Skip to main content
Log in

Brain effect of insulin and clonazepam in diabetic rats under depressive-like behavior

  • Original Paper
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Diabetes mellitus is characterized by hyperglycemia resulting from defects on insulin secretion, insulin action, or both. It has recently become clear that the central nervous system is not spared from the deleterious effects of diabetes, since diabetic encephalopathy was recognized as a complication of this heterogeneous metabolic disorder. There is a well recognized association between depression and diabetes, once prevalence of depression in diabetic patients is higher than in general population, and clonazepam is being used to treat this complication. Oxidative stress is widely accepted as playing a key mediatory role in the development and progression of diabetes and its complications. In this work we analyzed DNA damage by comet assay and lipid damage in prefrontal cortex, hippocampus and striatum of streptozotocin-induced diabetic rats submitted to the forced swimming test. It was verified that the diabetic group presented DNA and lipid damage in the brain areas evaluated, when compared to the control groups. Additionally, a significant reduction of the DNA and lipid damage in animals treated with insulin and/or clonazepam was observed. These data suggest that the association of these two drugs could protect against DNA and lipid damage in diabetic rats submitted to the forced swimming test, an animal model of depression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Barber M, Kasturi BS, Austin ME, Patel KP, MohanKumar SM, MohanKumar PS (2003) Diabetes-induced neuroendocrine changes in rats: role of brain monoamines, insulin and leptin. Brain Res 964(1):128–135

    Article  PubMed  CAS  Google Scholar 

  • Bhatia S, Shukla R, Venkata Madhu S, Kaur Gambhir J, Madhava Prabhu K (2003) Antioxidant status, lipid peroxidation and nitric oxide end products in patients of type 2 diabetes mellitus with nephropathy. Clin Biochem 36(7):557–562

    Article  PubMed  CAS  Google Scholar 

  • Biessels GJ, Gispen WH (2005) The impact of diabetes on cognition: what can be learned from rodent models? Neurobiol Aging 26(Suppl 1):36–41. doi:10.1016/j.neurobiolaging.2005.08.015

    Article  PubMed  Google Scholar 

  • Blasi C, Jeanrenaud B (1993) Insulin resistance syndrome: defective GABA neuromodulation as a possible hereditary pathogenetic factor (the ‘GABA hypothesis’). Med Hypotheses 40(4):197–206

    Article  PubMed  CAS  Google Scholar 

  • Bouwman V, Adriaanse MC, Van ’t Riet E, Snoek FJ, Dekker JM, Nijpels G (2010) Depression, anxiety and glucose metabolism in the general dutch population: the new Hoorn study. PLoS One 5(4):e9971. doi:10.1371/journal.pone.0009971

    Article  PubMed  Google Scholar 

  • Brands AM, Biessels GJ, de Haan EH, Kappelle LJ, Kessels RP (2005) The effects of type 1 diabetes on cognitive performance: a meta-analysis. Diabetes Care 28(3):726–735

    Article  PubMed  Google Scholar 

  • Ceretta LB, Reus GZ, Stringari RB, Ribeiro KF, Zappellini G, Aguiar BW, Pfaffenseller B, Lersh C, Kapczinski F, Quevedo J (2012) Imipramine treatment reverses depressive-like behavior in alloxan-diabetic rats. Diabetes Metab Res Rev 28(2):139–144

    Article  PubMed  CAS  Google Scholar 

  • Ceriello A (2003) New insights on oxidative stress and diabetic complications may lead to a “causal” antioxidant therapy. Diabetes Care 26(5):1589–1596

    Article  PubMed  CAS  Google Scholar 

  • da Silva Haeser A, Sitta A, Barschak AG, Deon M, Barden AT, Schmitt GO, Landgraff S, Gomez R, Barros HM, Vargas CR (2007) Oxidative stress parameters in diabetic rats submitted to forced swimming test: the clonazepam effect. Brain Res 1154:137–143. doi:10.1016/j.brainres.2007.03.088

    Article  CAS  Google Scholar 

  • Esterbauer H (1993) Cytotoxicity and genotoxicity of lipid-oxidation products. Am J Clin Nutr 57(5 Suppl):779S–785S, discussion 785S–786S

    PubMed  CAS  Google Scholar 

  • Figlewicz DP, Szot P (1991) Insulin stimulates membrane phospholipid metabolism by enhancing endogenous alpha 1-adrenergic activity in the rat hippocampus. Brain Res 550(1):101–107

    Article  PubMed  CAS  Google Scholar 

  • Figlewicz DP, Ikeda H, Hunt TR, Stein LJ, Dorsa DM, Woods SC, Porte D Jr (1986) Brain insulin binding is decreased in Wistar Kyoto rats carrying the ‘fa’ gene. Peptides 7(1):61–65

    Article  PubMed  CAS  Google Scholar 

  • Gomez R, Barros HM (2000) Ethopharmacology of the antidepressant effect of clonazepam in diabetic rats. Pharmacol Biochem Behav 66(2):329–335

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez JS, Peyrot M, McCarl LA, Collins EM, Serpa L, Mimiaga MJ, Safren SA (2008) Depression and diabetes treatment nonadherence: a meta-analysis. Diabetes Care 31(12):2398–2403. doi:10.2337/dc08-1341

    Article  PubMed  Google Scholar 

  • Hartmann A, Agurell E, Beevers C, Brendler-Schwaab S, Burlinson B, Clay P, Collins A, Smith A, Speit G, Thybaud V, Tice RR (2003) Recommendations for conducting the in vivo alkaline Comet assay. 4th International Comet Assay Workshop. Mutagenesis 18(1):45–51

    Article  PubMed  CAS  Google Scholar 

  • Hilakivi-Clarke LA, Wozniak KM, Durcan MJ, Linnoila M (1990) Behavior of streptozotocin-diabetic mice in tests of exploration, locomotion, anxiety, depression and aggression. Physiol Behav 48(3):429–433

    Article  PubMed  CAS  Google Scholar 

  • Holmes CS, Richman LC (1985) Cognitive profiles of children with insulin-dependent diabetes. J Dev Behav Pediatr 6(6):323–326

    Article  PubMed  CAS  Google Scholar 

  • Karatepe M (2004) Simultaneous determination of ascorbic acid and free malondialdehyde in human serum by HPLC-UV. LCGC North Am 22(5):362–365

    CAS  Google Scholar 

  • Kocic R, Pavlovic D, Kocic G (2007) Impact of intensive insulin treatment on the development and consequences of oxidative stress in insulin-dependent diabetes mellitus. Vojnosanit Pregl 64(9):623–628

    Article  PubMed  Google Scholar 

  • Landar A, Zmijewski JW, Dickinson DA, Le Goffe C, Johnson MS, Milne GL, Zanoni G, Vidari G, Morrow JD, Darley-Usmar VM (2006) Interaction of electrophilic lipid oxidation products with mitochondria in endothelial cells and formation of reactive oxygen species. Am J Physiol Heart Circ Physiol 290(5):H1777–H1787. doi:10.1152/ajpheart.01087.2005

    Article  PubMed  CAS  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193(1):265–275

    PubMed  CAS  Google Scholar 

  • Lustman PJ, Anderson RJ, Freedland KE, de Groot M, Carney RM, Clouse RE (2000) Depression and poor glycemic control: a meta-analytic review of the literature. Diabetes Care 23(7):934–942

    Article  PubMed  CAS  Google Scholar 

  • Manfredini V, Biancini GB, Vanzin CS, Dal Vesco AM, Cipriani F, Biasi L, Tremea R, Deon M, Peralba Mdo C, Wajner M, Vargas CR (2010) Simvastatin treatment prevents oxidative damage to DNA in whole blood leukocytes of dyslipidemic type 2 diabetic patients. Cell Biochem Funct 28(5):360–366. doi:10.1002/cbf.1654

    Article  PubMed  CAS  Google Scholar 

  • Marks JL, Maddison J, Eastman CJ (1988) Subcellular localization of rat brain insulin binding sites. J Neurochem 50(3):774–781

    Article  PubMed  CAS  Google Scholar 

  • Matsumoto H, Rhoads DE (1990) Specific binding of insulin to membranes from dendrodendritic synaptosomes of rat olfactory bulb. J Neurochem 54(1):347–350

    Article  PubMed  CAS  Google Scholar 

  • Mijnhout GS, Scheltens P, Diamant M, Biessels GJ, Wessels AM, Simsek S, Snoek FJ, Heine RJ (2006) Diabetic encephalopathy: a concept in need of a definition. Diabetologia 49(6):1447–1448. doi:10.1007/s00125-006-0221-8

    Article  PubMed  CAS  Google Scholar 

  • Morishita S (2009) Clonazepam as a therapeutic adjunct to improve the management of depression: a brief review. Hum Psychopharmacol 24(3):191–198. doi:10.1002/hup.1015

    Article  PubMed  CAS  Google Scholar 

  • Nadin SB, Vargas-Roig LM, Ciocca DR (2001) A silver staining method for single-cell gel assay. J Histochem Cytochem 49(9):1183–1186

    Article  PubMed  CAS  Google Scholar 

  • Naudi A, Jove M, Ayala V, Cassanye A, Serrano J, Gonzalo H, Boada J, Prat J, Portero-Otin M, Pamplona R (2012) Cellular dysfunction in diabetes as maladaptive response to mitochondrial oxidative stress. Exp Diabetes Res 2012:696215. doi:10.1155/2012/696215

    Article  PubMed  Google Scholar 

  • Pan HZ, Zhang H, Chang D, Li H, Sui H (2008) The change of oxidative stress products in diabetes mellitus and diabetic retinopathy. Br J Ophthalmol 92(4):548–551. doi:10.1136/bjo.2007.130542

    Article  PubMed  Google Scholar 

  • Ramanathan M, Jaiswal AK, Bhattacharya SK (1998) Differential effects of diazepam on anxiety in streptozotocin induced diabetic and non-diabetic rats. Psychopharmacology (Berl) 135(4):361–367

    Article  CAS  Google Scholar 

  • Robles GI, Singh-Franco D (2009) A review of exenatide as adjunctive therapy in patients with type 2 diabetes. Drug Des Dev Ther 3:219–240

    Article  CAS  Google Scholar 

  • Rudolph U, Mohler H (2006) GABA-based therapeutic approaches: GABAA receptor subtype functions. Curr Opin Pharmacol 6(1):18–23. doi:10.1016/j.coph.2005.10.003

    Article  PubMed  CAS  Google Scholar 

  • Schwartz MW, Figlewicz DP, Baskin DG, Woods SC, Porte D Jr (1992) Insulin in the brain: a hormonal regulator of energy balance. Endocr Rev 13(3):387–414

    PubMed  CAS  Google Scholar 

  • Sima AA, Kamiya H, Li ZG (2004) Insulin, C-peptide, hyperglycemia, and central nervous system complications in diabetes. Eur J Pharmacol 490(1–3):187–197. doi:10.1016/j.ejphar.2004.02.056

    Article  PubMed  CAS  Google Scholar 

  • Singh NP, McCoy MT, Tice RR, Schneider EL (1988) A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res 175(1):184–191

    Article  PubMed  CAS  Google Scholar 

  • Speit G, Hartmann A (1995) The contribution of excision repair to the DNA effects seen in the alkaline single cell gel test (comet assay). Mutagenesis 10(6):555–559

    Article  PubMed  CAS  Google Scholar 

  • Styskal J, Van Remmen H, Richardson A, Salmon AB (2012) Oxidative stress and diabetes: what can we learn about insulin resistance from antioxidant mutant mouse models? Free Radic Biol Med 52(1):46–58. doi:10.1016/j.freeradbiomed.2011.10.441

    Article  PubMed  CAS  Google Scholar 

  • Tice RR, Agurell E, Anderson D, Burlinson B, Hartmann A, Kobayashi H, Miyamae Y, Rojas E, Ryu JC, Sasaki YF (2000) Single cell gel/comet assay: guidelines for in vitro and in vivo genetic toxicology testing. Environ Mol Mutagen 35(3):206–221

    Article  PubMed  CAS  Google Scholar 

  • Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39(1):44–84. doi:10.1016/j.biocel.2006.07.001

    Article  PubMed  CAS  Google Scholar 

  • Wan Q, Xiong ZG, Man HY, Ackerley CA, Braunton J, Lu WY, Becker LE, MacDonald JF, Wang YT (1997) Recruitment of functional GABA(A) receptors to postsynaptic domains by insulin. Nature 388(6643):686–690. doi:10.1038/41792

    Article  PubMed  CAS  Google Scholar 

  • Wayhs CA, Manfredini V, Sitta A, Deon M, Ribas G, Vanzin C, Biancini G, Ferri M, Nin M, Barros HM, Vargas CR (2010a) Protein and lipid oxidative damage in streptozotocin-induced diabetic rats submitted to forced swimming test: the insulin and clonazepam effect. Metab Brain Dis 25(3):297–304. doi:10.1007/s11011-010-9211-0

    Article  PubMed  CAS  Google Scholar 

  • Wayhs CA, Manfredini V, Sitta A, Deon M, Ribas GS, Vanzin CS, Biancini GB, Nin MS, Barros HM, Vargas CR (2010b) Effects of insulin and clonazepam on DNA damage in diabetic rats submitted to the forced swimming test. Mutat Res 703(2):187–190. doi:10.1016/j.mrgentox.2010.08.017

    Article  PubMed  CAS  Google Scholar 

  • Wei LT, Matsumoto H, Rhoads DE (1990) Release of immunoreactive insulin from rat brain synaptosomes under depolarizing conditions. J Neurochem 54(5):1661–1665

    Article  PubMed  CAS  Google Scholar 

  • Wiernsperger NF (2003) Oxidative stress as a therapeutic target in diabetes: revisiting the controversy. Diabetes Metab 29(6):579–585

    Article  PubMed  CAS  Google Scholar 

  • Wilcox BJ, Corp ES, Dorsa DM, Figlewicz DP, Greenwood MR, Woods SC, Baskin DG (1989) Insulin binding in the hypothalamus of lean and genetically obese Zucker rats. Peptides 10(6):1159–1164

    Article  PubMed  CAS  Google Scholar 

  • Young IS, Woodside JV (2001) Antioxidants in health and disease. J Clin Pathol 54(3):176–186

    Article  PubMed  CAS  Google Scholar 

  • Zhao WQ, Alkon DL (2001) Role of insulin and insulin receptor in learning and memory. Mol Cell Endocrinol 177(1–2):125–134

    Article  PubMed  CAS  Google Scholar 

  • Zhao W, Chen H, Xu H, Moore E, Meiri N, Quon MJ, Alkon DL (1999) Brain insulin receptors and spatial memory. Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. J Biol Chem 274(49):34893–34902

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Mario Serapião for his technical support. We also appreciate the financial support from Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundo de Incentivo à Pesquisa e Eventos do Hospital de Clínicas de Porto Alegre (FIPE/HCPA). CRV is the recipient of a CNPq 2 Researcher Productivity Grant. HMTB is the recipient of a CNPq 1C Researcher Productivity Grant, and CAYW and CPM are recipients of fellowships from the CNPq or CAPES.

Conflict of interest

The authors declare that there are no conflicts of interest including any financial, personal or other relationships with other people or organizations.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Carlos Alberto Yasin Wayhs.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wayhs, C.A.Y., Mescka, C.P., Vanzin, C.S. et al. Brain effect of insulin and clonazepam in diabetic rats under depressive-like behavior. Metab Brain Dis 28, 563–570 (2013). https://doi.org/10.1007/s11011-013-9397-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-013-9397-z

Keywords

Navigation