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Reduced Brain Antioxidant Capacity in Rat Models of Betacytotoxic-Induced Experimental Sporadic Alzheimer’s Disease and Diabetes Mellitus

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Abstract

It is believed that oxidative stress (OS) plays a central role in the pathogenesis of metabolic diseases like diabetes mellitus (DM) and its complications (like peripheral neuropathy) as well as in neurodegenerative disorders like sporadic Alzheimer’s disease (sAD). Representative experimental models of these diseases are streptozotocin (STZ)-induced diabetic rats and STZ-intracerebroventricularly (STZ-icv) treated rats, in which antioxidant capacity (AC) against peroxyl (ORAC-ROO •) and hydroxyl (ORAC-OH •) free radicals (FR) was measured in three different brain regions: the hippocampus (HPC), the cerebellum (CB), and the brain stem (BS) by means of oxygen radical absorbance capacity (ORAC) assay. In the brain of both STZ-induced diabetic and STZ-icv treated rats decreased AC has been found demonstrating regionally specific distribution. In the diabetic rats these abnormalities were not associated with the development of peripheral diabetic neuropathy (PDN). Also, these abnormalities were not prevented by the intracerebroventricularly (icv) pretreatment of glucose transport inhibitor 5–thio-d-glucose (TG) in the STZ-icv treated rats, suggesting different mechanism of STZ-induced central effects from those at the periphery. Similarities of the OS alterations in the brain of STZ-icv rats and humans with sAD could be useful in the search for the new drugs in the treatment of sAD that have antioxidant activity. In the STZ-induced diabetic animals the existence of PDN was tested by the paw pressure test, 3 weeks following the diabetes induction. Mechanical nociceptive thresholds were measured three times at 10–min intervals by applying increased pressure to the hind paw until the paw-withdrawal or overt struggling was elicited. Only those diabetic animals which demonstrated decreased withdrawal threshold values in comparison with the control non-diabetic animals (C) were considered to have developed the PDN.

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Abbreviations

AAPH:

2,2′-Azobis (2–amidino-propane) dihydrochloride

AC:

Antioxidant capacity

AD:

Alzheimer’s disease

AL:

Alloxan

AUC:

Area under curve

BCT:

Betacytotoxic

β-PE :

Beta-phycoerythrin

BS:

Brain stem

BSA:

Albumin

C:

Control non-diabetic animals

CB:

Cerebellum

DM :

Diabetes mellitus

DNA:

Deoxyribonucleic acid

f.c. :

Final concentration

FL:

Fluorescein

FR:

Free radicals

GLUT2:

Glucose transporter two

HPC:

Hippocampus

icv :

Intracerebroventricularly

ip:

Intraperitoneal

LC/MS :

Liquid chromatography/mass spectrometry

ORAC :

Oxygen radical absorbance capacity

ORAC-ROO • :

Antioxidant capacity against peroxyl free radicals

ORAC–OH • :

Antioxidant capacity against hydroxyl free radicals

OS:

Oxidative stress

PDN :

Peripheral diabetic neuropathy

ROS :

Reactive oxygen species

sAD :

Sporadic Alzheimer’s disease

sc :

Subcutaneous

STZ :

Streptozotocin

Trolox:

6–Hydroxy-2,5,7,8-tetramethyl-2-carboxylic acid

TE :

Trolox equivalents

TG:

5-Thio-d-glucose

References

  1. Altan N, Dinçel AS, Koca C (2006) Diabetes mellitus and oxidative stress. Turk J Biochem 31:51–56

    CAS  Google Scholar 

  2. Sofic E, Rustembegovic A, Kroyer G, Cao G (2002) Serum antioxidant capacity in neurological, psychiatric, renal diseases and cardiomyopathy. J Neural Transm 109:711–719

    Article  PubMed  CAS  Google Scholar 

  3. Sharma RK, Pasqualotto FF, Nelson DR, Thomas AJ Jr, Agarwal A (1999) The reactive oxygen species-total antioxidant capacity score is a new measure of oxidative stress to predict male infertility. Hum reprod 14:2801–2807

    Article  PubMed  CAS  Google Scholar 

  4. Danova K, Dobisova A, Fischer V, Halcak L, Minarova H, Olejarova I, Pechan I (2005) Production of reactive oxygen species and antioxidant defense systems in patients after coronary artery bypass grafting: one-week follow-up study. J Clin Basic Cardiol 8:33–36

    CAS  Google Scholar 

  5. Prior RL, Hoang H, Gu L, Wu X, Bacchiocca M, Howard L, Hampsch-Woodill M, Huang D, Ou B, Jacob R (2003) Assays for hydrophilic and lipophilic antioxidant capacity [oxygen radical absorbance capacity (ORAC-FL)] of plasma and other biological and food samples. J Agric Food Chem 21:3273–3279

    Article  CAS  Google Scholar 

  6. Biessels GJ, van der Heide LP, Kamal A, Bleys RL, Gispen WH (2002) Ageing and diabetes: implications for brain function. Eur J Pharmacol 441:1–14

    Article  PubMed  CAS  Google Scholar 

  7. Kumar JS, Menon VP (1993) Effect of diabetes on levels of lipid peroxides and glycolipids in rat brain. Metabolism 42(11):1435–1439

    Article  PubMed  CAS  Google Scholar 

  8. Ohkuwa T, Sato Y, Naoi M (1995) Hydroxylradical formation in diabetic rats induced by streptozotocin. Life Sci 56(21):1789–1798

    Article  PubMed  CAS  Google Scholar 

  9. Szkudelski T (2001) The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res 50:537–546

    PubMed  CAS  Google Scholar 

  10. Ding A, Nitsch R, Hoyer S (1992) Changes in brain monoaminergic neurotransmitter concentrations in rat after intracerebroventricular injections of streptozotocin. J Cereb Blood Flow Metabol 12:103–109

    CAS  Google Scholar 

  11. Lacković Z, Šalković M (1990) Streptozocin and alloxan produce alterations in rat brain monoamines independently of pancreatic beta cells destruction. Life Sci 46:49–54

    Article  PubMed  Google Scholar 

  12. Salkovic M, Sabolic I, Lackovic Z (1995) Striatal D1 and D2 receptors after intracerebroventricular applications of alloxan and streptozotocin in rat. J Neural Transm 100:127–145

    Article  Google Scholar 

  13. Salkovic-Petrisic M, Lackovic Z (2003) Intracerebroventricular administration of betacytotoxics alters expression of brain monoamine transporter genes. J Neural Transm 110:15–29

    PubMed  CAS  Google Scholar 

  14. Lannert H, Hoyer S (1998) Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci 112:1199–1208

    Article  PubMed  CAS  Google Scholar 

  15. Prickaerts J, Fahring T, Blokland A (1999) Cognitive performance and biochemical markers in septum, hippocampus and striatum of rats after an i.c.v. injection of streptozotocin: a correlation analysis. Behav Brain Res 102:73–88

    Google Scholar 

  16. Hoyer S (1998) Is sporadic Alzheimer disease the brain type of non-insulin dependent diabetes mellitus? A challenging hypothesis. J Neural Transm 105:415–422

    Article  PubMed  CAS  Google Scholar 

  17. Salkovic-Petrisic M, Tribl F, Schmidt M, Hoyer S, Riederer P (2006) Alzheimer-like changes in protein kinase B and glycogen synthase kinase-3 in rat frontal cortex and hippocampus after damage to the insulin signalling pathway. J Neurochem 96:1005–1015

    Article  PubMed  CAS  Google Scholar 

  18. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274:99–102

    Article  PubMed  CAS  Google Scholar 

  19. Sharma M, Gupta YK (2001) Effect of chronic treatment of melatoninon learning, memory and oxidative deficiencies induced by intracerebroventricular streptozotocin in rats. Pharmacol Biochem Behav 70:325–331

    Article  PubMed  CAS  Google Scholar 

  20. Sharma M, Gupta YK (2002) Chronic treatment with trans resveratrol prevents intracerebroventricular streptozotocin induced cognitive impairment and oxidative stress in rats. Life Sci 71:2489–2498

    Article  PubMed  CAS  Google Scholar 

  21. Mariani E, Polidori MC, Cherubini A, Meccoci P (2005) Oxidative stress in brain aging, neurodegenerative and vascular diseases: an overview. J Chromatogr B Analyt Technol Biomed Life Sci 827:65–75

    Article  PubMed  CAS  Google Scholar 

  22. Cao G, Alessio HM, Cutler RG (1993) Oxygen-radical absorbance capacity assay for antioxidants. Free Radical Biol Med 14:303–311

    Article  CAS  Google Scholar 

  23. Cao G, Verdon C, Wu AHB, Wang H, Prior RL (1995) Automated oxygen radical absorbance capacity assay using the COBAS FARA II. Clin Chem 41:1738–1744

    PubMed  CAS  Google Scholar 

  24. Cao G, Sofic E, Prior RL (1996) Antioxidant capacity of tea and common vegetables. J Agric Food Chem 44(11):3426–3431

    Article  CAS  Google Scholar 

  25. Cao G, Sofic E, Prior R (1997) Antioxidant and prooxidant behavior of flavonoids: structure-activity relationships. Free Radical Biol Med 22:749–760

    Article  CAS  Google Scholar 

  26. Wang CC, Chu CY, Chy KO, Choy KW, Khaw KS, Rogers MS, Pang CP (2004) Trolox equivalent antioxidant capacity assay versus oxygen radical absorbance capacity assay in plasma. Clin Chem 50:952–954

    Article  PubMed  CAS  Google Scholar 

  27. Sofic E, Sapcanin A, Tahirovic I, Gavrankapetanovic I, Jellinger K, Reynolds GP, Tatschner T, Riederer P (2006) Antioxidant capacity in postmortem brain tissues of Parkinson’s and Alzheimer’s diseases. J Neural Transm Suppl 71:39–43

    Article  PubMed  CAS  Google Scholar 

  28. Wayner DDM, Burton GW, Ingold KU, Locke S (1985) Quantitative measurement of the total, peroxyl radical-trapping antioxidant capacity of human plasma by controlled peroxidation. FEBS Lett 187:33–37

    Article  PubMed  CAS  Google Scholar 

  29. Glazer AN (1990) Phycoerythrin fluorescence-based assay for reactive oxygen species. Methods Enzymol 186:161–168

    PubMed  CAS  Google Scholar 

  30. Ghiselli A, Serafini M, Maiani G, Assini E, Ferro-Luzzi A (1994) A fluorescence-based method for measuring total plasma antioxidant capability. Free Radical Biol Med 18:29–36

    Article  Google Scholar 

  31. Grisham MB (1992) Reactive metabolites of oxygen and nitrogen in biology and medicine. Landes RG Co., Austin, TX, p 10

    Google Scholar 

  32. Ou B, Hampsch-Woodill M, Prior RL (2001) Development and validation of an improved Oxygen Radical Absorbance Capacity assay using fluorescein as the fluorescent probe. J Agric Food Chem 49:4619–4626

    Article  PubMed  CAS  Google Scholar 

  33. Noble EP, Wurtman RJ, Axelrod J (1967) A simple and rapid method for injecting H3-norepinephrine into the lateral ventricle of the rat brain. Life Sci 6:281–291

    Article  PubMed  CAS  Google Scholar 

  34. Randall LO, Selitto JJ (1957) A method for measurements of analgesic activity on inflamed tissue. Arch Int Pharmacodyn Ther 111:409–419

    PubMed  CAS  Google Scholar 

  35. Bach-Rojecky L, Lackovic Z (2005) Antinociceptive effect of botulinum toxin type A in rat model of carrageenan and capsaicin induced pain. Croat Med J 46:201–208

    PubMed  Google Scholar 

  36. Bronstein IN, Semendjajev KA (1962) Matematički priručnik za inženjere i studente. «Tehnička knjiga», Zagreb, p S457

    Google Scholar 

  37. Gernot P (1977) Proteine. In: Clinische Chemie, Kurzlehrbuch und Kommentar zum Gegenstandskatalog für den Ersten Abschnitt der Ärztlichen Prüfung 1. Auflage, Rathgeber Verlag, München, pp 308–367

  38. Kuyvenhoven JP, Meinders AE (1999) Oxidative stress and diabetes mellitus. Pathogenesis of long-term complications. Eur J Intern Med 10:9–19

    Article  CAS  Google Scholar 

  39. Evans JL, Goldfine ID, Maddux BA, Grodsky GM (2002) Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocrine Rev 23:599–622

    Article  CAS  Google Scholar 

  40. Cao G, Giovanoni M, Prior R (1996a) Antioxidant capacity in different tissues of young and old rats. Proc Soc Exp Biol Med 211:359–365

    PubMed  CAS  Google Scholar 

  41. McEwen BS, Reagan LP (2004) Glucose transporter expression in the central nervous system: relationship to synaptic function. Eur J Pharmacol 490:13–24

    Article  PubMed  CAS  Google Scholar 

  42. Grünblatt E, Salkovic-Petrisic M, Osmanovic J, Riederer P, Hoyer S (2007) Brain insulin system dysfunction in streptozotocin intracerebroventricularly treated rats generates hyperphosphorylated tau protein. J Neurochem 101(3):757–770

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Research was supported by the DAAD-German Academic Exchange Service, Stability Pact for South-Eastern Europe (project No. A/04/20017) and the Croatian Ministry of Science, Education and Sport (project No. 0108253). Mrs. Bozica Hrzan is thanked for the technical assistance.

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Authors and Affiliations

  1. Department of Chemistry, Faculty of Science, University of Sarajevo, Zmaja od Bosne 35, 71 000, Sarajevo, Bosnia and Herzegovina

    Ismet Tahirovic, Emin Sofic & Aida Sapcanin

  2. School of Medicine, University of Sarajevo, Sarajevo, Bosnia and Herzegovina

    Ismet Gavrankapetanovic

  3. Department of Pharmacology, School of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia

    Lidija Bach-Rojecky

  4. Department of Pharmacology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia

    Melita Salkovic-Petrisic & Zdravko Lackovic

  5. Department of Pathology, University Clinic, University of Heidelberg, Heidelberg, Germany

    Siegfried Hoyer

  6. Clinical Neurochemistry, Clinic and Policlinic for Psychiatry, University of Wuerzburg, Wuerzburg, Germany

    Peter Riederer

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  1. Ismet Tahirovic
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  2. Emin Sofic
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  3. Aida Sapcanin
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Correspondence to Emin Sofic.

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Special issue dedicated to Dr. Moussa Youdim.

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Tahirovic, I., Sofic, E., Sapcanin, A. et al. Reduced Brain Antioxidant Capacity in Rat Models of Betacytotoxic-Induced Experimental Sporadic Alzheimer’s Disease and Diabetes Mellitus. Neurochem Res 32, 1709–1717 (2007). https://doi.org/10.1007/s11064-007-9410-1

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