type 2 diabetes mellitus: The link to tyrosine hydroxylase and probable nutritional strategies. CNS Neurol. Disord. Drug Targets, 2014, 13(3), 467-477.
[http://dx.doi.org/10.2174/18715273113126660153] [PMID: 24059309]
[35]
Siew Hua, G.; Kamal, M.A.; Lima, M.M.; Khalil, M.I.; Pasupuleti, V.R.; Aliev, G. Medicinal plants in management of type 2 diabetes and neurodegenerative disorders. Evid. Based Complement. Alternat. Med., 2015. 2015686872
[http://dx.doi.org/10.1155/2015/686872] [PMID: 25873981]
[36]
Aliev, G.; Ashraf, G.M.; Kaminsky, Y.G.; Sheikh, I.A.; Sudakov, S.K.; Yakhno, N.N.; Benberin, V.V.; Bachurin, S.O. Implication of the nutritional and nonnutritional factors in the context of preservation of cognitive performance in patients with dementia/depression and Alzheimer disease. Am. J. Alzheimers Dis. Other Demen., 2013, 28(7), 660-670.
[http://dx.doi.org/10.1177/1533317513504614] [PMID: 24085255]
[37]
Geerlings, M.I.; den Heijer, T.; Koudstaal, P.J.; Hofman, A.; Breteler, M.M. History of depression, depressive symptoms, and medial temporal lobe atrophy and the risk of Alzheimer disease. Neurology, 2008, 70(15), 1258-1264.
[http://dx.doi.org/10.1212/01.wnl.0000308937.30473.d1] [PMID: 18391157]
[38]
Speck, C.E.; Kukull, W.A.; Brenner, D.E.; Bowen, J.D.; McCormick, W.C.; Teri, L.; Pfanschmidt, M.L.; Thompson, J.D.; Larson, E.B. History of depression as a risk factor for Alzheimer’s disease. Epidemiology, 1995, 6(4), 366-369.
[http://dx.doi.org/10.1097/00001648-199507000-00006] [PMID: 7548342]
[39]
Green, R.C.; Cupples, L.A.; Kurz, A.; Auerbach, S.; Go, R.; Sadovnick, D.; Duara, R.; Kukull, W.A.; Chui, H.; Edeki, T.; Griffith, P.A.; Friedland, R.P.; Bachman, D.; Farrer, L. Depression as a risk factor for Alzheimer disease: the MIRAGE Study. Arch. Neurol., 2003, 60(5), 753-759.
[http://dx.doi.org/10.1001/archneur.60.5.753] [PMID: 12756140]
[40]
Jorm, A.F. History of depression as a risk factor for dementia: An updated review. Aust. N. Z. J. Psychiatry, 2001, 35(6), 776-781.
[http://dx.doi.org/10.1046/j.1440-1614.2001.00967.x] [PMID: 11990888]
[41]
Rapp, M.A.; Schnaider-Beeri, M.; Grossman, H.T.; Sano, M.; Perl, D.P.; Purohit, D.P.; Gorman, J.M.; Haroutunian, V. Increased hippocampal plaques and tangles in patients with Alzheimer disease with a lifetime history of major depression. Arch. Gen. Psychiatry, 2006, 63(2), 161-167.
[http://dx.doi.org/10.1001/archpsyc.63.2.161] [PMID: 16461859]
[42]
Ganguli, M. Depression, cognitive impairment and dementia: Why should clinicians care about the web of causation? Indian J. Psychiatry, 2009, 51(Suppl. 1), S29-S34.
[PMID: 21416013]
[43]
Caricati-Neto, A.; Bergantin, L.B. Pharmacological modulation of neural Ca2+/camp signaling interaction as therapeutic goal for treatment of Alzheimer’s disease. J. Syst. Integr. Neurosci., 2017.3.
[http://dx.doi.org/10.15761/JSIN.1000185]
[44]
Caricati-Neto, A.; Bergantin, L.B. The passion of a scientific discovery: the “calcium paradox” due to Ca2+/camp interaction. J. Syst. Integr. Neurosci., 2017, 2017, 3.
[http://dx.doi.org/10.15761/JSIN.1000186]
[45]
Caricati-Neto, A.; Bergantin, L.B. From a “eureka insight” to a novel potential therapeutic target to treat Parkinson’s disease: The Ca2+/camp signalling interaction. J. Syst. Integr. Neurosci., 2017.
[http://dx.doi.org/10.15761/JSIN.1000187]
[46]
Bergantin, L.B.; Caricati-Neto, A. The “Calcium Paradox” and its Impact on Neurological and Psychiatric Diseases; In Cambridge Scholars Publishing: UK, 2018.
[47]
Paul, K.C.; Jerrett, M. Ritz, B Type 2 Diabetes Mellitus and Alzheimer’s Disease: Overlapping biological mechanisms and environmental risk factors. Curr. Environ. Health Rep., 2018, 5(1), 44-58.
[http://dx.doi.org/10.1007/s40572-018-0176-1]
[48]
Sommer, N.; Löschmann, P.A.; Northoff, G.H.; Weller, M.; Steinbrecher, A.; Steinbach, J.P.; Lichtenfels, R.; Meyermann, R.; Riethmüller, A.; Fontana, A. The antidepressant rolipram suppresses cytokine production and prevents autoimmune encephalomyelitis. Nat. Med., 1995, 1(3), 244-248.
[http://dx.doi.org/10.1038/nm0395-244] [PMID: 7585041]
[49]
Xiao, L.; O’Callaghan, J.P.; O’Donnell, J.M. Effects of repeated treatment with phosphodiesterase-4 inhibitors on cAMP signaling, hippocampal cell proliferation, and behavior in the forced-swim test. J. Pharmacol. Exp. Ther., 2011, 338(2), 641-647.
[http://dx.doi.org/10.1124/jpet.111.179358] [PMID: 21566211]
[50]
Fujita, M. Richards, EM cAMP signaling in brain is decreased in unmedicated depressed patients and increased by treatment with a selective serotonin reuptake inhibitor. Mol. Psychiatry, 2017, 22(5), 754-759.


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VOLUME: 20
ISSUE: 2
Year: 2020
Published on: 29 September, 2020
Page: [103 - 109]
Pages: 7
DOI: 10.2174/1871524920666200129121232
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