sibutramina antioxidant

Prévia do material em texto

Original Basic 363
 Guzm á n DC et al. Eff ect of Sibutramine on Rat Brain … Horm Metab Res 2009; 41: 363 – 367 
 received 08.08.2008 
 accepted 15.12.2008 
 Bibliography 
 DOI 10.1055/s-0028-1128145 
Published online: 
February 4, 2009
 Horm Metab Res 2009; 
 41: 363 – 367 
 © Georg Thieme Verlag KG 
Stuttgart · New York 
 ISSN 0018-5043 
 Correspondence 
 H. J. Olgu í n 
 Laboratorio de Farmacolog í a 
 Instituto Nacional de Pediatr í a 
 Avenida Im á n N ° 1 
 3rd piso Colonia Cuicuilco 
 CP 04530 Mexico City 
 Mexico 
 Tel.: + 52 / 55 / 1084 38 83 
 Fax: + 52 / 55 / 1084 38 83 
 juarezol@yahoo.com 
 Key words 
 ● ▶ obesity 
 ● ▶ free radicals 
 ● ▶ ATPase 
 ● ▶ tryptophan 
 ● ▶ brain 
 Eff ect of Sibutramine on Na + , K + ATPase Activity and 
Tryptophan Levels on Male and Female Rat Brain 
sidered as a potential risk factor leading to neu-
rodegenerative disorders [5] . 
 Neurodegenerative disorders are induced to a 
great extent by the presence of free radicals (FR) 
within the CNS [6] . This tissue, due to its high 
oxygen demand and to the presence of consider-
able amounts of polyunsaturated fatty acids 
within neuron membranes, may be more vulner-
able to oxidative damage, caused by reactive oxy-
gen species, whose production takes place during 
a variety of pathologic processes [7] , and due to 
the susceptibility of membrane fatty acids to free 
radical attack or lipid peroxidation. 
 Lipid peroxidation is responsible of inhibiting 
Na + , K + ATPase activity [8] , and oxidative stress 
induces a 50 % decrease in this enzyme ’ s activity 
in synaptic membranes under the eff ect of 
chronic administration of homocysteine [9] , and 
also a plasma membrane fl uidity loss [10] . Na + , 
K + ATPase inhibition basically induces the release 
of excitatory amino acids in the CNS, such as 
serotonin (5-HT) and its metabolites [11] , which 
is well represented in female rat brains [12] . 
These neurotransmitters have an important role 
in hunger and body weight control [13] , by 
decreasing calories intake, for example, acting on 
 Introduction 
 & 
 Obesity could be described as the New World 
Syndrome. Its prevalence is continuously increas-
ing among people from a number of countries, 
irrespective of age or gender [1] . Obesity is char-
acterized by the excess of body fat, which most of 
the times, but not always, is accompanied by an 
increase in body weight, and it is present when 
the body mass index (BMI) is ≥ 30 units in the 
adults [2] . According to the latest Health National 
Questionnaire, overweight is represented with a 
39.4 % frequency in Mexico, whereas obesity had 
a 26.1 % frequency [3] . Obesity is better repre-
sented among women worldwide, with a fre-
quency of 30.9 % , compared with only 21.2 % in 
men; whereas overweight is better represented 
in men and it occurs when the BMI is > 27 [4] . 
BMI is higher among people with low educational 
level [3] . 
 Not so long ago, an overweight person was con-
sidered as having a healthy status, however, today 
it is well known that obesity carries multiple 
consequences in people ’ s health, shortens life 
expectancy, and induces, complicates or enhances 
other pathologic processes [2] , and it is now con-
 Authors D. C. Guzm á n 1 , N. L. Ru í z 1 , E. H. Garc í a 2 , G. B. Mej í a 1 , P. P. T é llez 1 , G. E. Jimenez 1 , M. De la Rosa Apreza 1 , 
 H. J. Olgu í n 2 , 3 
 Affi liations 1 Laboratorio de Neuroqu í mica, Instituto Nacional de Pediatr í a (INP), Mexico City, Mexico 
 2 Laboratorio de Farmacolog í a, INP, Mexico City, Mexico 
 3 Departamento de Farmacolog í a, Facultad de Medicina, Universidad Nacional Aut ó noma de M é xico, Mexico City Mexico 
 Abstract 
 & 
 Some drugs that are clinically used in weight 
control, like sibutramine, act on the serotoner-
gic metabolism, but its relation with free radi-
cal (FR) production in the CNS is still unknown. 
The aim of the work was to evaluate the eff ect 
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 sacrifi ced 
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 concen-
tration was increased and the levels of TBARS 
decreased by an eff ect 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 eff ect stimulated by 
the endogenously produced tryptophan and it 
protects the fl uidity of plasma membrane in rat 
brain. 
D
ow
nl
oa
de
d 
by
: U
ni
ve
rs
ite
 L
av
al
. C
op
yr
ig
ht
ed
 m
at
er
ia
l.
Original Basic364
 Guzm á n DC et al. Eff ect of Sibutramine on Rat Brain … Horm Metab Res 2009; 41: 363 – 367 
the subtype 6 5-HT receptor [14] , which also exerts an antioxi-
dant eff ect on damaged tissues [15] . 
 Free radicals are reactive species containing an unpaired elec-
tron, and may rise from either nitrogen or oxygen metabolism, 
and have been involved in oxidative stress as well as in brain 
dysfunction and age related neurodegenerative disorders [16] . 
Reduced glutathione (GSH) is an important active species to 
scavenge the endogenously produced free radicals during diverse 
processes, such as aging and during the pathogenesis of neuro-
degenerative diseases, insofar that its absence leads to oxidative 
stress (OS) [17] . It has been proposed that GSH interacts with 
nitric oxide (NO), leading to the formation of S -nitrosoglutath-
ione (GNSO), depending upon the presence of endogenous oxy-
gen [11] . Such interaction can be explained since NO requires 
the presence of GSH to diff use across the cells. It is worth men-
tioning that NO could also be a physiologically important media-
tor in alimentary behavior, since it is known to induce 
hyperphagia [18] . 
 Due to their undesirable eff ects, such as pulmonary hyperten-
sion and cardiovascular diseases [19] when prescribed to 
patients, the clinical use of some drugs such as fenfl uramine and 
dexfenfl uramine in the treatment of obesity has been stopped. 
The use of these products is given up, and some other novel 
drugs such as sibutramine ( N -[1-{(4-chlorophenyl)cyclobutyl]-
3-methylbutyl}- N , N -dimethylamine hydrochloride monohy-
drate) is now currently used as an alternative for the long-term 
treatment of morbidly obese patients [20] , which has recently 
been approved for prescription use in the U.S.A., Mexico, and 
Brazil; however, its possible interaction with the normal meta-
bolic routes producing hydrogen peroxide-derived free radicals 
is not elucidated yet [21] . Pharmacologically, sibutramine is 
known to induce hunger quenching, by inhibiting serotonine-
norepinephrine turnover, although its primary amine metabo-
lite M2 may increase lipolysis in human adipose tissue via a 
pathway involving beta-adrenoceptors [22] . The aim of this work 
was to determine the eff ect of sibutramine on the activity of 
Na + ,K + ATPase, lipid peroxidation, and levels of GSH and TRP in 
the brain of male and female rat. 
 Materials and Methods 
 & 
 Twenty-eight young Wistar rats, 12 males and 16 females, 
weighing 250 g, were used for this study, and randomly sepa-
rated into two groups consisting in 6 and 8 rats each one, respec-
tively. The two sets of each gender received: group 1, 0.9 % NaCl 
vehicle and group 2, sibutramine 10 mg / kg, given each 36 h dur-
ing a period of 15 days. At the end of this time, the animals were 
sacrifi ced by decapitation, their brains were extracted and kept 
in 0.9 % NaCl at 4 ° C until sliced. Brain dissection was carried out 
by cutting in the sagital plane, then the left portion was homo-
genized in 5 volumes of 0.05 M Tris-HCl (pH 7.2) and used to 
determine lipid peroxidation (TBARS) and Na + , K + ATPase activ-
ity; whereas the right portion was homogenized in 5 volumes of 
0.1 M perchloric acid (HClO 4 ) and used to evaluate reduced glu-
tathione (GSH) and tryptophan (TRP) levels. Homogenized brain 
samples were kept at − 20 ° C until analyzed. 
 Study design 
 Determination of Na + , K + ATPase and total ATPase 
activities 
 One mg of 0.05 M Tris-HCl-homogenized brain tissue was incu-
bated in a solution containing 3 mM MgCl 2 , 7 mM KCl, and 
100 mM NaCl, with or without 0.06 mM ouabain. Four mM Tris-
ATP was added and then incubated for another 30 min at 37 ° C in 
a Dubnoff Labconco shaking water bath. The reaction was 
stopped by adding 100 μ L of 5 % trichloroacetic acid. Samples 
were centrifuged at 3500 rpm for 5 min at 4 ° C [23] and a super-
natant aliquot was taken to measure inorganic phosphate (Pi) by 
means of the method developed by Fiske and Subarrow [24] . 
Supernatant absorbance was read at 660 nm in a Helios- α (UNI-
CAM) spectrophotometer and the diff erences between the 
absorbances of the solutions with or without ouabain was taken 
as the Na + , K + ATPase activity, which was expressed as Pi μ M per 
gram of wet tissue per minute, whereas the total ATPase activity 
was determined in the absence of ouabain. 
 Measurement of lipid peroxidation (TBARS) 
 TBARS determination was carried out according to the method 
of Gutteridge and co-workers [25] , as follows: Each tissue sam-
ple was homogenized in 5 mL of phosphate buff er pH 7.4, from 
which a 1 mL aliquot was taken and added to 2 mL of a thiobar-
bituric acid (TBA) solution containing TBA (1.25 g), trichloroace-
tic acid (40 g), and concentrated HCl (6.25 mL) dissolved in 
250 mL deionized water. The whole mixture was heated to the 
boiling point of water for 30 min (Thermomix 1420). Samples 
were then put in an ice bath for 5 min and then centrifuged at 
3000 × g for 15 min (Sorvall RC-5B Dupont). Supernatant absorb-
ances were read in a three-set scheme at 532 nm spectrophoto-
metrically (Helios- α , UNICAM). Thiobarbituric acid reactive 
substances concentration was expressed as malondialdehyde 
 μ moles per gram of wet tissue. 
 Determination of reduced glutathione (GSH) 
 According to a modifi ed method from Hissin and Hif [26] , HClO 4 -
homogenized tissue was centrifuged at 5000 rpm for 5 min 
(Mikro 12 – 42, Germany), and reduced glutathione levels were 
measured in the supernatant. An amount of 1.8 mL of phosphate 
buff er pH 8.0 / 0.2 % EDTA was poured in a test tube, then 1 mL 
aliquot of the supernatant and 100 μ L of 1 mg / ml orthophthalde-
hyde dissolved in methanol (w / v), were added. The entire mix-
ture was incubated at room temperature for 15 min, totally 
protected from light, and then the samples were read in a Perk-
inElmer LS 55 spectrofl uorometer at 350 nm / 420 nm, excitation /
 emission. To analyze the data, an FL Win Lab version 4.00.02 
software was used. GSH levels values were inferred from a previ-
ously constructed standard curve, and expressed as nanomoles 
of GSH per gram of wet tissue. 
 Determination of Tryptophan (TRP) 
 After centrifuging the HClO 4 -homogenized tissue at 10 000 rpm 
for 10 min in a microcentrifuge (Hettich Zentrifugen, Mikro 12 –
 42 model, Germany) [27] , tryptophan levels were determined in 
the supernatant fraction. Samples were fi ltered in a Millex HV 
 Groups 1 2 
 Females Control (NaCl 0.9 % ) (8) Sibutramine (10 mg / kg) (8) 
 Males Control (NaCl 0.9 % ) (6) Sibutramine (10 mg / kg) (6) 
 Number of animals in each group is shown in the parentheses. 
D
ow
nl
oa
de
d 
by
: U
ni
ve
rs
ite
 L
av
al
. C
op
yr
ig
ht
ed
 m
at
er
ia
l.
Original Basic 365
 Guzm á n DC et al. Eff ect of Sibutramine on Rat Brain … Horm Metab Res 2009; 41: 363 – 367 
(Sep-Pack C18, Millipore) fi lter, and 20 μ l was injected to the liq-
uid chromatograph to determine the TRP levels. Values were 
inferred from a standard curve and expressed as TRP nanomoles 
per gram of wet tissue. 
 HPLC equipment: High performance liquid chromatograph with 
turbochrom system version 4.1 (PerkinElmer) was used. It 
includes a variable wavelength detector Spectra System UV1000 
(Termo Separation Products), manual injector Rheodyne, four 
gradient pump LC-1150 (GBC Scientifi c Equipment), double 
channel interphase PerkinElmer, and 3.9 × 150 mm Nova Pack C 18 
column (Waters). 
 Chromatographic conditions: 0.01 M sodium acetate mobile 
phase pH 4.0, methanol (85:15, v / v), 1 ml / min fl ux velocity, 
254 nm wavelength. 
 Reagents: AcONa · 3H 2 O, perchloric acid (reagent grade, Merck), 
methanol (HPLC, Caledon Laboratories), TRP standard (Sigma), 
and deionized water. 
 Statistical analysis 
 The analysis of variance test (ANOVA) with its corresponding 
contrasts was used, having confi rmed variance homogeneity 
previously. Every probability value less than 0.05 was consid-
ered statistically signifi cant [28] . The analysis was carried out by 
using the JMP Statistical Discovery from SAS software, version 
6.0.0. 
 Results 
 & 
 The animal ’ s body weight showed no appreciable diff erences 
during the treatment with sibutramine ( Table 1 ). The Na + , 
K + ATPase activity was signifi cantly higher in male rats ( ● ▶ Fig. 1 ). 
Total ATPase activity showed a similar pattern ( ● ▶ Fig. 2 ), since 
in the brain of male rats it had a signifi cantly higher activity, 
ANOVA (p < 0.05). 
 ● ▶ Fig. 3 shows reduced glutathione levels indicating that female 
rats had higher levels than their male counterparts, furthermore, 
GSH levels increased notably in females that received sibu-
tramine, ANOVA (p < 0.05). Lipid peroxidation decreased in sibu-
tramine-treated animals ( ● ▶ Fig. 4 ), however, these changes 
were only statistically signifi cant in the case of the female rats, 
ANOVA (p < 0.05). 
 Tryptophan levels decreased in the female rats at the expense of 
sibutramine treatment, whereas this drug induced tryptophan 
levels to increase in the male rats. In both cases, the diff erences 
in tryptophan levels were statistically signifi cant ( ● ▶ Fig. 5 ). 
However, among the control groups, tryptophan concentration 
was notably higher in female than in male rats, ANOVA 
(p < 0.05). 
 Table 1 Body weight in female and male rat brain treated with sibutramine 
 Number of dose administered 
 Groups 1 2 3 4 5 6 7 
 Ctrl-F 219.73 ± 19.6 257.23 ± 22.87 259.06 ± 21.96 262.69 ± 22.34 262.25 ± 26.48 272.88 ± 25.28 280.0 ± 24.50 
 Sibu-F 225.19 ± 13.36 267.0 ± 15.77 261.44 ± 17.56 274.63 ± 17.64 274.19 ± 14.72 278.19± 17.61 283.20 ± 26.17 
 Ctrl-M 377.5 ± 38.72 389.83 ± 34.51 373.17 ± 32.76 397.83 ± 28.89 393.92 ± 27.59 424.75 ± 28.45 418 ± 24.52 
 Sibu-M 360.33 ± 21.81 363.83 ± 26.93 378.42 ± 30.17 360.08 ± 26.12 385.25 ± 26.30 406.08 ± 25.42 420.32 ± 20.40 
 Mean ± SD. Ctrl-F: control female; Ctrl-M = control male; Sibu-F = sibutramine female; Sibu-M = sibutramine male 
*
*
µM
 P
i/g
 o
f w
et
 ti
ss
ue
/m
in 25
30
20
15
10
5
0
CtrlF SibuF CtrlM SibuM
 Fig. 1 Activity of Na + , K + ATPase enzyme in female and male rat brain 
treated with sibutramine. Mean ± SD. Ctrl. = control; Sibu-F = sibutramine 
female; Sibu-M = sibutramine male. ANOVA * p < 0.05. 
70
µM
 P
i/g
 o
f w
et
 ti
ss
ue
/m
in
60
50
40
30
20
10
0
CtrlF
*
*
SibuF SibuMCtrlM
 Fig. 2 Activity of total ATPase enzyme in female and male rat brain 
treated with sibutramine. Mean ± SD. Ctrl. = control; Sibu-F = sibutramine 
female; Sibu-M = sibutramine male. ANOVA * p < 0.05. 
300
nM
/g
 o
f w
et
 ti
ss
ue
250
200
150
100
CtrlF
*
*
SibuF CtrlM SibuM
50
0
 Fig. 3 Leves of reduced glutathione in female and male rat brain treated 
with sibutramine. Mean ± SD. Ctrl. = control; Sibu-F = sibutramine female; 
Sibu-M = sibutramine male. ANOVA * p < 0.05. 
D
ow
nl
oa
de
d 
by
: U
ni
ve
rs
ite
 L
av
al
. C
op
yr
ig
ht
ed
 m
at
er
ia
l.
Original Basic366
 Guzm á n DC et al. Eff ect of Sibutramine on Rat Brain … Horm Metab Res 2009; 41: 363 – 367 
 Discussion 
 & 
 Sibutramine had null eff ect on the activity of Na + , K + ATPase, 
whereas total ATPase activity had a slight sibutramine-induced 
increase in both female and male rats. These diff erences were 
only related to gender, maybe due to the higher basal activity in 
male rats. These fi ndings suggest that sibutramine may not 
induce any disturbance on the plasma membrane fl uidity and, 
therefore, its use keeps the structural composition of plasma 
membrane intact, especially within the female brain [29] . Such 
results may be taken as positive, since in those subjects suff ering 
from obesity and overweight, the decreased membrane fl uidity 
or an impairment of physical-chemical properties as a conse-
quence of oxidative injury that might be part of obesity-related 
pathologies [30] is seen; so the use of sibutramine may reduce 
this eff ect. 
 Basal GSH levels were higher in females than in males, probably 
as consequence of the estrogens as natural antioxidants, which 
contain at least three rings of the steroid nucleus that are neces-
sary for the neuroprotective activity of the target tissue [31] . 
This eff ect was enhanced in the presence of sibutramine, which 
suggests that this drug may protect the brain from the endog-
enously generated oxidative damage [32] and, in doing so, may 
also get the entire central nervous system less vulnerable to 
hydrogen peroxide- and hydroxyl radicals-derived oxidative 
damage, whose production takes place during the normal meta-
bolic pathways in the female CNS [21] . 
 Both in female and in male rats, lipid peroxidation products 
were shown to decrease after sibutramine treatment, especially 
in females. This eff ect may be attributable to sibutramine chem-
ical structure, in which the presence of certain functional groups 
such as dimethylamine and chlorine in aromatic position may 
confer it a considerable electrophilic character, so that it can eas-
ily interact with lipid structures within the brain [16] . 
 Endogenous tryptophan was higher in female than in male rats, 
and the decrease in its concentration after sibutramine treat-
ment strongly suggests that there was an appreciable serotoner-
gic activity [33] . These results suggest that serotonergic pathways 
seem to protect the brain, due to the antioxidant activity of the 
indolamines, which take place in this pathway [15] . On the other 
hand, though the animal ’ s body weight showed no appreciable 
diff erences, it is advisable to take into account the presence of 
hypothalamic neuropeptides, such as 5-HT and its metabolites, 
and their interactions with subtype 6 5-HT receptors, when sib-
utramine is to be used in the control of food intake and lowering 
body weight in the clinical practice, since these neurotransmit-
ters play an active role in the control of hunger [34, 35] . In con-
clusion, sibutramine may exert an antioxidant eff ect mediated 
by endogenous tryptophan, which could impede membrane fl u-
idity to be disturbed within the 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 characteris-
tic curves . Am J Clin Nutr 1998 ; 67 : 44 – 49 
 3 Encuesta Nacional de Salud 2000 Obesidad en adultos derechohabi-
entes 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 . Eff ect of Rimonabant, a cannabinoid-
1 receptor blocker, on weight and cardiometabolic risk factors in 
overweight or obese patients: RIO-North America: A randomized con-
rolled 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 . Eff ect 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 neurodegen-
erative disorders . Science 1993 ; 262 : 689 – 695 
 8 Arkhipenko Y , Meerson FZ , Sazontova TG , Kagan VE . Mode of lipid per-
oxidation-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 eff ects of homocysteine on Na+, K+-ATPase activ-
ity 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 . Ribofl avin defi ciency and the 
function and fl uidity of rat erythrocyte membranes . J Nutr 1990 ; 120 : 
 857 – 861 
 11 Benuck M , Banay-Schwartz M , DeGuzman T , Lajtha A . Eff ect 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 diff erences in rat brain 
serotonin . Prog Neuropsychopharmacol Biol Psychiatry1998 ; 12 : 
 53 – 61 
 13 Prunet MB , Desbazeille M , Bros A , Louche K , Delagrange P , Renard P , 
 Casteilla L , P é nicaud 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: eff ects on appetite expresi ó n and use for the treatment of obe-
sity . Drugs 2007 ; 67 : 27 – 55 
3
2.5
µM
 m
al
on
di
al
de
hy
de
/g
 o
f w
et
 ti
ss
ue
2
*
*
1.5
1
0.5
0
CtrlF SibuF CtrlM SibuM
 Fig. 4 Lipid peroxidation in female and male rat brain treated with 
sibutramine. Mean ± SD. Ctrl. = control; Sibu-F = sibutramine female; Sibu-
M = sibutramine male. ANOVA * p < 0.05. 
700
600
500
*
*
400
300
200
100
0
CtrlF
nM
/g
 o
f w
et
 ti
ss
ue
SibuF CtrlM SibuM
 Fig. 5 Levels of tryptophan in female and male rat brain treated with 
sibutramine. Mean ± SD. Ctrl. = control; Sibu-F = sibutramine female; Sibu-
M = sibutramine male. ANOVA * p < 0.05. 
D
ow
nl
oa
de
d 
by
: U
ni
ve
rs
ite
 L
av
al
. C
op
yr
ig
ht
ed
 m
at
er
ia
l.
Original Basic 367
 Guzm á n DC et al. Eff ect of Sibutramine on Rat Brain … Horm Metab Res 2009; 41: 363 – 367 
 15 Mu ñ oz CJR , Montilla P , Padillo FJ , Bujalance I , Mu ñ oz MC , Muntan é 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 specifi c 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 fenfl uramine-phenter-
mine . 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 . Eff ect 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 Calder ó n-Guzm á n D , Espitia-V á zquez I , L ó pez-Dom í nguez A , Hern á ndez-
Garc í a E , Huerta-Gertrudis B , Coballase-Urrutia E , Ju á rez-Olgu í n H , 
 Garc í a-Fern á ndez B . Eff ect of toluene and nutritional status on sero-
tonin, 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 fl urometric method for determination of oxidized 
and reduced glutathione in tissue . Anal Biochem 1976 ; 74 : 214 – 226 
 27 Calderon GD , Toledo LA , Hernandez IJ , Barrag á n MG , Rodr í guez PR , Her-
nandez GE . Determinaci ó n de tript ó fano en cerebro de ratas expuestas 
a ozono . Arch Neurosci (Mex) 2001 ; 6 : 2 – 5 
 28 Castilla-Serna L . Estad í stica simplifi cada para la investigaci ó n en Cien-
cias de la Salud. Editorial Trillas . 2nd Edition M é xico, D.F. ; 1999 
 29 Holl á n S . Membrane fl uidity of blood cells . Haematologia (Budap) 
 1996 ; 27 : 109 – 127 
 30 Cazzola R , Rondanelli M , Russo VS , Ferrari E . Decreased membrane 
fl uidity and altered susceptibility to peroxidation and lipid composi-
tion 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 eff ects 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 intracere-
bro ventricular 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: eff ects on appetite expression and use for the treatment of 
obesity . Drugs 2007 ; 67 : 27 – 55 
D
ow
nl
oa
de
d 
by
: U
ni
ve
rs
ite
 L
av
al
. C
op
yr
ig
ht
ed
 m
at
er
ia
l.