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Effects of acute administration of mazindol on brain energy metabolism in adult mice

Published online by Cambridge University Press:  19 September 2013

Cinara Ludvig Gonçalves ,
Giselli Scaini ,
Gislaine Tezza Rezin ,
Isabela Casagrande Jeremias ,
Gisele Daiane Bez ,
Juliana Felipe Daufenbach ,
Lara Mezari Gomes ,
Gabriela Kozuchovski Ferreira ,
Alexandra Ioppi Zugno  and
Emilio Luiz Streck
Cinara Ludvig Gonçalves
Affiliation:
Laboratório de Bioenergética, Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, Porto Alegre, RS, Brazil Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Florianópolis, SC, Brazil
Giselli Scaini
Affiliation:
Laboratório de Bioenergética, Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, Porto Alegre, RS, Brazil Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Florianópolis, SC, Brazil
Gislaine Tezza Rezin
Affiliation:
Laboratório de Bioenergética, Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, Porto Alegre, RS, Brazil Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Florianópolis, SC, Brazil
Isabela Casagrande Jeremias
Affiliation:
Laboratório de Bioenergética, Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, Porto Alegre, RS, Brazil Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Florianópolis, SC, Brazil
Gisele Daiane Bez
Affiliation:
Laboratório de Bioenergética, Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, Porto Alegre, RS, Brazil Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Florianópolis, SC, Brazil
Juliana Felipe Daufenbach
Affiliation:
Laboratório de Bioenergética, Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, Porto Alegre, RS, Brazil Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Florianópolis, SC, Brazil
Lara Mezari Gomes
Affiliation:
Laboratório de Bioenergética, Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, Porto Alegre, RS, Brazil Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Florianópolis, SC, Brazil
Gabriela Kozuchovski Ferreira
Affiliation:
Laboratório de Bioenergética, Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, Porto Alegre, RS, Brazil Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Florianópolis, SC, Brazil
Alexandra Ioppi Zugno
Affiliation:
Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, Porto Alegre, RS, Brazil Laboratório de Neurociências, Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
Emilio Luiz Streck*
Affiliation:
Laboratório de Bioenergética, Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, Porto Alegre, RS, Brazil Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Florianópolis, SC, Brazil
*
Prof. Emilio L. Streck, Laboratório de Bioenergética, Universidade do Extremo Sul Catarinense, Av. Universitária, 1105, Criciúma, 88806-000 SC, Brazil. Tel: +55 48 3431 2539; Fax: +55 48 3431 2644; E-mail: emiliostreck@gmail.com
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Abstract

Objectives

Mazindol is a sympathomimetic amine, widely used as an anorectic agent in the treatment of obesity. This drug causes psychostimulant effects because of its pharmacological profile similar to amphetamine, acting like a monoamine reuptake inhibitor. However, the mechanisms underlying the action of mazindol are still not clearly understood.

Methods

Swiss mice received a single acute administration of mazindol (0.25, 1.25 and 2.5 mg/kg, ip) or saline. After 2 h, the animals were killed by decapitation; the brain was removed and used for the evaluation of activities of mitochondrial respiratory chain complexes, Krebs cycle enzymes and creatine kinase.

Results

Acute administration of mazindol decreased complex I activity only in the hippocampus. Complex IV activity was increased in the cerebellum (2.5 mg/kg) and cerebral cortex (0.25 mg/kg). Citrate synthase activity was increased in the cerebellum (1.25 mg/kg) and cerebral cortex (1.25 mg/kg), and creatine kinase activity was increased in the cerebellum (1.25 mg/kg).

Conclusion

We suggest that the inhibition of complex I in the hippocampus only and activation of complex IV, citrate synthase and creatine kinase occurs because of a stimulus effect of mazindol in the central nervous system, which causes a direct impairment on energy metabolism.

Keywords

braincreatine kinasekrebs cyclemazindolmitochondrial respiratory chain
Type
Original Articles
Information
Acta Neuropsychiatrica , Volume 26 , Issue 3 , June 2014 , pp. 146 - 154
Copyright
Copyright © Scandinavian College of Neuropsychopharmacology 2013 

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References

1.Sakane, N. Pharmacology in health foods: merits and demerits of food with health claims for the prevention of metabolic syndrome. J Pharmacol Sci 2011;115:476–480.Google Scholar
2.Haslam, W, James, WP. Obesity. Lancet 2005;366:1197–1209.Google Scholar
3.Brunt, EM. Pathology of non-alcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 2010;7:195–203.CrossRefGoogle Scholar
4.Barnes, DE, Yaffe, K. The projected effect of risk factor reduction on Alzheimer's disease prevalence. Lancet Neurol 2011;10:819–828.Google Scholar
5.Bray, GA, Greenway, FL. Current and potential drugs for treatment of obesity (review). Endocr Rev 1999;20:805–875.Google Scholar
6.World Health Organization (WHO). Consultation on obesity: preventing and managing the global epidemic. Geneva: World Health Organization, 1998.Google Scholar
7.Gogerty, J, Trapold, J. Chemistry and pharmacology of mazindol. Triangle 1976;15:25–36.Google Scholar
8.Enzi, G, Baritussio, A, Marchiori, E, Crepaldi, G. Short-term and long-term clinical evaluation of a non-amphetaminic anorexiant (mazindol) in the treatment of obesity. J Int Med Res 1976;4:305–319.CrossRefGoogle ScholarPubMed
9.Sapeika, N. Drugs in obesity. S Afr Med J 1974;48:2027–2030.Google Scholar
10.Samanin, R, Bendotti, C, Bernasconi, S, Borroni, E, Garattini, S. Role of brain monoamines in the anorectic activity of mazindol and d-amphetamine in the rat. Eur J Pharmacol 1977;43:117–124.Google Scholar
11.Inoue, S, Egawa, M, Satoh, Set al. Clinical and basic aspects of an anorexiant, mazindol, as antiobesity agent in Japan. Am J Clin Nutr 1992;55:199–202.CrossRefGoogle ScholarPubMed
12.Yoshida, T, Sakane, N, Umekawa, T, Yoshioka, K, Kondo, M, Wakabayashi, Y. Usefulness of mazindol in combined diet therapy consisting of a low-calorie diet and Optifast in severely obese women. Int J Clin Pharmacol Res 1994;14:125–132.Google ScholarPubMed
13.Lee, HK, Choi, EB, Pak, CS. The current status and future perspectives of studies of cannabinoid receptor 1 antagonists as antiobesity agents. Curr Top Med Chem 2009;9:482–503.CrossRefGoogle Scholar
14.Defelice, EA, Chaykin, LB, Cohen, A. Double-blind clinical evaluation of mazindol, dextroamphetamine, and placebo in treatment of exogenous obesity. Curr Ther Res Clin Exp 1973;15:358–366.Google Scholar
15.Aeberli, P, Eden, P, Gogerty, JHet al. 5-Aryl-2,3-dihydro-5H-imidazo [2,1-a]isoindol-5-ols. A novel class of anorectic agents. J Med Chem 1975;18:177–182.Google Scholar
16.Calabrese, V, Capagnini, G, Giuffrida-Stella, AM, Bates, TE, Clark, JB. Mitochondrial involvement in brain function and dysfunction: relevance to aging, neurodegenerative disorders and longevity. Neurochem Res 2001;26:739–764.CrossRefGoogle ScholarPubMed
17.Boekema, EJ, Braun, HP. Supramolecular structure of the mitochondrial oxidative phosphorylation system. J Biol Chem 2007;282:1–4.Google Scholar
18.Brookes, PS, Yoon, Y, Robotham, JL, Anders, MW, Sheu, SS. Calcium, ATP, and ROS: a mitochondrial love–hate triangle. Am J Physiol Cell Physiol 2004;287:817–833.CrossRefGoogle Scholar
19.Kitto, GB. Intra- and extramitochondrial malate dehydrogenases from chicken and tuna heart. Methods Enzymol 1969;13:106–116.CrossRefGoogle Scholar
20.Tyler, D. The mitochondrion in health and diseases. VCH Publishers, New York, 1992.Google Scholar
21.Bessman, SP, Carpenter, CL. The creatine–creatine phosphate energy shuttle. Annu Rev Biochem 1985;54:831–865.Google Scholar
22.Schnyder, T, Winkler, H, Gross, H, Eppenberger, HM, Wallimann, T. Crystallization of mitochondrial creatine kinase. Growing of large protein crystals and electron microscopic investigation of microcrystals consisting of octamers. J Biol Chem 1991;266:5318–5322.CrossRefGoogle ScholarPubMed
23.Wallimann, T, Wyss, M, Brdiczka, D, Nicolay, K, Eppenberger, HM. Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the ‘phosphocreatine circuit’ for cellular energy homeostasis. Biochem J 1992;281:21–40.Google Scholar
24.Bournat, JC, Brown, CW. Mitochondrial dysfunction in obesity. Curr Opin Endocrinol Diabetes Obes 2010;17:446–452.Google Scholar
25.Khan, N, Naz, L, Yasmeen, G. Obesity: an independent risk factor systemic oxidative stress. Pak J Pharm Sci 2006;19:62–69.Google Scholar
26.Monteiro, R, Azevedo, I. Chronic inflammation in obesity and the metabolic syndrome. Mediators Inflamm 2010:289645.Google ScholarPubMed
27.Martínez, J. Mitochondrial oxidative stress and inflammation: an slalom to obesity and insulin resistance. J Physiol Biochem 2006;62:303–306.Google Scholar
28.Bruguera, M, Bertran, A, Bombi, JA, Rodes, J. Giant mitochondria in hepatocytes: a diagnostic hint for alcoholic liver disease. Gastroenterology 1977;73:1383–1387.CrossRefGoogle ScholarPubMed
29.Petersen, P. Ultrastructure of periportal and centrilobular hepatocytes in human fatty liver of various aetiology. Acta Pathol Microbiol Scand 1977;85:421–427.Google Scholar
30.Robertson, NJ, Kendall, CH. Liver giant mitochondria revisited. J Clin Pathol 1992;45:412–415.CrossRefGoogle ScholarPubMed
31.Fraser, DR, Trayhurn, P. Mitochondrial Ca2+ transport in lean and genetically obese (ob/ob) mice. Biochem J 1983;214:163–170.CrossRefGoogle ScholarPubMed
32.Wellman, PJ. Systemic mazindol reduces food intake in rats via suppression of meal size and meal number. J Psychopharmacol 2008;22:532–535.Google Scholar
33.Lowry, OH, Rosebough, NG, Farr, AL, Randall, RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951;193:265–275.CrossRefGoogle ScholarPubMed
34.Srere, PA. Citrate synthase. Methods Enzymol 1969;13:3–11.Google Scholar
35.Fischer, JC, Ruitenbeek, W, Berden, JAet al. Differential investigation of the capacity of succinate oxidation in human skeletal muscle. Clin Chim Acta 1985;153:23–26.Google Scholar
36.Cassina, A, Radi, R. Differential inhibitory action of nitric oxide and peroxynitrite on mitochondrial electron transport. Arch Biochem Biophys 1996;328:309–316.CrossRefGoogle ScholarPubMed
37.Rustin, P, Chretien, D, Bourgeron, Tet al. Biochemical and molecular investigations in respiratory chain deficiencies. Clin Chim Acta 1994;228:35–51.Google Scholar
38.Hughes, BP. A method for estimation of serum creatine kinase and its use in comparing creatine kinase and aldolase activity in normal and pathologic sera. Clin Chim Acta 1962;7:597–604.Google Scholar
39.Inoue, S. Clinical studies with mazindol. Obes Res 1995;4:549S–552S.Google Scholar
40.Nishikawa, T, Iizuka, T, Omura, Met al. Effect of mazindol on body weight and insulin sensitivity in severely obese patients after a very-low-calorie diet therapy. Endocrine J 1996;43:671–677.Google Scholar
41.Yoshida, T, Umekawa, T, Wakabayashi, Y, Yoshimoto, K, Sakane, N, Kondo, M. Anti-obesity and anti-diabetic effects of mazindol in yellow KK mice: its activating effect on brown adipose tissue thermogenesis. Clin Exp Pharmacol Physiol 1996;23:476–482.Google Scholar
42.Adam-Vizi, V. Production of reactive oxygen species in brain mitochondria: contribution by electron transport chain and non-electron transport chain sources. Antioxid Redox Signal 2005;7:1140–1149.Google Scholar
43.Navarro, A, Boveris, A. The mitochondrial energy transduction system and the aging process. Am J Physiol Cell Physiol 2007;292:670–686.Google Scholar
44.Bailey, SM, Landar, A, Darley-Usmar, V. Mitochondrial proteomics in free radical research. Free Radic Biol Med 2005;38:175–188.Google Scholar
45.Dimauro, S, Hirano, M. Mitochondrial encephalomyopathies: an update. Neuromuscul Disord 2005;15:276–286.Google Scholar
46.Lenaz, G, Bovina, C, Castelluccio, Cet al. Mitochondrial complex I defects in aging. Mol Cell Biochem 1997;174:329–333.CrossRefGoogle ScholarPubMed
47.Javitch, JA, Blaustein, RO, Snyder, SH. [3H]mazindol binding associated with neuronal dopamine and norepinephrine uptake sites. Mol Pharmacol 1984;26:35–44.Google Scholar
48.Wyllie, MG, Fletcher, A, Rothwell, NJ, Stock, MJ. Thermogenic properties of ciclazindol and mazindol in rodents. Int J Obes 1984;1:85–92.Google Scholar
49.Bonnet, JJ, Benmansour, S, Costentin, J, Parker, EM, Cubeddu, LX. Thermodynamic analyses of the binding of substrates and uptake inhibitors on the neuronal carder of dopamine labeled with [3H]GBR 12783 or [3H]mazindol. J Pharmacol Exp Ther 1990;253:1206–1214.Google Scholar
50.Jana, S, Sinha, M, Chanda, Det al. Mitochondrial dysfunction mediated by quinone oxidation products of dopamine: implications in dopamine cytotoxicity and pathogenesis of Parkinson's disease. Biochim Biophys Acta 2011;1812:663–673.Google Scholar
51.Gould, E, Mcewen, BS. Neuronal birth and death. Curr Opin Neurobiol 1993;3:676–682.Google Scholar
52.Grandgirard, D, Steiner, O, Täuber, MG, Leib, SB. An infant mouse model of brain damage in pneumococcal meningitis. Acta Neuropathol 2007;114:609–617.Google Scholar
53.Gassner, B, Wuthrich, A, Scholtysik, G, Solioz, M. The pyrethroids permethrin and cyhalothrin are potent inhibitors of the mitochondrial complex I. J Pharmacol Exp Ther 1997;281:855–860.Google Scholar
54.Barja, G, Herrero, A. Localization at complex I and mechanism of the higher free radical production of brain nonsynaptic mitochondria in the short-lived rat than in the longevous pigeon. J Bioenerg Biomembr 1998;30:235–243.Google Scholar
55.Sherer, TB, Betarbet, R, Kim, JH, Greenamyre, JT. Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and alpha-synuclein aggregation. Exp Neurol 2003;179:9–16.Google Scholar
56.Burrows, KB, Gudelsky, G, Yamamoto, BK. Rapid and transient inhibition of mitochondrial function following methamphetamine or 3,4-methylenedioxymethamphetamine administration. Eur J Pharmacol 2000;398:11–18.Google Scholar
57.Rothwell N, J, Stock, MJ, Wyllie, MG. Sympathetic mechanisms in diet-induced thermogenesis: modification by ciclazindol and anorectic drugs. Br J Pharmacol 1981;74:539–546.Google Scholar
58.Rezin, GT, Jeremias, IC, Ferreira, GKet al. Brain energy metabolism is activated after acute and chronic administration of fenproporex in young rats. Int J Dev Neurosci 2011;29:937–942.Google Scholar
59.Wong-Riley, M. Changes in the visual system of monocularly sutured or enucleated cats demonstrable with cytochrome oxidase histochemistry. Brain Res 1979;171:11–28.Google Scholar
60.Erecinska, M, Silver, I. ATP and brain function. J Cereb Blood Flow Metab 1989;9:2–19.Google Scholar
61.Hevner, R, Duff, R, Wong-Riley, M. Coordination of ATP production and consumption in brain: parallel regulation of cytochrome oxidase and Na+, K+-ATPase. Neurosci Lett 1992;138:188–192.Google Scholar
62.Sugrue, MF, Shaw, G, Charlton, KG. Some effects of mazindol, an anorectic drug, on rat brain monoaminergic systems. Eur J Pharmacol 1977;42:319–385.Google Scholar
63.Moreira, PI, Santos, MS, Oliveira, CR. Alzheimer's disease: a lesson from mitochondrial dysfunction. Antioxid Redox Signal 2007;9:1621–1630.Google Scholar
64.Moreira, PI, Santos, MS, Seiça, R, Oliveira, CR. Brain mitochondrial dysfunction as a link between Alzheimer's disease and diabetes. J Neurol Sci 2007;257:206–214.Google Scholar
65.Graham, DG, Tiffany, SM, Bell, WB, Gutknecht, WF. Autoxidation versus covalent binding of quinones as the mechanism of toxicity of dopamine, 6-hydroxy dopamine, and related compounds toward C1300 neuroblastoma cells in vitro. Mol Pharmacol 1978;14:644–653.Google Scholar
66.Mclaughlin, BA, Nelson, D, Erecinska, M, Chesselet, MF. Toxicity of dopamine to striatal neurons in vitro and potentiation of cell death by a mitochondrial inhibitor. J Neurochem 1998;70:2406–2415.Google Scholar