Abstract
Diabetes mellitus type 2 (T2DM) is characterized by resistance of insulin receptors and/or inadequate insulin secretion resulting in metabolic and structural complications including vascular diseases, arterial hypertension and different behavioral alterations. We aimed to study the effects of the antihypertensive angiotensin AT1 receptor antagonist losartan on the T2DM-induced changes of exploratory behavior, anxiety, nociception and short term memory in normotensive Wistar and spontaneously hypertensive rats (SHRs). The experimental model of T2DM induced by a combination of high fat diet and streptozotocin, decreased exploratory activity and increased the level of carbonylated proteins in selected brain structures in both strains; as well it increased corticosterone level, pain threshold, anxiety-like behavior, and decline short term memory only in SHRs. Losartan treatment alleviated some of the T2DM- induced metabolic complications, abolished the T2DM-induced hypo activity, and normalized the corticosterone level, carbonylated proteins in brain, nociception and memory. Losartan did not exert effect on the anxiety behavior in both strains. We showed that T2DM exerted more pronounced negative effects on the rats with comorbid hypertension as compared to normotensive rats. Overall effects on the studied behavioral parameters are related to decreased exploration of the new environment, increased anxiety-like behavior, and decline in short-term memory. The systemic sub-chronic treatment with an angiotensin AT1 receptor antagonist losartan ameliorated most of these complications.
Similar content being viewed by others
References
Aksu I, Ates M, Baykara B, Kiray M, Sisman AR, Buyuk E, Baykara B, Cetinkaya C, Gumus H, Uysal N (2012) Anxiety correlates to decreased blood and prefrontal cortex IGF-1 levels in streptozotocin induced diabetes. Neurosci Lett 531(2):176–181. https://doi.org/10.1016/j.neulet.2012.10.045
Ali Q, Wu Y, Hussain T (2013) Chronic AT2 receptor activation increases renal ACE2 activity, attenuates AT1 receptor function and blood pressure in obese Zucker rats. Kidney Int 84(5):931–939. https://doi.org/10.1038/ki.2013.193
Anseloni VC, Ennis M, Lidow MS (2003) Optimization of the mechanical nociceptive threshold testing with the Randall–Selitto assay. J Neurosci Methods 131:93–97
Barnard ND, Bunner AE, Agarwal U (2014) Saturated and trans fats and dementia: a systematic review. Neurobiol Aging 35(2):S65–S73. https://doi.org/10.1016/j.neurobiolaging.2014.02.030
Bosnyak S, Welungoda IK, Hallberg A, Alterman M, Widdop RE, Jones ES (2010) Stimulation of angiotensin AT2 receptors by the non-peptide agonist, compound 21, evokes vasodepressor effects in conscious spontaneously hypertensive rats. Br J Pharmacol 159(3):709–716. https://doi.org/10.1111/j.1476-5381.2009.00575.x
Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S (2001) Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345(12):861–869
Bunnemann B, Iwai N, Metzger R, Fuxe K, Inagami T, Ganten D (1992) The distribution of angiotensin II AT1 receptor subtype mRNA in the rat brain. Neurosci Lett 142:155–158
Cade WT (2008) Diabetes-related microvascular and macrovascular diseases in the physical therapy setting. Phys Ther 88(11):1322–1335. https://doi.org/10.2522/ptj.20080008
Carlini VP, Ghersi M, Gabach L, Schiöth HB, Pérez MF, Ramirez OA, Fiol de Cuneo M, de Barioglio SR (2011) Hippocampal effects of neuronostatin on memory, anxiety-like behavior and food intake in rats. Neuroscience 197:145–152. https://doi.org/10.1016/j.neuroscience.2011.09.040
Castanon N, Hendley ED, Fan XM, Mormede P, Castanon N, Hendley ED, Fan XM, Mormede P (1993) Psychoneuroendocrine profile associated with hypertension or hyperactivity in spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol 265(6). https://doi.org/10.1152/ajpregu.1993.265.6.R13047
Chen R, Shi J, Yin Q, Li X, Sheng Y, Han J, Zhuang P, Zhang Y (2018) Morphological and pathological characteristics of brain in diabetic encephalopathy. J Alzheimers Dis 65(1):15–28. https://doi.org/10.3233/JAD-180314
Coppey LJ, Davidson EP, Rinehart TW, Gellett JS, Oltman CL, Lund DD, Yorek MA (2006) ACE inhibitor or angiotensin II receptor antagonist attenuates diabetic neuropathy in streptozotocin-induced diabetic rats. Diabetes 55(2):341–348
Costa-Ferreira W, Morais-Silva G, Gomes-de-Souza L, Marin MT, Crestani CC (2019) The AT1 receptor antagonist losartan does not affect depressive-like state and memory impairment evoked by chronic stressors in rats. Front Pharmacol 10:705
Da Silva CZ, Menani JV, Callera JC (2011) AT1 receptor blockade in the lateral parabrachial nucleus reduces the effects of muscimol on sodium intake. Brain Res 1403:28–36. https://doi.org/10.1016/j.brainres.2011.06.004
Dalle-Donne I, Aldini G, Carini M, Colombo R, Rossi R, Milzani A (2006) Protein carbonylation, cellular dysfunction, and disease progression. J Cell Mol Med 10:389–406
de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T (2000) International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev 52(3):415–472
De Rosa S, Arcidiacono B, Chiefari E, Brunetti A, Indolfi C, Foti DP (2018) Type 2 diabetes mellitus and cardiovascular disease: genetic and epigenetic links. Front Endocrinol (Lausanne). 9:2. https://doi.org/10.3389/fendo.2018.00002 eCollection 2018
Gard PR (2002) The role of angiotensin II in cognition and behaviour. Eur J Pharmacol 438(1–2):1–14
Giacchetti G, Sechi LA, Rilli S, Carey RM (2005) The renin-angiotensin-aldosterone system, glucose metabolism and diabetes. Trends Endocrinol Metab 16(3):120–126
Gispen WH, Biessels GJ (2000) Cognition and synaptic plasticity in diabetes mellitus. Trends Neurosci 23(11):542–549
Guimond MO, Gallo-Payet N (2012) How does angiotensin AT (2) receptor activation help neuronal differentiation and improve neuronal pathological situations? Front Endocrinol (Lausanne) 3:164. https://doi.org/10.3389/fendo.2012.00164 eCollection 2012
Hecker M, Wagner AH (2018) Role of protein carbonylation in diabetes. Inherit Metab Dis 41(1):29–38. https://doi.org/10.1007/s10545-017-0104-9
Holmes A, Coppey LJ, Davidson EP, Yorek MA (2015) Rat Models of Diet-Induced Obesity and High Fat/Low Dose Streptozotocin Type 2 Diabetes: Effect of Reversal of High Fat Diet Compared to Treatment with Enalapril or Menhaden Oil on Glucose Utilization and Neuropathic Endpoints. J Diabetes Res, Article ID 307285, 8 pages. https://doi.org/10.1155/2015/307285
Hu B, Qiao H, Sun B, Jia R, Fan Y, Wang N, Lu B, Yan JQ (2015) AT1 receptor blockade in the central nucleus of the amygdala attenuates the effects of muscimol on sodium and water intake. Neuroscience 307:302–310. https://doi.org/10.1016/j.neuroscience.2015.08.069
Irani DN (2017) Cerebrospinal fluid protein carbonylation identifies oxidative damage in autoimmune demyelination. Ann Clin Transl Neurol 4:145–150
Irvine RJ, White JM, Head RJ (1995) The renin angiotensin system and nociception in spontaneously hypertensive rats. Life Sci 56(13):1073–1078
Iwanami J, Horiuchi M (2012) Peroxisome proliferator-activated receptor- activation with angiotensin II type 1 receptor blockade is pivotal for the prevention of blood-brain barrier impairment and cognitive decline in type 2 diabetic mice. Hypertension. 59:1079–1088
Iwanami J, Mogi M, Tsukuda K, Jing F, Ohshima K, Wang XL, Nakaoka H, Kanno H, Chisaka T, Bai HY, Min LJ, Horiuchi M (2014) Possible synergistic effect of direct angiotensin II type 2 receptor stimulation by compound 21 with memantine on prevention of cognitive decline in type 2 diabetic mice. Eur J Pharmacol 724:9–15. https://doi.org/10.1016/j.ejphar.2013.12.015
Kalani A, Chaturvedi P, Maldonado C, Bauer P, Joshua IG, Tyagi SC, Tyagi N (2017) Dementia-like pathology in type-2 diabetes: a novel microRNA mechanism. Mol Cell Neurosci 80:58–65. https://doi.org/10.1016/j.mcn.2017.02.005
Kim MS, Lee GH, Kim YM, Lee BW, Nam HY, Sim UC, Choo SJ, Yu SW, Kim JJ, Kim Kwon Y, Who KS (2017) Angiotensin II causes apoptosis of adult hippocampal neural stem cells and memory impairment through the action on AMPK-PGC1α signaling in heart failure. Stem Cells Transl Med 6(6):1491–1503. https://doi.org/10.1002/sctm.16-0382
Kubo T, Yamaguchi H, Tsujimura M, Hagiwara Y, Fukumori R (2000) An angiotensin system in the anterior hypothalamic area anterior is involved in the maintenance of hypertension in spontaneously hypertensive rats. Brain Res Bull 52:291–296
Lewis EJ, Hunsicker LG, Berl T, Clarke WR, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I (2001) Renoprotective effect of the angiotensin receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345:851–860. https://doi.org/10.1056/NEJMoa011303
Li Y, Nishimura T, Teruya K, Maki T, Komatsu T, Hamasaki T, Kashiwagi T, Kabayama S, Shim SY, Katakura Y, Osada K, Kawahara T, Otsubo K, Morisawa S, Ishii Y, Gadek Z, Shirahata S (2002) Protective mechanism of reduced water against alloxan-induced pancreatic beta-cell damage: Scavenging effect against reactive oxygen species. Cytotechnology 40(1–3):139–149. https://doi.org/10.1023/A:1023936421448
Liu J, Wang YH, Li W, Liu L, Yang H, Meng P, Han YS (2019) Structural and functional damage to the hippocampal neurovascular unit in diabetes-related depression. Neural Regen Res 14(2):289–297
Miesel A, Müller-Fielitz H, Jöhren O, Vogt FM, Raasch W (2012) Double blockade of angiotensin II (AT(1) )-receptors and ACE does not improve weight gain and glucose homeostasis better than single-drug treatments in obese rats. Br J Pharmacol 165(8):2721–2735. https://doi.org/10.1111/j.1476-5381.2011.01726.x
Müller-Fielitz H, Markert A, Wittmershaus C, Pahlke F, Jöhren O, Raasch W (2011) Weight loss and hypophagia after high-dose AT1-blockade is only observed after high dosing and depends on regular leptin signalling but not blood pressure. Naunyn Schmiedeberg's Arch Pharmacol 383(4):373–384. https://doi.org/10.1007/s00210-011-0602-5
Müller-Fielitz H, Hübel N, Mildner M, Vogt FM, Barkhausen J, Raasch W (2014) Chronic blockade of angiotensin AT1 receptors improves cardinal symptoms of metabolic syndrome in diet-induced obesity in rats. Br J Pharmacol 171(3):746–760. https://doi.org/10.1111/bph.12510
Müller-Fielitz H, Lau M, Geißler C, Werner L, Winkler M, Raasch W (2015) Preventing leptin resistance by blocking angiotensin II AT1 receptors in diet-induced obese rats. Br J Pharmacol 172(3):857–868. https://doi.org/10.1111/bph.12949
Murali B, Goyal RK (2002) Effect of chronic treatment with losartan on streptozotocin induced diabetic rats. Indian J Exp Biol 40(1):31–34
Nomaр K, Toshinaiр K, Koshinakaр K, Nakazatoр M (2011) Telmisartan suppresses food intake in mice via the melanocortin pathway. Obes Res Clin Pract 5(2):e79–e156. https://doi.org/10.1016/j.orcp.2010.11.003
Ogata Y, Nemoto W, Nakagawasai O, Yamagata R, Tadano T, Tan-No K (2016) Involvement of spinal Angiotensin II system in Streptozotocin-induced diabetic neuropathic pain in mice. Mol Pharmacol 90(3):205–213. https://doi.org/10.1124/mol.116.104133
Paxinos G, Watson C (1998) The rat brain, 4th edn. Academic Press, Cambidge
Pechlivanova DM, Stoynev AG (2013) Effect of chronic treatment with angiotensin receptor ligands on water-salt balance in Wistar and spontaneously hypertensive rats. Folia Med (Plovdiv) 55(3–4):63–69
Pechlivanova DM, Markova PP, Stoynev AG (2010) Effect of the AT1 receptor antagonist losartan on diurnal variation in pain threshold in spontaneously hypertensive rats. Methods Find Exp Clin Pharmacol 32(9):663–668. https://doi.org/10.1358/mf.2010.32.9.1529826
Pechlivanova DM, Stoynev AG, Tchekalarova JD (2011) The effects of chronic losartan pretreatment on restraint stress-induced changes in motor activity, nociception and pentylenetetrazol generalized seizures in rats. Folia Med (Plovdiv) 53:69–73
Pechlivanova D, Petrov K, Grozdanov P, Nenchovska Z, Tchekalarova J, Stoynev A (2018) Intracerebroventricular infusion of angiotensin AT2 receptor agonist novokinin aggravates some diabetes-mellitus-induced alterations in Wistar rats. Can J Physiol Pharmacol 96(5):471–478. https://doi.org/10.1139/cjpp-2017-0428
Pellow S, Chopin P, File S, Briley M (1985) Validation of open:closed arm entries in an elevated plus maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167
Pietranera L, Saravia F, Gonzalez Deniselle MC, Roig P, Lima A, De Nicola AF (2006) Abnormalities of the hippocampus are similar in deoxycorticosterone acetate-salt hypertensive rats and spontaneously hypertensive rats. J Neuroendocrinol 18(6):466–474
Premkumar LS, Pabbidi RM (2013) Diabetic peripheral neuropathy: role of reactive oxygen and nitrogen species. Cell Biochem Biophys 67(2):373–383. https://doi.org/10.1007/s12013-013-9609-5
Raghavendra V, Chopra K, Kulkarni SK (1999) Brain renin angiotensin system (RAS) in stress-induced analgesia and impaired retention. Peptides 20(3):335–342
Raizada MK, Sumners C, Lu D (1993) Angiotensin II type 1 receptor mRNA levels in the brains of normotensive and spontaneously hypertensive rats. J Neurochem 60:1949–1952
Risérus U, Willett WC, Hu FB (2009) Dietary fats and prevention of type 2 diabetes. Prog Lipid Res 48(1):44–51. https://doi.org/10.1016/j.plipres.2008.10.002
Saavedra JM (1999) Emerging features of brain angiotensin receptors. Regul Pept 85:31–45
Saavedra JM (2012) Angiotensin II AT(1) receptor blockers as treatments for inflammatory brain disorders. Clin Sci (Lond) 123(10):567–590. https://doi.org/10.1042/CS20120078
Sharieh Hosseini SG, Khatamsaz S, Shariati M (2014) The effects of losartan on memory performance and leptin resistance induced by obesity and high-fat diet in adult male rats. Iran J Basic Med Sci 17(1):41–48
Shi Y, Sun X, Sun Y, Hou L, Yao M, Lian K, Li J, Lu X, Jiang L (2016) Elevation of cortical C26:0 due to the decline of peroxisomal β-oxidation potentiates amyloid β generation and spatial memory deficits via oxidative stress in diabetic rats. Neuroscience 315:125–135. https://doi.org/10.1016/j.neuroscience.2015.11.067
Silva KC, Rosales MAB, Biswas SK, Lopes de Faria JB, Lopes de Faria JM (2009) 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 58(6):1382–1390. https://doi.org/10.2337/db09-0166
Sinnreich M, Taylor BV, Dyck PJ (2005) Diabetic neuropathies. Classification, clinical features, and pathophysiological basis. Neurologist 11(2):63–79
Sumners C, de Kloet AD, Krause EG, Unger T, Steckelings UM (2015) Angiotensin type 2 receptors: blood pressure regulation and end organ damage. Curr Opin Pharmacol 21:115–121. https://doi.org/10.1016/j.coph.2015.01.004
Van Dyk DJ, Erman A, Erman T, Chen-Gal B, Sulkes J, Boner G (1994) Increased serum angiotensin converting enzyme activity in type I insulin-dependent diabetes mellitus: its relation to metabolic control and diabetic complications. Eur J Clin Investig 24:463–467
Veerasingham SJ, Raizada MK (2003) Brain renin-angiotensin system dysfunction in hypertension: recent advances and perspectives. Br J Pharmacol 139(2):191–202
Winkler M, Schuchard J, Stölting I, Vogt FM, Barkhausen J, Thorns C, Bader M, Raasch W (2016) The brain renin-angiotensin system plays a crucial role in regulating body weight in diet-induced obesity in rats. Br J Pharmacol 173(10):1602–1617. https://doi.org/10.1111/bph.13461
Wright JW, Harding JW (1995) Brain angiotensin receptor subtypes AT1, AT2, and AT4 and their functions. Regul Pept 59(3):269–295
Yamada Y, Yamauchi D, Yokoo M, Ohinata K, Usui H, Yoshikawa M (2008) A potent hypotensive peptide, novokinin, induces relaxation by AT2- and IP-receptor-dependent mechanism in the mesenteric artery from SHRs. Biosci Biotechnol Biochem 72(1):257–259
Acknowledgements
The research was supported by Grant 20/2016 of the Medical University of Sofia, Bulgaria.
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Pechlivanova, D., Krumova, E., Kostadinova, N. et al. Protective effects of losartan on some type 2 diabetes mellitus-induced complications in Wistar and spontaneously hypertensive rats. Metab Brain Dis 35, 527–538 (2020). https://doi.org/10.1007/s11011-020-00534-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-020-00534-1