Daily rhythms of physiological parameters in the dromedary camel under natural and laboratory conditions.

Camels are well adapted to hot arid environments and can contribute significantly to the economy of developing countries in arid regions of the world. Full understanding of the physiology of camels requires understanding of the internal temporal order of the body, as reflected in daily or circadian rhythms. In the current study, we investigated the daily rhythmicity of 20 physiological variables in camels exposed to natural oscillations of ambient temperature in a desert environment and compared the daily temporal courses of the variables. We also studied the rhythm of core body temperature under experimental conditions with constant ambient temperature in the presence and absence of a light-dark cycle. The obtained results indicated that different physiological variables exhibit different degrees of daily rhythmicity and reach their daily peaks at different times of the day, starting with plasma cholesterol, which peaks 24min after midnight, and ending with plasma calcium, which peaks 3h before midnight. Furthermore, the rhythm of core body temperature persisted in the absence of environmental rhythmicity, thus confirming its endogenous nature. The observed delay in the acrophase of core body temperature rhythm under constant conditions suggests that the circadian period is longer than 24h. Further studies with more refined experimental manipulation of different variables are needed to fully elucidate the causal network of circadian rhythms in dromedary camels.

Chamomile decoction extract inhibits human neutrophils ROS production and attenuates alcohol-induced haematological parameters changes and erythrocytes oxidative stress in rat.

BACKGROUND: The aim of this study was to evaluate the protective effects of subacute pre-treatment with chamomile (Matricaria recutita L.) decoction extract (CDE) against stimulated neutrophils ROS production as well as ethanol (EtOH)-induced haematological changes and erythrocytes oxidative stress in rat. METHODS: Neutrophils were isolated and ROS generation was measured by luminol-amplified chemiluminescence. Superoxide anion generation was detected by the cytochrome c reduction assay. Adult male wistar rats were used and divided into six groups of ten each: control, EtOH, EtOH + various doses of CDE (25, 50, and 100 mg/kg, b.w.), and EtOH+ ascorbic acid (AA). Animals were pre-treated with CDE extract during 10 days. RESULTS: We found that CDE inhibited (P ≤ 0.0003) luminol-amplified chemiluminescence of resting neutrophils and N-formyl methionylleucyl-phenylalanine (fMLF) or phorbolmyristate acetate (PMA) stimulated neutrophils, in a dose-dependent manner. CDE had no effect on superoxide anion, but it inhibited (P ≤ 0.0004) H2O2 production in cell free system. In vivo, CDE counteracted (P ≤ 0.0034) the effect of single EtOH administration which induced (P < 0.0001) an increase of white blood cells (WBC) and platelets (PLT) counts. Our results also demonstrated that alcohol administration significantly (P < 0.0001) induced erythrocytes lipoperoxidation increase and depletion of sulfhydryl groups (-SH) content as well as antioxidant enzyme activities as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). More importantly, we found that acute alcohol administration increased (P < 0.0001) erythrocytes and plasma hydrogen peroxide (H2O2), free iron, and calcium levels while the CDE pre-treatment reversed increased (P ≤ 0.0051) all these intracellular disturbances. CONCLUSIONS: These findings suggest that CDE inhibits neutrophil ROS production and protects against EtOH-induced haematologiacal parameters changes and erythrocytes oxidative stress. The haematoprotection offered by chamomile might involve in part its antioxidant properties as well as its opposite effect on some intracellular mediators such as H2O2, free iron, and calcium.

Blooming rhythms of cactus Cereus peruvianus with nocturnal peak at full moon during seasons of prolonged daytime photoperiod.

Cereus peruvianus (Peruvian apple cactus) is a large erect and thorny succulent cactus characterized by column-like (cereus [L]: column), that is, candle-shaped, appendages. For three successive years (1100 days), between early April and late November, we studied the flowering patterns of eight cacti growing in public gardens and rural areas of north and central Tunisia, far from nighttime artificial illumination, in relation to natural environmental light, temperature, relative humidity and precipitation parameters. Flower blooming was assessed nightly between 23:00 h and until at least 02:00 h, and additionally around-the-clock at ~1 h intervals for 30 consecutive days during the late summer of each year of study to quantify both nyctohemeral (day-night) and lunar patterns. During the summer months of prolonged daytime photoperiod, flower blooming of C. peruvianus exhibited predictable-in-time variation as "waves" with average period of 29.5 days synchronized by the light of the full moon. The large-sized flower (~16 cm diameter) opens almost exclusively at night, between sunset and sunrise, as a 24 h rhythm during a specific 3-4-day span of the lunar cycle (full moon), with a strong correlation between moon phase and number and proportion of flowers in bloom (ranging from r = +0.59 to +0.91). Black, blue and red cotton sheets were used to filter specific spectral bands of nighttime moonlight from illuminating randomly selected plant appendages as a means to test the hypothesis of a "gating" 24 h rhythm phenomenon of photoreceptors at the bud level. Relative to control conditions (no light filtering), black sheet covering inhibited flower bud induction by 87.5%, red sheet covering by 46.6% and blue sheet covering by 34%, and the respective inhibiting effects on number of flowers in bloom were essentially 100%, ~81% and ~44%. C. peruvianus is a unique example of a terrestrial plant that exhibits a circadian flowering rhythm (peak ~00:00 h) "gated" by 24 h, lunar 29.5-day (bright light of full moon) and annual 365.25-day (prolonged summertime day length) environmental photoperiod cycles.

Effects of sodium nitroprusside on mouse erythrocyte catalase activity and malondialdehyde status.

There is controversy about the anti- or pro-oxidative effects of the nitric oxide (NO)-donor sodium nitroprusside (SNP). Hence, the activity of the antioxidant enzyme catalase (CAT) and the status of malondialdehyde (MDA) were investigated after a 2.5 mg/kg dose of SNP had been i.p. administered to different and comparable groups of mice (n = 48). The drug was administered at two different circadian times (1 and 13 h after light onset [HALO]). There were, irrespectively of sampling time, no significant differences in the means of CAT activity and MDA status between control and SNP-treated groups, no matter the treatment time. However, CAT activity was significantly (Student's t-test, p < 0.001) increased 1 h following SNP administration at 1 HALO, whereas the significant (p < 0.001) increase in the enzyme activity was found only 3 h after injection at 13 HALO. The drug dosing either at 1 or 13 HALO resulted in no significant differences of MDA status between control and treated groups regardless to the sampling time. Two-way analysis of variance (ANOVA) detected a significant (F0.05(7,88)= 5.3; p < 0.0006) interaction between sampling time and treatment in mice injected at 1 HALO, suggesting the influence of treatment on sampling-time-related changes in CAT activity. However, ANOVA validated no interaction between the two factors in mice treated at 13 HALO, illustrating that the sampling-time differences in enzyme activity were greater. Furthermore, two-way ANOVA revealed no interaction in the variation of MDA status in animals treated either at 1 or 13 HALO. This study indicates that SNP significantly affected the anti-oxidant system.

Evidence for daily and weekly rhythmicity but not lunar or seasonal rhythmicity of physical activity in a large cohort of individuals from five different countries.

BACKGROUND: Biological rhythmicity has been extensively studied in animals for many decades. Although temporal patterns of physical activity have been identified in humans, no large-scale, multi-national study has been published, and no comparison has been attempted of the ubiquity of activity rhythms at different time scales (such as daily, weekly, monthly, and annual). METHODS: Using individually worn actigraphy devices, physical activity of 2,328 individuals from five different countries (adults of African descent from Ghana, South Africa, Jamaica, Seychelles, and the United States) was measured for seven consecutive days at different times of the year. RESULTS: Analysis for rhythmic patterns identified daily rhythmicity of physical activity in all five of the represented nationalities. Weekly rhythmicity was found in some, but not all, of the nationalities. No significant evidence of lunar rhythmicity or seasonal rhythmicity was found in any of the groups. CONCLUSIONS: These findings extend previous small-scale observations of daily rhythmicity to a large cohort of individuals from around the world. The findings also confirm the existence of modest weekly rhythmicity but not lunar or seasonal rhythmicity in human activity. These differences in rhythm strength have implications for the management of health hazards of rhythm misalignment.

Daily activity patterns of 2316 men and women from five countries differing in socioeconomic development.

Daily rhythmicity in the locomotor activity of laboratory animals has been studied in great detail for many decades, but the daily pattern of locomotor activity has not received as much attention in humans. We collected waist-worn accelerometer data from more than 2000 individuals from five countries differing in socioeconomic development and conducted a detailed analysis of human locomotor activity. Body mass index (BMI) was computed from height and weight. Individual activity records lasting 7 days were subjected to cosinor analysis to determine the parameters of the daily activity rhythm: mesor (mean level), amplitude (half the range of excursion), acrophase (time of the peak) and robustness (rhythm strength). The activity records of all individual participants exhibited statistically significant 24-h rhythmicity, with activity increasing noticeably a few hours after sunrise and dropping off around the time of sunset, with a peak at 1:42 pm on average. The acrophase of the daily rhythm was comparable in men and women in each country but varied by as much as 3 h from country to country. Quantification of the socioeconomic stages of the five countries yielded suggestive evidence that more developed countries have more obese residents, who are less active, and who are active later in the day than residents from less developed countries. These results provide a detailed characterization of the daily activity pattern of individual human beings and reveal similarities and differences among people from five countries differing in socioeconomic development.

Dosing-time dependent effects of sodium nitroprusside on cerebral, renal, and hepatic catalase activity in mice.

To investigate the time dependence of sodium nitroprusside- (NPS-) induced oxidative effects, the authors study the variation of the antioxidant enzyme CAT activity in various tissues after the administration of a single 2.5 mg/kg dose of SNP or sodium chloride (NaCl 0.9%). For each of the two dosing times (1 and 13 hours after light onset, HALO, which correspond to the beginning of diurnal rest span and of nocturnal activity span of mice, resp.), brain, kidney, and liver tissues were excised from animals at 0, 1, 3, 6, 9, 12, 24, and 36 h following the drug administration and CAT activity was assayed. The results suggest that SNP-induced stimulation of CAT activity is greater in all three tissues when the drug is administered at 1 HALO than at 13 HALO. Two-way ANOVA revealed that CAT activity significantly (P < 0.004) varied as a function of the sampling time but not of the treatment in all three tissues. Moreover, a statistically significant (P < 0.004) interaction between the organ sampling-time and the SNP treatment was revealed in kidney regardless of the dosing time, whereas a highly significant (P < 0.0002) interaction was validated in liver only in animals injected at 13 HALO.

Circadian (about 24-hour) variation in malondialdehyde content and catalase activity of mouse erythrocytes.

Lipid peroxidation is a part of normal metabolism that may cause biological molecule damage leading to the formation of several specific metabolites that include aldehydes of variable chains, such as malondialdehyde (MDA). These biological effects are controlled in vivo by a wide spectrum of enzymatic and non-enzymatic defense mechanisms among which catalase (CAT) is considered as an important regulator of oxidative stress. The present study aimed to investigate the possible relationship between the temporal patterns of the formation of MDA and the activity of CAT in the erythrocytes of mice. Twenty-four-hour studies were performed on male Swiss albino mice, 12 weeks old, synchronized to a 12:12 light: dark cycle for 3 weeks. Different and comparable groups of animals (n = 10) were sacrificed at an interval of 4 hours (1, 5, 9, 13, 17, and 21 hours after light onset (HALO)). The levels of erythrocyte MDA concentration and CAT activity both significantly (analysis of variance: F = 6.4, P < 0.002) varied according to the time of sampling under non-stressed conditions. The characteristics of the waveform describing the temporal patterns differed between the two studied variables, e.g. MDA content showing one peak (≅21 HALO) and CAT activity showing three peaks (≅9, 17, and 21 HALO). Cosinor analysis revealed a significant (adjusted Cosinor: P ≤ 0.018) circadian (τ ≅ 24 hours) rhythm in MDA level and no statistically significant rhythmicity in CAT activity. The differences and the absence of correlation between the curve patterns of erythrocyte MDA content and CAT activity under physiological conditions are hypothesized to explain that variation in lipid peroxidation may depend on several factors. Moreover, the identification of peak/trough levels of MDA accumulation in erythrocytes may reflect the degree of oxidative stress in these blood cells. In addition, the observed significant time-of-day effect suggests that, in both clinical and scientific settings, appropriate comparison of MDA production and CAT activity levels can only be achieved on data obtained at the same time of day.

Dosing-time dependent oxidative effects of sodium nitroprusside in brain, kidney, and liver of mice.

UNLABELLED: The purpose of this study was to investigate if the oxidative effects of sodium nitroprusside (SNP) are dosing-time dependent. Therefore, the variation of malondialdehyde (MDA) status was assessed after a single i.p. administration of SNP (2.5mgkg(-1) b.w.) or vehicle (9‰ NaCl) to different and comparable groups of mice (n=48) at two different circadian times (1 and 13h after light onset [HALO]). Brain, kidney, and liver tissues were excised over 36h, and their MDA contents were estimated at 0, 1, 3, 6, 9, 12, 24, and 36h after SNP administration. RESULTS: indicated mean MDA level was not significantly changed in each investigated tissue compared with the control. In contrast, the mean MDA value varied among organs and was comparable in brain and liver but lower than in kidney. The data show SNP significantly (P<0.05) increases MDA status in both tissues and exerts time-dependent oxidative effects with the greatest toxicity coinciding with the beginning of the diurnal rest span (local time: 08:00h, i.e., at 1 HALO). The obtained results reveal SNP-induced oxidative damage (evidenced by MDA accumulation) varies according to both the dosing-time and the target organ.

Time-of-day dependence of neurological deficits induced by sodium nitroprusside in young mice.

Sodium nitroprusside (SNP) is widely used in pharmacological studies as a potent vasodilator or a nitric oxide donor. SNP-induced ataxic effects were assessed in mice by the Joulou-Couvoisier test. Swiss albino mice of both genders, 2-8 weeks of age, were acclimated at least for 2 weeks to 12 h light (rest span)/12 h dark (activity span). In 2 and 4 week old mice, maxima of ataxia were found following intraperitoneal administration of a dose ranging from 3 to 3.6 mg.kg-1 SNP at ≈ 1 and 13 HALO (Hours After Light Onset). The sublethal toxicity was statistically dosing-time dependent (χ2 test: P < 0.005). No rhythm was validated in neurotoxicity by cosinor analyses. At the 8th week of post-natal development (PND), SNP-induced ataxia was greatest at ≈ 1 HALO (69% in males vs. 49% in females) and lowest at ≈ 13 HALO (21% in males vs. 11% in females) (χ2 test: P < 0.00001). Cosinor analysis also revealed no statistically significant rhythm in mice injected with 3 or 3.3 mg.kg-1. However, a significant circadian (τ = 24 h) rhythm was detected by adjusted cosinor in 3.6 mg.kg-1-treated mice (P < 0.004). In all studied groups, SNP-induced motor impairment (expressed in %) was lower during the dark than the light phase. Furthermore, there was a non-significant gender-related difference in SNP-induced neuronal toxicity with the males more sensitive than females at every studied PND. The ataxic effects were inversely proportional to the lag time from injection and to the age of animals (with P < 0.05 only between 2 and 8 week old mice). These data indicate that both the administration time and age of the animal significantly affect the neurotoxic effects of SNP.

Cardioprotective effect of resveratrol on lipopolysaccharide-induced oxidative stress in rat.

Lipopolysaccharide (LPS) is a glycolipid component of the cell wall of Gram-negative bacteria, which induces a deleterious effect on several organs, including the heart, eventually leading to septic shock and death. Endotoxemia-induced cardiotoxicity is characterized by disturbed intracellular redox balance, excessive reactive oxygen species (ROS) accumulation, inducing DNA, protein, and membrane lipid damage. Resveratrol (trans-3,5,4' trihydroxystilbene; RVT) is a phytoalexin polyphenol that exhibits antioxidant and -inflammatory properties. We investigated the putative effect of a subacute treatment with this natural compound on LPS-induced cardiotoxicity in the rat. We found that resveratrol counteracted LPS-induced lipoperoxidation and decreased superoxide dismutase (SOD) activity, but had no effect on the LPS-induced decrease in catalase (CAT) nor on the increase in peroxidase (POD) activity. Resveratrol also reversed LPS-induced myocardial nitric oxide (NO) elevation. More important, LPS-induced iron depletion from plasma to the myocardial compartment was abolished upon resveratrol treatment. All these data suggest that resveratrol is capable of alleviating LPS-induced cardiotoxicity, and that its mode of action may involve iron-shuttling proteins.

Prevention of lipopolysaccharide-induced mouse lethality by resveratrol.

The present study was undertaken to determine whether subacute treatment with resveratrol (RVT) protects mice against lipopolysaccharide (LPS)-induced oxidative stress and mortality as well as the mechanism involved in such protection. Mice were divided into three groups: control, LPS and LPS+RVT. Animals were pre-treated with RVT during 7 days. The survival rate was monitored over 48 h after LPS administration. Survival animals were sacrificed, their kidney, liver and brain homogenized for malondialdehyde (MDA), catalase (CAT) activity, free iron and nitric oxide (NO) determination. Plasma was also processed for transaminases, creatinine, urea, NO and iron measurement. Pre-treatment with resveratrol greatly improved the survival rate of LPS-treated mice. Resveratrol counteracted LPS-induced tissue lipoperoxidation and catalase activity depletion. The polyphenol abrogated LPS-induced liver and kidney dysfunction as increased creatinine and urea as well as transaminases activities. In addition, pre-treatment with resveratrol abrogated LPS-induced tissues and plasma NO elevation and iron sequestration from plasma to tissue compartment. These data suggest that resveratrol prevents LPS-induced lethality and that its mode of action may involve differential iron deposition via iron shuttling proteins.

Resveratrol, a red wine polyphenol, attenuates lipopolysaccharide-induced oxidative stress in rat liver.

Lipopolysaccharide (LPS) is a glycolipid component of the cell wall of gram-negative bacteria inducing deleterious effects on several organs including the liver and eventually leading to septic shock and death. Endotoxemia-induced hepatotoxicity is characterized by disturbed intracellular redox balance, excessive reactive oxygen species (ROS) accumulation inducing DNA, proteins and membrane lipid damages. Resveratrol (trans-3,5,4' trihydroxystilbene) is a phytoalexin polyphenol exhibiting antioxidant and anti-inflammatory properties. In this study, we investigated the effect of subacute pre-treatment with this natural compound on LPS-induced hepatotoxicity in rat. Resveratrol counteracted LPS-induced lipoperoxidation and depletion of antioxidant enzyme activities as superoxide dismutase (SOD) and catalase (CAT) but slightly glutathione peroxidase (GPx) activity. The polyphenol also abrogated LPS-induced liver and plasma nitric oxide (NO) elevation and attenuated endotoxemia-induced hepatic tissue injury. Importantly resveratrol treatment abolished LPS-induced iron sequestration from plasma to liver compartment. Our data suggest that resveratrol is capable of alleviating LPS-induced hepatotoxicity and that its mode of action may involve differential iron compartmentalization via iron shuttling proteins.

Protective effect of resveratrol against lipopolysaccharide-induced oxidative stress in rat brain.

PRIMARY OBJECTIVE: To study the protective effect of resveratrol on endotoxemia-induced neurotoxicity. METHODS: Rats were pre-treated during 7 days with 20 mg kg(-1) body weight (b.w.) resveratrol and challenged with a single dose of lipopolysaccharide (LPS: 8 mg kg(-1) b.w.) for 24 hours. Brains were harvested to determine LPS-induced lipoperoxidation level, antioxidant enzyme activities, nitric monoxide (NO) and iron distribution as well as the impact of resveratrol on these parameters. RESULTS: Resveratrol counteracted LPS-induced brain malondialdehyde (MDA) level and antioxidant enzyme activities depletion as superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD). Resveratrol also reversed LPS-induced brain and plasma NO elevation as well as iron sequestration from plasma to brain compartment. CONCLUSION: The data suggest that resveratrol is capable of alleviating LPS-induced neurotoxicity by a mechanism that may involve iron shuttling proteins.

Protective effect of resveratrol in endotoxemia-induced acute phase response in rats.

Lipopolysaccharide (LPS), a glycolipid component of the cell wall of gram-negative bacteria can elicit a systemic inflammatory process leading to septic shock and death. Acute phase response is characterized by fever, leucocytosis, thrombocytopenia, altered metabolic responses and redox balance by inducing excessive reactive oxygen species (ROS) generation. Resveratrol (trans-3,5,4' trihydroxystilbene) is a natural polyphenol exhibiting antioxidant and anti-inflammatory properties. We investigated the protective effect of resveratrol on endotoxemia-induced acute phase response in rats. When acutely administered by i.p. route, resveratrol (40 mg/kg b.w.) counteracted the effect of a single injection of LPS (4 mg/kg b.w.) which induced fever, a decrease in white blood cells (WBC) and platelets (PLT) counts. When i.p. administered during 7 days at 20 mg/kg per day (subacute treatment), resveratrol abrogated LPS-induced erythrocytes lipoperoxidation and catalase (CAT) activity depression to control levels. In the plasma compartment, LPS increased malondialdehyde (MDA) via nitric monoxide (NO) elevation and decreased iron level. All these deleterious LPS effects were reversed by a subacute resveratrol pre-treatment via a NO independent way. Resveratrol exhibited potent protective effect on LPS-induced acute phase response in rats.

Protective effect of resveratrol on acute endotoxemia-induced nephrotoxicity in rat through nitric oxide independent mechanism.

Lipopolysaccharide (LPS) is a glycolipid component of the cell wall of gram negative bacteria inducing deleterious effects on the kidney. Endotoxemia-induced nephrotoxicity is characterized by disturbed intracellular redox balance and reactive oxygen species (ROS) accumulation leading to DNA, proteins and membrane lipid damages. Resveratrol (trans-3,5,4'-trihydroxystilbene) is a polyphenol displaying antioxidant and anti-inflammatory properties. This study investigated its effects on LPS-induced nephrotoxicity in rats. Resveratrol counteracted all LPS-induced changes in renal haemodynamic parameters. In the kidney resveratrol abrogated LPS-induced lipoperoxidation and antioxidant enzyme activities depletion as superoxide dismutase (SOD) and catalase (CAT) but not peroxidase (POD) activity. LPS increased plasma and urine nitric oxide (NO) level and resveratrol reversed them. More importantly, LPS-induced iron mobilization from plasma to kidney, which was also abolished by resveratrol treatment. All these results suggest that resveratrol exerted strong antioxidant properties against LPS-induced nephrotoxicity and that its mode of action seemed to involve iron shuttling proteins.

Circadian time-effect of orally administered loratadine on plasma pharmacokinetics in mice.

Little is known about the chronopharmacokinetics of loratadine, a long-acting tricyclic antihistamine H(1) widely used in the treatment of allergic diseases. Hence, the pharmacokinetics of loratadine and its major metabolite, desloratadine, were investigated after a 20 mg/kg dose of loratadine had been orally administered to comparable groups of mice (n=33), synchronized for three weeks to 12 h light (rest span)/12 h dark (activity span). The drug was administered at three different circadian times (1, 9, and 17 h after light onset [HALO]). Multiple blood samples were collected over 48 h, and plasma concentrations of loratadine and desloratadine were determined by high performance liquid chromatography. There were no significant differences in T(max) of loratadine and desloratadine between treatment-time different groups. However, the elimination half-life (t1/2) of the parent compound and its metabolite was significantly longer (p<0.01) following administration at 9 HALO (t1/2 loratadine and desloratadine 5.62 and 4.08 h at 9 HALO vs. 4.29 and 2.6 h at 17 HALO vs. 3.26 and 3.27 at 1 HALO). There were relevant (p<0.05) differences in C(max) between the three treated groups for loratadine and desloratadine; 133.05+/-3.55 and 258.07+/-14.45 ng/mL at 9 HALO vs. 104.5+/-2.61 and 188.62+/-7.20 ng/mL at 1 HALO vs. 94.33+/-20 and 187.75+/-10.79 ng/mL at 17 HALO. Drug dosing at 17 HALO resulted in highest loratadine and desloratadine total apparent clearance values: 61.46 and 15.97 L/h/kg, respectively, whereas loratadine and desloratadine clearances (CL) were significantly slower (p<0.05) at the other administration times (loratadine and desloratadine CL was 57.3 and 14.22 L/h/kg at 1 HALO vs. 43.79 and 12.89 L/h/kg at 9 HALO, respectively). The area under the concentration-time curve (AUC) of loratadine and desloratadine was significantly (p<0.05) greater following drug administration at 9 HALO (456.75 and 1550.57 (ng/mL) . h, respectively); it was lowest following treatment at 17 HALO (325.39 and 1252.53 (ng/mL) . h, respectively). These pharmacokinetic data indicate that the administration time of loratadine significantly affected its pharmacokinetics: the elimination of loratadine and its major metabolite desloratadine.

Age-related changes in the activity of cerebral rhodanese in mice during the first four months of life.

Rhodanese (thiosulfate sulfurtransferase) is a ubiquitous enzyme that accelerates the transformation of cyanide into the very less toxic thiocyante. Influence of cerebral rhodanese level on cyanide toxicity has already been shown in mice. However, age-related changes in rhodanese activity have not been previously examined. The aim of the experiments was to investigate age-related changes of cerebral rhodanese activity in male and female mice maintained from birth to age 16 weeks under 12:12 light:dark (LD) cycle conditions. The rhythm of enzyme activity was quantified by Cosinor test programme in 2-, 4-, 8-, 12-, and 16-week-old mice. Significant ultradian (tau =1 2h) rhythms were validated both by ANOVA (P < 0.05) and Cosinor analyses (P < or = 0.01) in 2- and 4-week-old mice. However, in addition to the ultradian rhythm, a significant (P < or = 0.01) prominent circadian (tau = 24h) rhythm, whose peak time located at approximately 9 Hours After Light Onset (HALO), was detected in 4-week-old females. In 8-, 12-, and 16-week-old mice, the Cosinor validated significant (P < or = 0.0001) circadian rhythms in both genders. The circadian peak time initially located at approximately 5 HALO in 8-week-old mice, moved to approximately 9 HALO and then to be stabilized at approximately 17 HALO in 12- and 16-week-old mice, respectively. Furthermore, the ultradian components were detected in 8- and 12-week-old females. On the other hand, at age 16 weeks, no significant ultradian rhythm was detected in males or in females. The enzyme activity was greater in females compared to males during the first 8 postnatal weeks. Two-way ANOVA revealed a significant (P < 0.02) interaction between circadian time and gender in 4-, 8-, 12-, and 16-week-old mice, suggesting the influence of gender on time-related changes in rhodanese activity. However, though ANOVA validated significant changes related to both sampling-time and gender, no interaction was detected between the two factors in 2-week-old mice, illustrating the gender-related difference in enzyme activity was greater. Moreover, the obtained results showed that rhodanese activity significantly increased with age during the postnatal development (PND). However, this increase would be limited by age in old mice as early as 12 weeks after birth. The data also showed a 12h phase-shift of the circadian rhodanese peak time during PND, suggesting that the rhythm stabilization is age dependent. The main findings of this study indicated that the increased sensitivity to cyanide, generally reported in old mice, may be due in part to a decrease in the activity of brain rhodanese.

Seasonal modulation of the 8-and 24-hour rhythms of ondansetron tolerance in mice.

Ondansetron (Zophren((R))) is a serotonin 5HT(3)-receptor antagonist used primarily to control nausea and vomiting caused by cytotoxic chemo-and radio-therapy. Tolerance to this drug shows both 24 and 8 h periodicities. In this framework, this study aimed to determine whether these ondansetron tolerance rhythms are modulated by season. The chronotoxic effect of a fixed dose (3.5 mg/kg, i.p.) of the drug was investigated with reference to both time of the day and year dependencies. Season-related studies were performed on 560 male Swiss mice, 10 to 12 wks old, synchronized with L:D=12:12 for three weeks. During a 1 yr span (2005), four 24 h studies were performed with a single dosing time at 1, 7, 13, and 19 hours after light onset (HALO), respectively. Tolerance was assessed daily during a 40-day span after acute ondansetron treatment. Both chi(2) test and cosinor methods were used to analyze the time series data. Statistically significant dosing time-dependent changes were validated in both yearly and daily time scales. The 24 h mean survival rate peaked in spring (92%) compared to fall (72%), the 20% difference being statistically significant (chi(2) test with p<0.05 and cosinor with p<0.0001 for seasonal rhythm detection and with a peak time, Ø,=April 3+/-6.6 days). A 24 h rhythm was also detected in each of the seasonal time points. However, the curve pattern was monophasic in fall as well as spring. In fall, a large amplitude (A) circadian rhythm was detected that peaked at 19 HALO, while in the spring, a small circadian rhythm was detected that peaked at 1 HALO. The curve pattern was biphasic in summer (with large A) and in winter (with a small A). The existence of two peaks of equal magnitude in winter (100% survival rate) and in summer (100% and 90%) suggests the presence of both circadian and ultradian rhythms rather than an ultradian component of the 24 h period. The seasonal modulation of ondansetron circadian chronotolerance seems to involve several rhythm parameters: season-related changes in the 24 h mean (M), amplitude (A), acrophase location (Ø), as well as bimodal curve patterns including the coexistence of rhythms with respectively 24 and 8 h periods in winter and summer. In conclusion, tolerance to ondansetron varies not only according to the 24 and 8 h periods but also according to seasons, which suggests the complexity of ondansetron toxicity rhythms. Seasonal modulation of ondansetron tolerance may also influence the strategies of chemo-and chrono-therapy, and it is therefore necessary to take it into account in clinical drug-delivery protocols to minimize side effects of cytotoxic anticancer and antiemetic agents.

Malondialdehyde content and circadian variations in brain, kidney, liver, and plasma of mice.

In aerobic organisms, the use of oxygen (O(2)) to produce energy is associated with the production of Reactive Oxygen Species (ROS), which reacts with biological molecules to produce oxidized metabolites such as malondialdehyde (MDA). This experiment focused on male Swiss mice 12 weeks of age synchronized for 3 weeks by the 12 h light (rest)/12 h dark (activity) span. Different and comparable groups of animals (n=10) were sacrificed at six different circadian stages: 1, 5, 9, 13, 17, and 21 h after light onset (HALO). The 24 h mean MDA level varied among organs of mice in non-stress conditions and was comparable in brain and liver but lower than in kidney. As the MDA 24 h status constitutes only a part of ROS damages in sites differing by their oxygen use, lipid composition, and detoxification capacity, the temporal patterns of their MDA content were comparatively studied in relationship to the animal rest-activity cycle. The results revealed significant circadian rhythms with the peak time located during the rest span (approximately =5 HALO) for both brain and liver, but during the activity span for the kidney ( approximately =21 HALO) and plasma (approximately =13 HALO). This chronobiological study showed that under physiological conditions, lipid peroxidation depends on several factors. The MDA peak/trough might be used as a tool to detect moments of high/low sensitivity of tissues to ROS attack in rodents.