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Dosing-time dependent oxidative effects of sodium nitroprusside in brain, kidney, and liver of mice
e n v i r o n m e n t a l t o x i c o l o g y a n d p h a r m a c o l o g y 3 8 ( 2 0 1 4 ) 625–633
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Dosing-time dependent oxidative effects of sodium nitroprusside in brain, kidney, and liver of mice Mamane Sani a,∗ , Hichem Sebai b , Néziha Ghanem-Boughanmi b , Naceur A. Boughattas c , Mossadok Ben-Attia d a
UMR Biosurveillance et Toxicologie Environnementale, Département de Biologie, Faculté des Sciences et Techniques de Maradi, 465 Maradi, Niger b UR Ethnobotanie et Stress Oxydant, Département des Sciences de la Vie, Faculté des Sciences de Bizerte, 7021 Zarzouna, Tunisia c Laboratoire de Pharmacologie, Faculté de Médecine, 5019 Monastir, Tunisia d Laboratoire de Biosurveillance de l‘Environnement, Faculté des Sciences de Bizerte, 7021 Zarzouna, Tunisia
a r t i c l e
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a b s t r a c t
Article history:
The purpose of this study was to investigate if the oxidative effects of sodium nitroprusside
Received 7 May 2014
(SNP) are dosing-time dependent. Therefore, the variation of malondialdehyde (MDA) status
Received in revised form
was assessed after a single i.p. administration of SNP (2.5 mg kg−1 b.w.) or vehicle (9‰ NaCl)
17 August 2014
to different and comparable groups of mice (n = 48) at two different circadian times (1 and
Accepted 18 August 2014
13 h after light onset [HALO]). Brain, kidney, and liver tissues were excised over 36 h, and
Available online 24 August 2014
their MDA contents were estimated at 0, 1, 3, 6, 9, 12, 24, and 36 h after SNP administration. Results: indicated mean MDA level was not significantly changed in each investigated tissue
Keywords:
compared with the control. In contrast, the mean MDA value varied among organs and was
Malondialdehyde
comparable in brain and liver but lower than in kidney. The data show SNP significantly
Sodium nitroprusside
(P < 0.05) increases MDA status in both tissues and exerts time-dependent oxidative effects
Mice
with the greatest toxicity coinciding with the beginning of the diurnal rest span (local time:
Brain
08:00 h, i.e., at 1 HALO). The obtained results reveal SNP-induced oxidative damage (evidenced by MDA accumu-
Kidney
lation) varies according to both the dosing-time and the target organ.
Liver
© 2014 Elsevier B.V. All rights reserved.
1.
Introduction
Nitrovasodilator-SNP (Na2 [Fe(CN)5 NO]·2H2 O) is an excellent drug clinically used for treating acute myocardial infarction (Franciosa et al., 1972), chronic heart failure (Guiha et al., 1974), cardiac (Moffett and Price, 2008), and hypertension emergencies (Gifford, 1959). Several scientific reports (Smith and
Kruszyna, 1974; Vesey and Cole, 1985) revealed that SNP in human and other mammalian species undergoes metabolism in vivo to release toxic free cyanide (CN− ). Indeed, the lethal effects of CN− have been known for more than a century and HCN, cyanide salts or cyanogenic compounds have been used in suicides, homicides, and chemical warfare. It is generally believed that in vivo the primary pathway for CN− detoxification is its oxidation to thiocyanate by the enzyme thiosulfate
∗ Corresponding author. Department of Biology, Faculty of Sciences and Techniques, University of Maradi, BP 465 Maradi, Niger. Tel.: +227 20 41 01 32; fax: +227 20 41 01 33. E-mail address: [email protected] (M. Sani). http://dx.doi.org/10.1016/j.etap.2014.08.013 1382-6689/© 2014 Elsevier B.V. All rights reserved.
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sulfurtransferase (rhodanese) that is present in various tissues (Drawbaugh and Marrs, 1987; Sani et al., 2008a,b) and particularly high in liver (Sani et al., 2006a). However, it has been established that the SNP-induced oxidative stress may be due to its ability to release several other potential toxic products such as NO and iron ions (Nazari et al., 2012; Lozinsky et al., 2012; Ibrahim et al., 2012). The molecular mechanism of NO-related SNP-induced neurotoxic effects is not fully understood. Other findings firmly confirmed the hypothesis that biological effects of the exogenous NO donor, SNP, depend on the redox status of the cell (Sokołowska et al., 2003). Therefore, the cytotoxicity of SNP was attributed to enhanced ROS production, which in turn resulted in decrease in antioxidant levels. Nevertheless, it has been demonstrated that oxidative stress is a main mediator in NO-induced neurotoxicity and apoptosis in human cells in a concentration and time-dependent manner (Zhang and Zhao, 2003). These concerns have hindered the general enthusiasm in using SNP in the management of acute hypertension emergencies, even though its potency, rapid onset, and short duration of action. However, there is nowadays the resurgence of interest in the use of SNP, particularly in the management of acute decompensated heart failure (Mullens et al., 2008; Opasich et al., 2009) and in the prediction of blood pressure during certain cardio-vascular surgical procedures (Roitberg et al., 2008; Spielberg et al., 2014; Zhao et al., 2014). Although the increased usefulness of SNP in several cardio-vascular diseases cares, prolonged use of SNP has often been associated with the risk of its end-products toxicity on brain, kidney, and muscle of patients (Guo et al., 2013; Moerman et al., 2013). Therefore, there is a great necessity to discuss possible strategies by which the safety and efficacy of SNP as part of the treatment regimen for hospitalized heart failure patients might be improved. Time-of-day of exposure is rarely considered in the study of desired (efficacious) and nondesired (toxic) effects of drugs. In rodents, the nephrotoxicity of heavy metal (Hg, Cd) as well as that of some antibiotics (amikacine, dibekacine) exhibits large amplitude circadian rhythms, with a peak located at the rest span and a trough at the activity span (Cal et al., 1986; Cambar et al., 1987). It seems, therefore, that a temporal relation may be observed between the circadian variation in MDA and chronotoxic effects of some agents, respectively, in the liver and kidney. Our previous data revealed that the neurotoxic effects of SNP varied markedly within the 24-h period depending on the time of administration (Sani et al., 2011). The circadian variation in drug effects are suggested not to be due to rhythmic changes in the pharmacokinetics of drugs but rather to an endogenous rhythm in drug susceptibility resulting from a circadian rhythm controlled by an inner clock (Moore and Eichler, 1972). It would be expected that the drug concentration as well as the dosing-/sampling-time would affect both the efficacy and the toxicity of an antihypertensive drug. However, little is known about the time-of-day dependence of either measured levels of neuronal toxicity or lipid peroxidation induced by SNP. Such information would be of importance to both exercise scientists and clinicians, since it would help to minimize the drug-induced side effects by a better optimization of drug use at the adequate time-of-day. Thus, the dosing of medication at the targeted biological time
with reference to circadian rhythms can result in modulation of its toxicity (Hrushesky et al., 1989). To this end, the oxidative effects of SNP could be dependent on the period of waxing and waning of motor activity. Therefore, the purpose of this study was to assess if time-of-day of exposure influences the oxidative effects of SNP in terms of its effects on MDA production in the brain, kidney, and liver of mice.
2.
Materials and methods
2.1.
Animals and housing
Animals used in this study were Swiss albino mice obtained from the Central Animal House (SIPHAT, 2013 FoundoukChoucha, Tunisia) at 9 weeks of age (≈25 g body weight) and experiments lasted from June to November 2007. The animals were housed 4–5 per cage with free access to food and water. They were acclimated for at least 3 weeks prior to and during each study (Reinberg and Smolensky, 1983), to controlled conditions of temperature (22 ± 2 ◦ C), relative humidity (50–60%), and 12-h light: 12-h dark photoperiod (light on at 07:00 h). The desired synchronization of mice was documented by the quantification of normal circadian rhythmicity in rectal temperature, the acrophase (peak time) used as marker rhythm index. In this study carried out at the FSB Toxicometry and Chronobiometry Laboratory (Bizerte, Tunisia), all experimental procedures conformed to the NIH recommendations and current guidelines (Portaluppi et al., 2008).
2.2.
Drug
SNP (Na2 [Fe(CN)5 NO]·2H2 O) brown–red powder was kindly supplied by the National Laboratory of Drug Control (1006 Tunis, Tunisia). The SNP is a chemical product of synthesis that is hydrosoluble but little soluble in alcohol. Based on our previous experience with SNP in chronotoxicological studies, in adult mice neurotoxic effects of SNP were triggered with doses raging from 2.5 to 5 mg · Kg−1 -a median toxic dose TD50 (dose inducing 50% motor-inco-ordination) equal to 3.6 ± 0.5 mg · Kg−1 . Since oxidative effects of SNP are seemed to be related to its neurotoxicity, the lowest neurotoxic SNP dose (of 2.5 mg · Kg−1 ) was used to investigate SNP-induced oxidative damage. Thus, the solution was freshly prepared each experiment day by adding an adequate volume of sterile distilled water to obtain the 2.5 mg/kg concentration of SNP. That single dose was administered to mice in a fixed fluid volume (10 mL · Kg−1 b.w.).
2.3.
Study designs and tissue samplings
The study design is summarized in Table 1. A total of 192 synchronized male mice were randomly assigned to four groups (48/group) for treatment with SNP (2.5 mg · kg−1 ) or sodium chloride (0.9%). The first two groups of animals were treated once with an i.p. injection of saline (group 1) or SNP (group 2) at a fixed local time (08:00 h, i.e., at 1 HALO), whereas the two last groups were similarly dosed with saline (group 3) or SNP (group 4) at later 12 h (20:00 h local time, e.g., 13 HALO). Each dosing-time involved different but comparable
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Table 1 – Main characteristics of the study investigating chronotoxicity of SNP in male Swiss albinos mice. Drugs
Doses
NaCl solution (control)
0.9%
48
SNP
2.5 mg/kg 0.9%
48 48
2.5 mg/kg
48
NaCl solution (control) SNP
Number of mice
Dosing-time (HALO)
Toxicity variable
Time-of-sampling (HALO)
1
MDA
0, 1, 3, 6, 9, 12, 24, 36
13
MDA
0, 1, 3, 6, 9, 12, 24, 36
sub-groups of mice (n = 6) corresponding to animals sacrificed by decapitation at 0, 1, 3, 6, 9, 12, 24, and 36 h after injection. Thereafter, brain, kidney, and liver tissue were quickly removed and individually categorized with respect to tissue, dosing-time, sampling-time, and then stored frozen at −84 ◦ C until assayed.
2.4.
Assay procedure of lipid peroxidation
For each animal, whole brain (minus brain stem), kidney, and a portion of liver were separately placed in an ice-cold Petri dish maintained in finely crushed ice. Brain, kidney, and liver tissue were homogenized in ice-cold Tris-Buffered Saline (TBS: 26 mM, pH 7.4) using glass/Teflon homogenizer. Tissue lipid peroxides were monitored by determining the index of lipid peroxidation, MDA using the Thio-Barbutiric Acid (TBA) test as described by Buege and Aust (1978). All results are expressed as mol MDA/mg protein.
2.5.
Protein assay
The protein content of different samples was determined by the method of Lowry et al. (1951) as modified by Hartree (1972) and by using bovine serum albumin as a standard.
2.6.
Statistical analysis
The “Cosinorwin” circadian software programme (http://www. circadian.org/softwar.html) was used to analyse time series of rectal temperature for circadian rhythm by approximating the time series data with single cosine curves of the designated periods using the method of least squares (Nelson et al., 1979). Sampling-time-point data were computed as means ± standard error of means (S.E.M.) and pertinent histograms were drawn. Student’s t-test for paired data (InStat for MacIntosh, GraphPad Software, San Diego, CA, USA) was used to compare treatment and control groups at designated sampling-times. The reproducibility of MDA status variation from one sampling-time to the next was tested by examining the interaction between sampling-time and treatment on the content values, using two-way analysis of variance (ANOVA). All conclusions are based on at least 5% level of significance (P < 0.05).
3.
Table 2 – Two-way ANOVA analyses of MDA variation in brain, kidney, and liver of Swiss albinos mice after acute NPS (2.5 mg/kg) injection at 1 HALO. Brain Source of variance F Time Treatment Interaction
Liver
F
F
P
P
4.9 <0.008 14.3 <0.0001 11.8 <0.0001 13.4 <0.0006 5.5 <0.03 1.2 NS 2.8 <0.03 0.4 NS 2.0 NS
confirming the synchronization of the mice to the environmental 12 L:12 D schedule. No significant differences in mean MDA status were detected between controls and SNP-treated animals, no matter the dosing-time or the investigated organ (Fig. 1). In contrast, at 1, 3, and 6 h after administration of SNP, brain MDA content was increased significantly (Student t-test, P < 0.01) in mice treated at 1 HALO compared to controls (Fig. 2A). In animals treated at 13 HALO, significant increase of cerebral MDA status was found only 12 h after injection (Fig. 2B). Mice receiving SNP at 1 HALO showed increased kidney MDA status 1 and 3 h after injection (Fig. 3A), whereas animals treated at 13 HALO showed increased MDA content only 3 h after injection (Fig. 3B). Two-way repeated measures analysis of variance (ANOVA) indicated the MDA status varied as a function of both the sampling-time and treatment in brain and kidney of mice injected at 1 HALO (Table 2). Nonetheless, the observed significant (Table 2) interaction between sampling-time and treatment in cerebral tissue was no longer validated in kidney. The MDA content varied as a function of only sampling-time in brain and Kidney of mice treated at 13 HALO (Tables 2 and 3). Thus, no significant (Table 3) interaction was validated neither in brain nor in kidney of mice treated at 13 HALO. Significant (Table 3) time-related differences were observed 12 and 24 h following the SNP administration at 1 HALO (Fig. 4A), since MDA level was significantly (Student t-test, P < 0.01) increased in liver, but not in mice dosed at 13 HALO (Fig. 4B). Two-way ANOVA revealed a highly significant (Tables 2 and 3) effect of sampling-time, but not of treatment, on hepatic MDA status whatever the dosing-time. Furthermore, no significant
Table 3 – Two-way ANOVA analyses of MDA variation in brain, kidney, and liver of Swiss albinos mice after acute NPS (2.5 mg/kg) injection at 13 HALO.
Results
A circadian rhythm in rectal temperature was validated by Cosinor analysis a day before each experiment (P < 0.001). The acrophase (peak time) of this 24 h rhythm was located during the dark (activity) span, more precisely at ≈17 HALO,
P
Kidney
Brain
Kidney
Liver
Source of variance
F
P
F
P
F
P
Time Treatment Interaction
5.4 1.0 1.8
<0.0004 NS NS
8.4 2.5 1.0
<0.0005 NS NS
5.0 3.5 1.5
<0.0008 NS NS
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Fig. 1 – Changes in brain, kidney, and liver MDA content after dosing with SNP (2.5 mg · Kg−1 b.w.) at 1 HALO (A) and 13 HALO (B). Values are expressed as mean ± S.E.M. (n = 48) and assays carried out in triplicate. Paired Student t-test indicated no statistically significant differences (P ≥ 0.05) between control and treated groups across the three investigated different organs.
interaction between the organ sampling-time and SNP treatment was revealed in animals treated either at 1 or at 13 HALO.
4.
Discussion
Lipid peroxidation is a normal physiological phenomenon that persistently occurs in aerobic organisms (Sohal, 1997). Thereby, organism possesses efficient defense systems that are thorough to prevent oxidative damage (Sastre et al., 2003). However, the use of many chemical products of synthesis such as NO donors, including the SNP, may result in the overproduction of ROS (Geetha et al., 2002; Fukushina et al., 2006; Cardaci et al., 2008), leading to the membrane lipid peroxidation in aerobic livings. The data reveal statistically significant organassociated differences in malondialdehyde (MDA, an index of lipid peroxidation) content between the kidney and the liver or brain. The renal MDA level was higher compared with that of
the liver and brain whatever the dosing-time, whereas hepatic and cerebral levels were statistically comparable. These findings are in agreement with our previous evidence, which demonstrated that MDA production varied according to organtype in non-stress conditions (Sani et al., 2007). Moreover, the observed increase of MDA status in brain, kidney, and liver after the SNP administration at 1 or 13 HALO was statistically comparable between controls and treated-groups, irrespective of sampling-time. As it has been previously reported in rats by other authors (Subramanian et al., 2000), the liver MDA level was lower than the kidney level in mice. These observed variations of oxidative damage among organs might be related to their respective enzymatic (Maggi-Capeyron et al., 2002; Sani et al., 2006b) and/or non-enzymatic (Choi et al., 2004) antioxidants. Indeed, the activities of many detoxifying enzymes, such as catalase, are greater in the liver than kidney (Sani et al., 2006a; Sani et al., 2006b), and melatonin particularly acts on rat liver tissue (Baydas et al., 2001). Moreover, since the liver
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Fig. 2 – Effects of sampling-time on MDA status levels in brain of mice treated with a single dose of SNP (2.5 mg · Kg−1 b.w.) at 1 HALO (A) and 13 HALO (B). Each data point is the mean ± S.E.M. of six individual animals and assays are carried out in triplicate. Paired Student t-test revealed statistically significance: (A & B) * P < 0.05; (A) ** P < 0.005; *** P < 0.0001 significantly different from control groups. Two-way ANOVA: time of sampling (A: F = 4.9; P < 0.008; B: F = 5.4; P < 0.0004); treatment ((A) F = 13.4; P < 0.0006; (B) NS); time-treatment interaction ((A) F = 2.8; P < 0.03; (B) NS).
and kidney are metabolically active and the main sites of xenobiotic detoxification, they are considered to be powerful ROS generators (Halliwell and Gutteridge, 1989). The higher level of MDA in the kidney might also be related to its more pronounced mitochondria activity compared to the liver (Hulbert et al., 2006). Furthermore, the high amount of MDA in the kidney might also be due to its involvement in MDA excretion (Akubue et al., 1994). On the other hand, despite containing large amounts of polyunsaturated fatty acids that are targets of free radicals, the brain tissue showed low levels of MDA. Thus, the enzymatic detoxification does not correlate with these damages, as activities of several enzymes such as catalase are lower in the brain than liver and kidney tissues (Sani et al., 2006a; Sani et al., 2006b). This low level of MDA observed in brain tissue might further be related to non-enzymatic antioxidants such as Zinc (Zn), which is present in high level in this tissue (Frederickson, 1989) and is known to possess
powerful antioxidants properties (Cao and Chen, 1991). Other studies have also reported that many non-enzymatic systems such vitamin E and glutathione which are found in high concentration in brain contribute to the protection of this tissue against ROS damages (Dringen, 2000). Further, low levels of MDA might also be related to melatonin, which causes a reduction in lipid peroxidation, especially in the brain (Baydas et al., 2001). Melatonin, which is known to easily cross the blood–brain barrier (Reiter et al., 1997), stimulates the main antioxidant enzyme of brain, glutathione peroxidase (Reiter, 1995). Moreover, it has recently been shown that endomorphins secreted by the hypothalamus contribute to the scavenging of free radicals in the brain (Lin et al., 2006). Another relevant finding of the present study is that SNP administration at 1 or 13 HALO induces sampling-timerelated variations of MDA status in both three studied tissues. Thus, the SNP dosed at 1 HALO significantly increased lipid
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Fig. 3 – Effects of sampling-time on MDA status levels in kidney of mice treated with a single dose of SNP (2.5 mg · Kg−1 b.w.) at 1 HALO (A) and 13 HALO (B). Each data point is the mean ± S.E.M. of six individual animals and assays are carried out in triplicate. Paired Student t-test revealed statistically significance: (A) * P < 0.05; (A & B) ** P < 0.005 significantly different from control groups. Two-way ANOVA: time of sampling ((A) F = 14.3; P < 0.0001; (B) F = 8.4; P < 0.0005); treatment ((A) F = 5.5; P < 0.03; (B) NS); time-treatment interaction ((A & B) NS).
peroxidation evidenced by the accumulation of MDA in brain 1, 3, and 6 h following the injection. The same dose of SNP administered at 13 HALO induced significant differences in lipid peroxidation between controls and treated-groups later 12 h after injection. Several other studies have demonstrated that SNP injection induces oxidative damage in the brain of mouse (Nazari et al., 2012, 2013), rat (Sabir et al., 2012) or human (Li et al., 2013). The original and interesting finding of this study is that administration of the SNP revealed a marked influence of both time of exposure and time of sampling. As shown previously (Sani et al., 2011) the peak and trough times of SNP-induced neurotoxic effects were localized at the early rest span (≈1 HALO) and early activity span (≈13 HALO) of the rodents, respectively. Thus, the circadian peak and trough times of behavioral neurotoxicity (ataxia) matched well with the observed maximum and minimum of lipid peroxidation (MDA level) after SNP administration at the early light and dark spans, respectively (Fukushina et al., 2006). The similar dosing-time effects were observed in kidney tissue, which
showed statistically significant increases of MDA status 1 and 3 h after SNP administration at 1 HALO, whereas the drug dosing at 13 HALO significantly increased renal MDA content only 3 h after injection. Such results fit well with other findings indicating that the SNP may induce the nephrotoxicity and renal oxidative injury (Khan et al., 2012). In contrast, the drug dosed at 1 HALO induced significant increases of liver MDA content 12 and 24 h after injection, while the mice treated at 13 HALO showed no significant differences with controls. Therefore, the significant increases of MDA status observed in brain, kidney and liver indirectly revealed the involvement of SNP in the mechanism of cytotoxicity towards cerebral, renal, and hepatic cells. Thus, the strong accumulation of MDA in these tissues might be related to the oxidative damage induced by ROS during the reductive reactions of NO rather than CN− released by SNP (Bernabe et al., 2001). However, it has been suggested that NO (released by SNP) may also have antioxidant properties. Indeed, many reports have demonstrated that NO may act as atypical antioxidant both
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Fig. 4 – Effects of sampling-time on MDA status levels in liver of mice treated with a single dose of SNP (2.5 mg · Kg−1 b.w.) at 1 HALO (A) and 13 HALO (B). Each data point is the mean ± S.E.M. of six individual animals and assays are carried out in triplicate. Paired Student t-test revealed statistically significance: * P < 0.05; ** P < 0.005 significantly different from control groups in (A), but not in (B). Two-way ANOVA: time of sampling ((A) F = 11.8; P < 0.0001; B: F = 5.0; P < 0.0008); treatment ((A & B) NS); time-treatment interaction ((A & B) NS).
in vitro (Rubbo et al., 1994; Rauhala et al., 1996a) and in vivo (Rauhala et al., 1996b). Thus, the SNP-induced oxidative effects on tissues might depend on type of cells and probably on time of exposure. That hypothesis (Laskin et al., 2001) fits well with our findings which showed a slight decrease, but not significant of hepatic MDA status after the SNP administration at 13 HALO. Two-way ANOVA revealed the changes (induced by SNP administration at 1 HALO) in brain and kidney MDA statuses were statistically significant with respect to two factors: sampling-time and treatment. A statistically significant interaction between time and treatment was validated only in brain, illustrating the influence of treatment on time-related differences in this tissue. This interaction was no longer statistically validated either in kidney or in liver. It
seems the treatment-related difference was reduced in kidney and liver compared with the brain tissue. Furthermore, two-way ANOVA indicated that the MDA status significantly differed according to only the sampling-time in brain, kidney, and liver tissues of mice injected at 13 HALO. Thus, cytotoxicity to the brain, kidney, and liver induced by SNP is greatly reduced when administered to rodents during the beginning of dark span, the beginning of the animal’s nocturnal activity span. Finally, the present investigation provides evidence for an increase in oxidative damage which is supported by the increase in the levels of MDA content in various organs of mice after SNP administration. This increase in oxidative stress may indicate an increase in free radical reactions in mitochondria
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and may contribute to the induction of apoptosis. Despite the SNP dose (2.5 mg · Kg−1 ) and its administration route (i.p.) used in these studies are different from those (i.v. route, 0.5 to 400 g · Kg−1 · min−1 ) used in clinical studies (Mullens et al., 2008; Cavolli et al., 2008), this framework revealed some interesting findings that deserve to be reported. Thus, the results of these studies and our recent findings (Sani et al., 2011) are greatly inter-related, indicating that the circadian dosing-time dependent difference of SNP neurotoxicity appeared to contribute to that of SNP oxidative damage. This study shows that on the one hand, SNP-induced side oxidative effects vary not only according to the target organ, but also according to the time of day, that might influence the strategies by which SNP treatment can be beneficial in the management of cardiovascular diseases. Thus, it is necessary to take it into account in clinical protocols to minimize the side effects of SNP used as a powerful vasodilator both for treatment of hypertension emergencies and in postoperative cardiac surgical patients.
Transparency document The Transparency document associated with this article can be found in the online version.
Acknowledgments This work was supported by “le Secrétariat d’Etat de la Recherche Scientifique et de la Technologie” and by “le Ministère de l’Enseignement Supérieur de la République Tunisienne”. We wish to express our gratitude to Prof. Ezzedine Aouani for his advice and help regarding the paper.
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Available online at www.sciencedirect.com
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Dosing-time dependent oxidative effects of sodium nitroprusside in brain, kidney, and liver of mice Mamane Sani a,∗ , Hichem Sebai b , Néziha Ghanem-Boughanmi b , Naceur A. Boughattas c , Mossadok Ben-Attia d a
UMR Biosurveillance et Toxicologie Environnementale, Département de Biologie, Faculté des Sciences et Techniques de Maradi, 465 Maradi, Niger b UR Ethnobotanie et Stress Oxydant, Département des Sciences de la Vie, Faculté des Sciences de Bizerte, 7021 Zarzouna, Tunisia c Laboratoire de Pharmacologie, Faculté de Médecine, 5019 Monastir, Tunisia d Laboratoire de Biosurveillance de l‘Environnement, Faculté des Sciences de Bizerte, 7021 Zarzouna, Tunisia
a r t i c l e
i n f o
a b s t r a c t
Article history:
The purpose of this study was to investigate if the oxidative effects of sodium nitroprusside
Received 7 May 2014
(SNP) are dosing-time dependent. Therefore, the variation of malondialdehyde (MDA) status
Received in revised form
was assessed after a single i.p. administration of SNP (2.5 mg kg−1 b.w.) or vehicle (9‰ NaCl)
17 August 2014
to different and comparable groups of mice (n = 48) at two different circadian times (1 and
Accepted 18 August 2014
13 h after light onset [HALO]). Brain, kidney, and liver tissues were excised over 36 h, and
Available online 24 August 2014
their MDA contents were estimated at 0, 1, 3, 6, 9, 12, 24, and 36 h after SNP administration. Results: indicated mean MDA level was not significantly changed in each investigated tissue
Keywords:
compared with the control. In contrast, the mean MDA value varied among organs and was
Malondialdehyde
comparable in brain and liver but lower than in kidney. The data show SNP significantly
Sodium nitroprusside
(P < 0.05) increases MDA status in both tissues and exerts time-dependent oxidative effects
Mice
with the greatest toxicity coinciding with the beginning of the diurnal rest span (local time:
Brain
08:00 h, i.e., at 1 HALO). The obtained results reveal SNP-induced oxidative damage (evidenced by MDA accumu-
Kidney
lation) varies according to both the dosing-time and the target organ.
Liver
© 2014 Elsevier B.V. All rights reserved.
1.
Introduction
Nitrovasodilator-SNP (Na2 [Fe(CN)5 NO]·2H2 O) is an excellent drug clinically used for treating acute myocardial infarction (Franciosa et al., 1972), chronic heart failure (Guiha et al., 1974), cardiac (Moffett and Price, 2008), and hypertension emergencies (Gifford, 1959). Several scientific reports (Smith and
Kruszyna, 1974; Vesey and Cole, 1985) revealed that SNP in human and other mammalian species undergoes metabolism in vivo to release toxic free cyanide (CN− ). Indeed, the lethal effects of CN− have been known for more than a century and HCN, cyanide salts or cyanogenic compounds have been used in suicides, homicides, and chemical warfare. It is generally believed that in vivo the primary pathway for CN− detoxification is its oxidation to thiocyanate by the enzyme thiosulfate
∗ Corresponding author. Department of Biology, Faculty of Sciences and Techniques, University of Maradi, BP 465 Maradi, Niger. Tel.: +227 20 41 01 32; fax: +227 20 41 01 33. E-mail address: [email protected] (M. Sani). http://dx.doi.org/10.1016/j.etap.2014.08.013 1382-6689/© 2014 Elsevier B.V. All rights reserved.
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e n v i r o n m e n t a l t o x i c o l o g y a n d p h a r m a c o l o g y 3 8 ( 2 0 1 4 ) 625–633
sulfurtransferase (rhodanese) that is present in various tissues (Drawbaugh and Marrs, 1987; Sani et al., 2008a,b) and particularly high in liver (Sani et al., 2006a). However, it has been established that the SNP-induced oxidative stress may be due to its ability to release several other potential toxic products such as NO and iron ions (Nazari et al., 2012; Lozinsky et al., 2012; Ibrahim et al., 2012). The molecular mechanism of NO-related SNP-induced neurotoxic effects is not fully understood. Other findings firmly confirmed the hypothesis that biological effects of the exogenous NO donor, SNP, depend on the redox status of the cell (Sokołowska et al., 2003). Therefore, the cytotoxicity of SNP was attributed to enhanced ROS production, which in turn resulted in decrease in antioxidant levels. Nevertheless, it has been demonstrated that oxidative stress is a main mediator in NO-induced neurotoxicity and apoptosis in human cells in a concentration and time-dependent manner (Zhang and Zhao, 2003). These concerns have hindered the general enthusiasm in using SNP in the management of acute hypertension emergencies, even though its potency, rapid onset, and short duration of action. However, there is nowadays the resurgence of interest in the use of SNP, particularly in the management of acute decompensated heart failure (Mullens et al., 2008; Opasich et al., 2009) and in the prediction of blood pressure during certain cardio-vascular surgical procedures (Roitberg et al., 2008; Spielberg et al., 2014; Zhao et al., 2014). Although the increased usefulness of SNP in several cardio-vascular diseases cares, prolonged use of SNP has often been associated with the risk of its end-products toxicity on brain, kidney, and muscle of patients (Guo et al., 2013; Moerman et al., 2013). Therefore, there is a great necessity to discuss possible strategies by which the safety and efficacy of SNP as part of the treatment regimen for hospitalized heart failure patients might be improved. Time-of-day of exposure is rarely considered in the study of desired (efficacious) and nondesired (toxic) effects of drugs. In rodents, the nephrotoxicity of heavy metal (Hg, Cd) as well as that of some antibiotics (amikacine, dibekacine) exhibits large amplitude circadian rhythms, with a peak located at the rest span and a trough at the activity span (Cal et al., 1986; Cambar et al., 1987). It seems, therefore, that a temporal relation may be observed between the circadian variation in MDA and chronotoxic effects of some agents, respectively, in the liver and kidney. Our previous data revealed that the neurotoxic effects of SNP varied markedly within the 24-h period depending on the time of administration (Sani et al., 2011). The circadian variation in drug effects are suggested not to be due to rhythmic changes in the pharmacokinetics of drugs but rather to an endogenous rhythm in drug susceptibility resulting from a circadian rhythm controlled by an inner clock (Moore and Eichler, 1972). It would be expected that the drug concentration as well as the dosing-/sampling-time would affect both the efficacy and the toxicity of an antihypertensive drug. However, little is known about the time-of-day dependence of either measured levels of neuronal toxicity or lipid peroxidation induced by SNP. Such information would be of importance to both exercise scientists and clinicians, since it would help to minimize the drug-induced side effects by a better optimization of drug use at the adequate time-of-day. Thus, the dosing of medication at the targeted biological time
with reference to circadian rhythms can result in modulation of its toxicity (Hrushesky et al., 1989). To this end, the oxidative effects of SNP could be dependent on the period of waxing and waning of motor activity. Therefore, the purpose of this study was to assess if time-of-day of exposure influences the oxidative effects of SNP in terms of its effects on MDA production in the brain, kidney, and liver of mice.
2.
Materials and methods
2.1.
Animals and housing
Animals used in this study were Swiss albino mice obtained from the Central Animal House (SIPHAT, 2013 FoundoukChoucha, Tunisia) at 9 weeks of age (≈25 g body weight) and experiments lasted from June to November 2007. The animals were housed 4–5 per cage with free access to food and water. They were acclimated for at least 3 weeks prior to and during each study (Reinberg and Smolensky, 1983), to controlled conditions of temperature (22 ± 2 ◦ C), relative humidity (50–60%), and 12-h light: 12-h dark photoperiod (light on at 07:00 h). The desired synchronization of mice was documented by the quantification of normal circadian rhythmicity in rectal temperature, the acrophase (peak time) used as marker rhythm index. In this study carried out at the FSB Toxicometry and Chronobiometry Laboratory (Bizerte, Tunisia), all experimental procedures conformed to the NIH recommendations and current guidelines (Portaluppi et al., 2008).
2.2.
Drug
SNP (Na2 [Fe(CN)5 NO]·2H2 O) brown–red powder was kindly supplied by the National Laboratory of Drug Control (1006 Tunis, Tunisia). The SNP is a chemical product of synthesis that is hydrosoluble but little soluble in alcohol. Based on our previous experience with SNP in chronotoxicological studies, in adult mice neurotoxic effects of SNP were triggered with doses raging from 2.5 to 5 mg · Kg−1 -a median toxic dose TD50 (dose inducing 50% motor-inco-ordination) equal to 3.6 ± 0.5 mg · Kg−1 . Since oxidative effects of SNP are seemed to be related to its neurotoxicity, the lowest neurotoxic SNP dose (of 2.5 mg · Kg−1 ) was used to investigate SNP-induced oxidative damage. Thus, the solution was freshly prepared each experiment day by adding an adequate volume of sterile distilled water to obtain the 2.5 mg/kg concentration of SNP. That single dose was administered to mice in a fixed fluid volume (10 mL · Kg−1 b.w.).
2.3.
Study designs and tissue samplings
The study design is summarized in Table 1. A total of 192 synchronized male mice were randomly assigned to four groups (48/group) for treatment with SNP (2.5 mg · kg−1 ) or sodium chloride (0.9%). The first two groups of animals were treated once with an i.p. injection of saline (group 1) or SNP (group 2) at a fixed local time (08:00 h, i.e., at 1 HALO), whereas the two last groups were similarly dosed with saline (group 3) or SNP (group 4) at later 12 h (20:00 h local time, e.g., 13 HALO). Each dosing-time involved different but comparable
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Table 1 – Main characteristics of the study investigating chronotoxicity of SNP in male Swiss albinos mice. Drugs
Doses
NaCl solution (control)
0.9%
48
SNP
2.5 mg/kg 0.9%
48 48
2.5 mg/kg
48
NaCl solution (control) SNP
Number of mice
Dosing-time (HALO)
Toxicity variable
Time-of-sampling (HALO)
1
MDA
0, 1, 3, 6, 9, 12, 24, 36
13
MDA
0, 1, 3, 6, 9, 12, 24, 36
sub-groups of mice (n = 6) corresponding to animals sacrificed by decapitation at 0, 1, 3, 6, 9, 12, 24, and 36 h after injection. Thereafter, brain, kidney, and liver tissue were quickly removed and individually categorized with respect to tissue, dosing-time, sampling-time, and then stored frozen at −84 ◦ C until assayed.
2.4.
Assay procedure of lipid peroxidation
For each animal, whole brain (minus brain stem), kidney, and a portion of liver were separately placed in an ice-cold Petri dish maintained in finely crushed ice. Brain, kidney, and liver tissue were homogenized in ice-cold Tris-Buffered Saline (TBS: 26 mM, pH 7.4) using glass/Teflon homogenizer. Tissue lipid peroxides were monitored by determining the index of lipid peroxidation, MDA using the Thio-Barbutiric Acid (TBA) test as described by Buege and Aust (1978). All results are expressed as mol MDA/mg protein.
2.5.
Protein assay
The protein content of different samples was determined by the method of Lowry et al. (1951) as modified by Hartree (1972) and by using bovine serum albumin as a standard.
2.6.
Statistical analysis
The “Cosinorwin” circadian software programme (http://www. circadian.org/softwar.html) was used to analyse time series of rectal temperature for circadian rhythm by approximating the time series data with single cosine curves of the designated periods using the method of least squares (Nelson et al., 1979). Sampling-time-point data were computed as means ± standard error of means (S.E.M.) and pertinent histograms were drawn. Student’s t-test for paired data (InStat for MacIntosh, GraphPad Software, San Diego, CA, USA) was used to compare treatment and control groups at designated sampling-times. The reproducibility of MDA status variation from one sampling-time to the next was tested by examining the interaction between sampling-time and treatment on the content values, using two-way analysis of variance (ANOVA). All conclusions are based on at least 5% level of significance (P < 0.05).
3.
Table 2 – Two-way ANOVA analyses of MDA variation in brain, kidney, and liver of Swiss albinos mice after acute NPS (2.5 mg/kg) injection at 1 HALO. Brain Source of variance F Time Treatment Interaction
Liver
F
F
P
P
4.9 <0.008 14.3 <0.0001 11.8 <0.0001 13.4 <0.0006 5.5 <0.03 1.2 NS 2.8 <0.03 0.4 NS 2.0 NS
confirming the synchronization of the mice to the environmental 12 L:12 D schedule. No significant differences in mean MDA status were detected between controls and SNP-treated animals, no matter the dosing-time or the investigated organ (Fig. 1). In contrast, at 1, 3, and 6 h after administration of SNP, brain MDA content was increased significantly (Student t-test, P < 0.01) in mice treated at 1 HALO compared to controls (Fig. 2A). In animals treated at 13 HALO, significant increase of cerebral MDA status was found only 12 h after injection (Fig. 2B). Mice receiving SNP at 1 HALO showed increased kidney MDA status 1 and 3 h after injection (Fig. 3A), whereas animals treated at 13 HALO showed increased MDA content only 3 h after injection (Fig. 3B). Two-way repeated measures analysis of variance (ANOVA) indicated the MDA status varied as a function of both the sampling-time and treatment in brain and kidney of mice injected at 1 HALO (Table 2). Nonetheless, the observed significant (Table 2) interaction between sampling-time and treatment in cerebral tissue was no longer validated in kidney. The MDA content varied as a function of only sampling-time in brain and Kidney of mice treated at 13 HALO (Tables 2 and 3). Thus, no significant (Table 3) interaction was validated neither in brain nor in kidney of mice treated at 13 HALO. Significant (Table 3) time-related differences were observed 12 and 24 h following the SNP administration at 1 HALO (Fig. 4A), since MDA level was significantly (Student t-test, P < 0.01) increased in liver, but not in mice dosed at 13 HALO (Fig. 4B). Two-way ANOVA revealed a highly significant (Tables 2 and 3) effect of sampling-time, but not of treatment, on hepatic MDA status whatever the dosing-time. Furthermore, no significant
Table 3 – Two-way ANOVA analyses of MDA variation in brain, kidney, and liver of Swiss albinos mice after acute NPS (2.5 mg/kg) injection at 13 HALO.
Results
A circadian rhythm in rectal temperature was validated by Cosinor analysis a day before each experiment (P < 0.001). The acrophase (peak time) of this 24 h rhythm was located during the dark (activity) span, more precisely at ≈17 HALO,
P
Kidney
Brain
Kidney
Liver
Source of variance
F
P
F
P
F
P
Time Treatment Interaction
5.4 1.0 1.8
<0.0004 NS NS
8.4 2.5 1.0
<0.0005 NS NS
5.0 3.5 1.5
<0.0008 NS NS
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Fig. 1 – Changes in brain, kidney, and liver MDA content after dosing with SNP (2.5 mg · Kg−1 b.w.) at 1 HALO (A) and 13 HALO (B). Values are expressed as mean ± S.E.M. (n = 48) and assays carried out in triplicate. Paired Student t-test indicated no statistically significant differences (P ≥ 0.05) between control and treated groups across the three investigated different organs.
interaction between the organ sampling-time and SNP treatment was revealed in animals treated either at 1 or at 13 HALO.
4.
Discussion
Lipid peroxidation is a normal physiological phenomenon that persistently occurs in aerobic organisms (Sohal, 1997). Thereby, organism possesses efficient defense systems that are thorough to prevent oxidative damage (Sastre et al., 2003). However, the use of many chemical products of synthesis such as NO donors, including the SNP, may result in the overproduction of ROS (Geetha et al., 2002; Fukushina et al., 2006; Cardaci et al., 2008), leading to the membrane lipid peroxidation in aerobic livings. The data reveal statistically significant organassociated differences in malondialdehyde (MDA, an index of lipid peroxidation) content between the kidney and the liver or brain. The renal MDA level was higher compared with that of
the liver and brain whatever the dosing-time, whereas hepatic and cerebral levels were statistically comparable. These findings are in agreement with our previous evidence, which demonstrated that MDA production varied according to organtype in non-stress conditions (Sani et al., 2007). Moreover, the observed increase of MDA status in brain, kidney, and liver after the SNP administration at 1 or 13 HALO was statistically comparable between controls and treated-groups, irrespective of sampling-time. As it has been previously reported in rats by other authors (Subramanian et al., 2000), the liver MDA level was lower than the kidney level in mice. These observed variations of oxidative damage among organs might be related to their respective enzymatic (Maggi-Capeyron et al., 2002; Sani et al., 2006b) and/or non-enzymatic (Choi et al., 2004) antioxidants. Indeed, the activities of many detoxifying enzymes, such as catalase, are greater in the liver than kidney (Sani et al., 2006a; Sani et al., 2006b), and melatonin particularly acts on rat liver tissue (Baydas et al., 2001). Moreover, since the liver
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Fig. 2 – Effects of sampling-time on MDA status levels in brain of mice treated with a single dose of SNP (2.5 mg · Kg−1 b.w.) at 1 HALO (A) and 13 HALO (B). Each data point is the mean ± S.E.M. of six individual animals and assays are carried out in triplicate. Paired Student t-test revealed statistically significance: (A & B) * P < 0.05; (A) ** P < 0.005; *** P < 0.0001 significantly different from control groups. Two-way ANOVA: time of sampling (A: F = 4.9; P < 0.008; B: F = 5.4; P < 0.0004); treatment ((A) F = 13.4; P < 0.0006; (B) NS); time-treatment interaction ((A) F = 2.8; P < 0.03; (B) NS).
and kidney are metabolically active and the main sites of xenobiotic detoxification, they are considered to be powerful ROS generators (Halliwell and Gutteridge, 1989). The higher level of MDA in the kidney might also be related to its more pronounced mitochondria activity compared to the liver (Hulbert et al., 2006). Furthermore, the high amount of MDA in the kidney might also be due to its involvement in MDA excretion (Akubue et al., 1994). On the other hand, despite containing large amounts of polyunsaturated fatty acids that are targets of free radicals, the brain tissue showed low levels of MDA. Thus, the enzymatic detoxification does not correlate with these damages, as activities of several enzymes such as catalase are lower in the brain than liver and kidney tissues (Sani et al., 2006a; Sani et al., 2006b). This low level of MDA observed in brain tissue might further be related to non-enzymatic antioxidants such as Zinc (Zn), which is present in high level in this tissue (Frederickson, 1989) and is known to possess
powerful antioxidants properties (Cao and Chen, 1991). Other studies have also reported that many non-enzymatic systems such vitamin E and glutathione which are found in high concentration in brain contribute to the protection of this tissue against ROS damages (Dringen, 2000). Further, low levels of MDA might also be related to melatonin, which causes a reduction in lipid peroxidation, especially in the brain (Baydas et al., 2001). Melatonin, which is known to easily cross the blood–brain barrier (Reiter et al., 1997), stimulates the main antioxidant enzyme of brain, glutathione peroxidase (Reiter, 1995). Moreover, it has recently been shown that endomorphins secreted by the hypothalamus contribute to the scavenging of free radicals in the brain (Lin et al., 2006). Another relevant finding of the present study is that SNP administration at 1 or 13 HALO induces sampling-timerelated variations of MDA status in both three studied tissues. Thus, the SNP dosed at 1 HALO significantly increased lipid
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Fig. 3 – Effects of sampling-time on MDA status levels in kidney of mice treated with a single dose of SNP (2.5 mg · Kg−1 b.w.) at 1 HALO (A) and 13 HALO (B). Each data point is the mean ± S.E.M. of six individual animals and assays are carried out in triplicate. Paired Student t-test revealed statistically significance: (A) * P < 0.05; (A & B) ** P < 0.005 significantly different from control groups. Two-way ANOVA: time of sampling ((A) F = 14.3; P < 0.0001; (B) F = 8.4; P < 0.0005); treatment ((A) F = 5.5; P < 0.03; (B) NS); time-treatment interaction ((A & B) NS).
peroxidation evidenced by the accumulation of MDA in brain 1, 3, and 6 h following the injection. The same dose of SNP administered at 13 HALO induced significant differences in lipid peroxidation between controls and treated-groups later 12 h after injection. Several other studies have demonstrated that SNP injection induces oxidative damage in the brain of mouse (Nazari et al., 2012, 2013), rat (Sabir et al., 2012) or human (Li et al., 2013). The original and interesting finding of this study is that administration of the SNP revealed a marked influence of both time of exposure and time of sampling. As shown previously (Sani et al., 2011) the peak and trough times of SNP-induced neurotoxic effects were localized at the early rest span (≈1 HALO) and early activity span (≈13 HALO) of the rodents, respectively. Thus, the circadian peak and trough times of behavioral neurotoxicity (ataxia) matched well with the observed maximum and minimum of lipid peroxidation (MDA level) after SNP administration at the early light and dark spans, respectively (Fukushina et al., 2006). The similar dosing-time effects were observed in kidney tissue, which
showed statistically significant increases of MDA status 1 and 3 h after SNP administration at 1 HALO, whereas the drug dosing at 13 HALO significantly increased renal MDA content only 3 h after injection. Such results fit well with other findings indicating that the SNP may induce the nephrotoxicity and renal oxidative injury (Khan et al., 2012). In contrast, the drug dosed at 1 HALO induced significant increases of liver MDA content 12 and 24 h after injection, while the mice treated at 13 HALO showed no significant differences with controls. Therefore, the significant increases of MDA status observed in brain, kidney and liver indirectly revealed the involvement of SNP in the mechanism of cytotoxicity towards cerebral, renal, and hepatic cells. Thus, the strong accumulation of MDA in these tissues might be related to the oxidative damage induced by ROS during the reductive reactions of NO rather than CN− released by SNP (Bernabe et al., 2001). However, it has been suggested that NO (released by SNP) may also have antioxidant properties. Indeed, many reports have demonstrated that NO may act as atypical antioxidant both
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Fig. 4 – Effects of sampling-time on MDA status levels in liver of mice treated with a single dose of SNP (2.5 mg · Kg−1 b.w.) at 1 HALO (A) and 13 HALO (B). Each data point is the mean ± S.E.M. of six individual animals and assays are carried out in triplicate. Paired Student t-test revealed statistically significance: * P < 0.05; ** P < 0.005 significantly different from control groups in (A), but not in (B). Two-way ANOVA: time of sampling ((A) F = 11.8; P < 0.0001; B: F = 5.0; P < 0.0008); treatment ((A & B) NS); time-treatment interaction ((A & B) NS).
in vitro (Rubbo et al., 1994; Rauhala et al., 1996a) and in vivo (Rauhala et al., 1996b). Thus, the SNP-induced oxidative effects on tissues might depend on type of cells and probably on time of exposure. That hypothesis (Laskin et al., 2001) fits well with our findings which showed a slight decrease, but not significant of hepatic MDA status after the SNP administration at 13 HALO. Two-way ANOVA revealed the changes (induced by SNP administration at 1 HALO) in brain and kidney MDA statuses were statistically significant with respect to two factors: sampling-time and treatment. A statistically significant interaction between time and treatment was validated only in brain, illustrating the influence of treatment on time-related differences in this tissue. This interaction was no longer statistically validated either in kidney or in liver. It
seems the treatment-related difference was reduced in kidney and liver compared with the brain tissue. Furthermore, two-way ANOVA indicated that the MDA status significantly differed according to only the sampling-time in brain, kidney, and liver tissues of mice injected at 13 HALO. Thus, cytotoxicity to the brain, kidney, and liver induced by SNP is greatly reduced when administered to rodents during the beginning of dark span, the beginning of the animal’s nocturnal activity span. Finally, the present investigation provides evidence for an increase in oxidative damage which is supported by the increase in the levels of MDA content in various organs of mice after SNP administration. This increase in oxidative stress may indicate an increase in free radical reactions in mitochondria
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and may contribute to the induction of apoptosis. Despite the SNP dose (2.5 mg · Kg−1 ) and its administration route (i.p.) used in these studies are different from those (i.v. route, 0.5 to 400 g · Kg−1 · min−1 ) used in clinical studies (Mullens et al., 2008; Cavolli et al., 2008), this framework revealed some interesting findings that deserve to be reported. Thus, the results of these studies and our recent findings (Sani et al., 2011) are greatly inter-related, indicating that the circadian dosing-time dependent difference of SNP neurotoxicity appeared to contribute to that of SNP oxidative damage. This study shows that on the one hand, SNP-induced side oxidative effects vary not only according to the target organ, but also according to the time of day, that might influence the strategies by which SNP treatment can be beneficial in the management of cardiovascular diseases. Thus, it is necessary to take it into account in clinical protocols to minimize the side effects of SNP used as a powerful vasodilator both for treatment of hypertension emergencies and in postoperative cardiac surgical patients.
Transparency document The Transparency document associated with this article can be found in the online version.
Acknowledgments This work was supported by “le Secrétariat d’Etat de la Recherche Scientifique et de la Technologie” and by “le Ministère de l’Enseignement Supérieur de la République Tunisienne”. We wish to express our gratitude to Prof. Ezzedine Aouani for his advice and help regarding the paper.
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