Effect of Sibutramine on Na⁺, K⁺ ATPase Activity and Tryptophan Levels on Male and Female Rat Brain

Abstract

Some drugs that are clinically used in weight control, like sibutramine, act on the serotonergic metabolism, but its relation with free radical (FR) production in the CNS is still unknown. The aim of the work was to evaluate the effect of sibutramine on FR production. Female and male Wistar rats (250 g weight) were used; the animals received sibutramine (10 mg/kg each 36 hours) intraperitoneally during 15 days. At the end of the study, the rats were sacrificed and their brains used to measure lipid peroxida-tion (TBARS), Na⁺, K⁺ATPase activity, reduced glutathione (GSH), and tryptophan (TRP) levels, by means of validated methods. The activity of Na⁺, K⁺ATPase and total ATPase was increased in males and decreased in females. GSH concentration was increased and the levels of TBARS decreased by an effect related to sibutramine in the female group. Sibutramine decreased TRP concentration in the female group, but increased it in the male one, with respect to the control group. Our results suggest that sibutramine produce an antioxidant effect stimulated by the endogenously produced tryptophan and it protects the fluidity of plasma membrane in rat brain.

Key words

obesity - free radicals - ATPase - tryptophan - brain

References

• 1 Nammi S, Koka S, Chinnala K, Boini K. Obesity: An overview on its current perspectives and treatment options.  Nutr J. 2004;  3 1-8
• 2 Taylor RW, Keil D, Gold EJ, Williams SM, Goulding A. Body mass index, waist girth and waist-to-hip ratio as indexes of total and regional adiposity in women: evaluation using receiver operating characteristic curves.  Am J Clin Nutr. 1998;  67 44-49
• 3 Encuesta Nacional de Salud 2000 . Obesidad en adultos derechohabientes del IMSS.  Rev Med IMSS. 2004;  42 239-245
• 4 Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J. for the RIO-North America Study Group . Effect of Rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: A randomized conrolled Trial.  JAMA. 2006;  295 761-775
• 5 Sriram K, Benkovic SA, Miller DB, O’Callaghan JP. Obesity exacerbates chemically induced neurodegeneration.  Neuroscience. 2002;  115 1335-1346
• 6 Tang MX, Jacobs D, Stern Y. Effect of oestrogen during menopause on risk and age at onset of Alzheimer disease.  Lancet. 1996;  348 429-432
• 7 Coyle JT, Puttfarcken P. Oxidative stress, glutamate, and neurodegenerative disorders.  Science. 1993;  262 689-695
• 8 Arkhipenko Y, Meerson FZ, Sazontova TG, Kagan VE. Mode of lipid peroxidation-induced inhibition of Na, K-ATPase.  Acta Physiol Pharmacol Bulg. 1985;  11 70-78
• 9 Matte C, Monteiro SC, Calcagnotto T, Bavaresco CS, Netto CA, Wyse AT. In vivo and in vitro effects of homocysteine on Na+, K+-ATPase activity in parietal, prefrontal and cingulate cortex of young rats.  Int J Dev Neurosci. 2004;  22 185-190
• 10 Levin G, Cogan U, Levy Y, Mokady S. Riboflavin deficiency and the function and fluidity of rat erythrocyte membranes.  J Nutr. 1990;  120 857-861
• 11 Benuck M, Banay-Schwartz M, DeGuzman T, Lajtha A. Effect of food deprivation on glutathione and amino acid levels in brain and liver of young and aged rats.  Brain Res. 1995;  678 259-264
• 12 Carlsson M, Carlsson A. A regional study of sex differences in rat brain serotonin.  Prog Neuropsychopharmacol Biol Psychiatry. 1998;  12 53-61
• 13 Prunet MB, Desbazeille M, Bros A, Louche K, Delagrange P, Renard P, Casteilla L, Pénicaud L. Melatonin reduces body weight gain in sprague dawley rats with diet-induced obesity.  Endocrinology. 2003;  144 5347-5352
• 14 Halford JC, Harrold JA, Boyland EJ, Lawton CL, Blundell JE. Serotonergic drugs: effects on appetite expresión and use for the treatment of obesity.  Drugs. 2007;  67 27-55
• 15 Muñoz CJR, Montilla P, Padillo FJ, Bujalance I, Muñoz MC, Muntané J. Role of serotonin in cerebral oxidative stress in rats.  Acta Neurobiol Exp. 2006;  66 1-6
• 16 Driver AS, Kodavanti PR, Mundy WR. Age-related changes in reactive oxygen species production in rat brain homogenates.  Neurotoxicol Teratol. 2000;  22 175-181
• 17 Wu F, Fang YZ, Yang S, Lupton JR, Turner ND. Glutathione metabolism and its implications for health.  J Nutr. 2004;  134 489-492
• 18 Stricker KA, Beck B, Burlet C. Nitric oxide mediates hyperphagia of obese Zucker rats: relation to specific changes in the microstructure of feeding behavior.  Life Sci. 1996;  58 9-15
• 19 Connolly HM, Crary JL, MacGoon MD, Hensud DD, Edwards BS, Edwards WD. Valvular Heart disease associated with fenfluramine-phentermine.  N Engl J Med. 1997;  337 783
• 20 James WP, Astrup A, Finer N, Hilsted J, Kopelman P, Rossner S, Saris WH, Van Gaal LF. Effect of sibutramine on weight maintenance after weight loss: a randomized trial. STORM study group. Sibutramine Trial of Obesity Reduction and Maintenance.  Lancet. 2000;  356 2119-2125
• 21 Sun Y. Free radicals, antioxidants enzymes and carcinogenesis.  Free Rad Biol Med. 1990;  8 583-599
• 22 Richardson DK, Jones RB, Bailey CJ. The primary amine metabolite of sibutramine stimulates lipolysis in adipocytes isolated from lean and obese mice and in isolated human adipocytes.  Horm Metab Res. 2006;  38 727-731
• 23 Calderón-Guzmán D, Espitia-Vázquez I, López-Domínguez A, Hernández-García E, Huerta-Gertrudis B, Coballase-Urrutia E, Juárez-Olguín H, García-Fernández B. Effect of toluene and nutritional status on serotonin, lipid peroxidation levels and Na⁺/K⁺-ATPase in adult rat brain.  Neurochem Res. 2005;  5 619-624
• 24 Fiske CH, Subbarow Y. The colorimetric determination of phosphorus.  J Biol Chem. 1925;  66 375-400
• 25 Gutteridge JM, Halliwell B. The measurement and mechanism of lipid peroxidation in biological systems.  Trends Biochem Sci. 1990;  15 129-135
• 26 Hissin PJ, Hif R. A flurometric method for determination of oxidized and reduced glutathione in tissue.  Anal Biochem. 1976;  74 214-226
• 27 Calderon GD, Toledo LA, Hernandez IJ, Barragán MG, Rodríguez PR, Hernandez GE. Determinación de triptófano en cerebro de ratas expuestas a ozono.  Arch Neurosci (Mex). 2001;  6 2-5
• 28 Castilla-Serna, L. Estadística simplificada para la investigación en Ciencias de la Salud. Editorial Trillas. 2nd Edition México, D.F. 1999
• 29 Hollán S. Membrane fluidity of blood cells.  Haematologia (Budap). 1996;  27 109-127
• 30 Cazzola R, Rondanelli M, Russo VS, Ferrari E. Decreased membrane fluidity and altered susceptibility to peroxidation and lipid composition in overweight and obese female erythrocytes.  J Lipid Res. 2004;  45 1846-1851
• 31 Green SP, Gordon K, Simpkins JW. Phenolic a ring requirement for the neuroprotective effects of steroids.  J Steroid Biochem Mol Biol. 1997;  63 229-235
• 32 Goudas LC, Langlade A, Serrie A, Matson W, Milbury P, Thurel C. Acute decreases in cerebrospinal fluid glutathione levels after intracerebroventricular morphine for cancer pain.  Anesth Analg. 1999;  89 1209-1215
• 33 Fernstrom JD, Wurtman RJ. Brain serotonin content: Physiological regulation by plasma neutral amino acids.  Science. 1972;  178 414-416
• 34 Prunet MB, Desbazeille M, Bros A, Louche K, Delagrange P, Renard P. Melatonin reduces body weight gain in sprague dawley rats with diet-induced obesity.  Endocrinology. 2003;  144 5347-5352
• 35 Halford JC, Harrold JA, Boyland EJ, Lawton CL, Blundell JE. Serotonergic drugs: effects on appetite expression and use for the treatment of obesity.  Drugs. 2007;  67 27-55

Correspondence