Salicylate In Rats Research Articles

Protective Effect of Resveratrol in an Experimental Model of Salicylate-Induced Tinnitus.

To date, the effect of resveratrol on tinnitus has not been reported. The attenuative effects of resveratrol (RSV) on a salicylate-induced tinnitus model were evaluated by in vitro and in vivo experiments. The gene expression of the activity-regulated cytoskeleton-associated protein (ARC), tumor necrosis factor-alpha (TNFα), and NMDA receptor subunit 2B (NR2B) in SH-SY5Y cells was examined using qPCR. Phosphorylated cAMP response element-binding protein (p-CREB), apoptosis markers, and reactive oxygen species (ROS) were evaluated by in vitro experiments. The in vivo experiment evaluated the gap-prepulse inhibition of the acoustic startle reflex (GPIAS) and auditory brainstem response (ABR) level. The NR2B expression in the auditory cortex (AC) was determined by immunohistochemistry. RSV significantly reduced the salicylate-induced expression of NR2B, ARC, and TNFα in neuronal cells; the GPIAS and ABR thresholds altered by salicylate in rats were recovered close to their normal range. RSV also reduced the salicylate-induced NR2B overexpression of the AC. These results confirmed that resveratrol exerted an attenuative effect on salicylate-induced tinnitus and may have a therapeutic potential.

Curcumin mitigates neurotoxic and neurobehavioral changes of gentamicin and sodium salicylate in rats by adjusting oxidative stress and apoptosis

Currently, antibiotics and salicylates are the most highly consumed medications worldwide. The side effects of these pharmaceuticals on the nervous system have been little investigated. Thus, this study aimed to examine the influence of the gentamicin (GM) and sodium salicylates (SS) on neurobehavioral functions, including locomotors function, memory, and sensorimotor functions together with gamma-aminobutyric acid (GABA) neurotransmitter levels. Also, oxidative stress, lipid peroxidation, and apoptotic indicators of brain tissue were assessed. Additionally, the histopathological architecture of brain tissues was investigated. This study also evaluated the curcumin (CUR) efficacy to counteract the GM or SS induced neurotoxic impacts in rats. For this purpose, seven groups were administered physiological saline (1 ml/rat; orally), olive oil (1 ml/rat; orally), CUR (50 mg/kg bwt; orally), GM (120 mg/kg bwt; intraperitoneally), SS (300 mg /kg bwt; intraperitoneally), CUR + GM, or CUR + SS for consecutive 15 days. The results revealed that GM and SS exposure evoked impaired memory, sensorimotor deficit functions, and depressive-like behavior together with the depletion of GABA. GM and SS exposure elevated malondialdehyde and Caspase-3 levels, but total antioxidant capacity and Bcl-2 levels were reduced. Besides, GM and SS exposure induced distinct pathological perturbations in cerebral cortices and hippocampus tissues. CUR significantly reversed the GM and SS harmful impacts. In conclusion, these findings verified that CUR could be a biologically efficient protective intervention against GM and SS induced neurotoxic impacts and neurobehavioral aberrations.

Up-regulation of Ca2+/CaMKII/CREB signaling in salicylate-induced tinnitus in rats.

The purpose of the study was to investigate the changes of Ca2+/calmodulin-dependent protein kinases II (CaMKII)/cAMP response element-binding protein (CREB) signaling pathway in a rat tinnitus model. Eighteen Wistar rats were randomly divided into three groups: normal control (NC), normal saline (NS), and tinnitus model (TM) groups. Tinnitus model was induced by intraperitoneal injection of salicylate. The concentration of intracellular calcium level in auditory cortex cells was determined using Fura-2 acetoxymethyl ester (Fura-2 AM) method with fluorospectrophotometer. Expressions of calmodulin (CaM), N-methyl-D-aspartate receptor 2B subunit (NR2B), calcium-calmodulin kinase II (CaMKII), and cAMP response element-binding protein (CREB) were detected with Western blot. Tinnitus model was successfully established by the intraperitoneal administration of salicylate in rats. Compared with rats in NC and NS groups, salicylate administration significantly elevated CaM, NR2B, phospho-CaMKII and phospho-CREB expression in auditory cortex from tinnitus model group (p < 0.05), and the free intracellular Ca2+ concentrations (p < 0.05). Our data reveal that salicylate administration causes tinnitus symptoms and elevates Ca2+/CaMKII/CREB signaling pathway in auditory cortex cells. Our study likely provides a new understanding of the development of tinnitus.

Pretreatment effects of moxibustion on the skin permeation and skin and muscle concentrations of salicylate in rats

The effect of moxibustion on the in vitro and in vivo skin permeation of salicylate was evaluated in rats. First, the effect of moxibustion pretreatment on the elimination pharmacokinetics of salicylate after i.v. injection in rats was determined: no clear difference was observed in the plasma profiles of salicylate (SA) with or without moxibustion pretreatment. However, much higher skin and muscle concentrations of salicylate were observed after its i.v. injection. Next, an in vitro skin permeation study of SA was performed after moxibustion pretreatment. Moxibustion pretreatment increased the skin permeation of SA, and the extent of the increase in SA skin permeation was related to the strength of moxibustion ignition. More intense treatments produced higher skin permeation. A similar enhancement effect on the skin permeation of SA was observed in in vivo studies. Interestingly, the skin/plasma and muscle/plasma ratios of SA were markedly increased by moxibustion pretreatment. These results were due to the induction of enhanced skin permeation and lower clearance into the cutaneous vessels by moxibustion ignition. Combination treatment involving moxibustion and the topical application of drugs such as NSAID may be useful for increasing local pharmaceutical effects by enhancing the drug concentration in the skin and muscle underneath the topical application site.

Role of Lipoxygenases and Lipoxin A4/Annexin-1 Receptor in Gastric Protection Induced by 20% Ethanol or Sodium Salicylate in Rats

The role of cyclooxygenases and prostaglandins in experimental models of gastroprotection is well established. We investigated the effects of the 5-lipoxygenase inhibitor A63162, the 12-lipoxygenase inhibitor baicalein and the 15-lipoxygenase inhibitor PD146176 as well as the nonspecific lipoxin A₄/annexin-1 antagonist Boc1 on adaptive protection induced by 20% ethanol against 70% ethanol, and on protection induced by sodium salicylate against the mucosal-damage-aggravating effects of celecoxib and dexamethasone during local ischemia-reperfusion in rats. It was found that both types of gastroprotection were antagonized by the lipoxygenase inhibitors and the lipoxin A₄/annexin-1 antagonist in doses that have no direct damaging effect on gastric mucosa. The results suggest that not only cyclooxygenases, but also active lipoxygenases and, possibly, annexin-1 are required for these types of gastroprotection to occur.

Differential changes in Fos-immunoreactivity at the auditory brainstem after chronic injections of salicylate in rats

In human, salicylate-induced tinnitus sometimes occurs a few days after its administration, but the chronic effects of salicylate in animal models are not fully known. In this study, we revealed the distribution of active cells in the rat auditory brainstem by staining an activity marker Fos-protein after multiple daily injections of salicylate. Experimental animals were first given five daily doses of sodium salicylate (250 mg/kg, i.p.). On day 6 they were placed inside a sound room for 8 h before sacrifice. Immunohistochemistry showed a significant increase in the number of Fos-positive cells at the inferior colliculus (IC), particularly its central division. At the cochlear nucleus (CN), only a few Fos-stains were found at the dorsal nucleus while no Fos-stain appeared at the ventral nucleus. The scarcity of Fos-stains at the CN reflected more a lack of external sound inputs than an adaptation in Fos-expression. Since Fos-stains in CN could still be induced on day 6 following brief tonal stimulation. Results are consistent with the hypothesis that salicylate-induced tinnitus is a phantom sound perception related to overactivity of cells at the IC.

Attenuation of iminodipropionitrile induced behavioral syndrome by sodium salicylate in rats

Iminodipropionitrile (IDPN) produces irreversible behavioral abnormalities characterized by excitation with choreiform and circling movements (ECC) syndrome in rodents. Concomitant exposure to drugs or environmental chemicals has been shown to alter IDPN-induced neurobehavioral toxicity. This investigation was undertaken to study the effect of sodium salicylate (SS) on IDPN-induced behavioral abnormalities in rats. The animals were exposed to IDPN (100 mg/kg ip) daily for 8 days. SS was administered daily 30 min before IDPN in the doses of 50, 100 and 200 mg/kg ip for 12 days. The animals were observed for neurobehavioral abnormalities including dyskinetic head movements, circling, tail hanging, air righting reflex and contact inhibition of the righting reflex. Horizontal and vertical locomotor activities and forelimbs grip strength were also measured. After behavioral studies, the animals were sacrificed, and the cerebrum and temporal bones were collected for glutathione analysis and inner ear histopathology, respectively. The onset of ECC syndrome was observed on Day 9 in the IDPN-alone group with 100% incidence on Day 12. Cotreatment with salicylate dose-dependently delayed the onset time and significantly attenuated the incidence and severity of IDPN-induced neurobehavioral signs. IDPN alone significantly increased horizontal motor activity and reduced vertical motor activity and forelimbs grip strength; these effect were significantly reversed by salicylate treatment. Treatment with salicylate also attenuated IDPN-induced depletion of GSH in the cerebrum, suggesting its free radical scavenging property.

Development of a thermo-reversible insulin liquid suppository with bioavailability enhancement

The purpose of this work is to develop a thermo-reversible insulin liquid suppository, which undergoes a phase transition to bioadhesive gels at body temperature and enhances the bioavailability of insulin. The effects of insulin and sodium salicylate on the physicochemical properties of a liquid suppository composed of poloxamer P 407, P 188 and polycarbophil were investigated. The pharmacodynamic study and quantitative histological assessment of the rectal mucosa of rats were carried out after the dose of insulin-loaded liquid suppositories with different amounts of sodium salicylate into streptozotocin-treated rats. Only thermo-reversible insulin liquid suppository [insulin/P407/P188/polycarbophil/sodium salicylate (100 (IU/g)/15/20/0.2/10%)] showed the optimal physicochemical properties and good safety in rats. It gave significantly lower plasma glucose levels, AUC 0→4h (the area below basal glucose level) and C nadir (the plasma glucose levels at the nadir) than did the solid and liquid suppositories without sodium salicylate in rats, indicating that the insulin from liquid suppository with sodium salicylate could be well absorbed in rats due to the absorption enhancing effect of sodium salicylate. It is concluded that thermo-reversible insulin liquid suppository [insulin/P 407/P 188/polycarbophil/sodium salicylate (100 (IU/g)/15/20/0.2/10%)], which was easy to administer without any pain during insertion and remained at the administered sites, could have a potential to be developed as a more convenient, safe and effective rectal delivery system of insulin.

O-212 - Diurnal variation in the hypocalcemic effect of sodium salicylate in rats.

O-212 - Diurnal variation in the hypocalcemic effect of sodium salicylate in rats.

Modification of transplacental distribution of salicylate in rats by acidosis and alkalosis.

1. The basis for the existence of a lower concentration of salicylate in the foetal than in the maternal blood was investigated in rats on day 20 of gestation. 2. Bolus injections of sodium salicylate were made into the mother and of [14C]-salicylic acid into its foetuses and serial maternal and foetal blood samples were collected. When derived on the basis of serum salicylic acid uncorrected for differences in ionization in the maternal and foetal blood, the placental clearance was 2.2 fold greater from the foetal to maternal side than that from the maternal to foetal side. 3. The greater foetal placental clearance relative to the maternal placental clearance was not due to any active placental transfer, since there was no evidence of saturation of this process and it was not affected by pretreatment with probenecid. Moreover, salicylic acid was not concentrated by placental slices in vitro and its placental uptake was not affected by dinitrophenol or by cooling. 4. Maternal blood pH was 0.19 units higher than the foetal blood pH. Administration of ammonium chloride or of sodium bicarbonate into the mother increased the foetal to maternal ratio of salicylic acid from 0.6 to approximately 1. 5. It is concluded that a foetal to maternal serum salicylate concentration-ratio of less than 1 simply reflects lower ionization in the foetus than in the mother, because foetal blood pH is lower than the maternal blood pH.

In vitro/in vivo Comparison of the Teratogenic Effects of Excess Sodium Salicylate in Rats

In vitro/in vivo Comparison of the Teratogenic Effects of Excess Sodium Salicylate in Rats

Influence of age, sex, pregnancy and protein-calorie malnutrition on the pharmacokinetics of salicylate in rats.

The influence of age, sex, pregnancy and protein-calorie malnutrition (PCM) on the plasma t1/2, plasma clearance (Clp) and apparent volume of distribution (Vd) of sodium salicylate (62 mumol kg-1) was determined in Sprague-Dawley rats. Female and male rats of five different age groups (ages in weeks: pups 1, weanling 3, young 8-9, adult including pregnant 14-15, old 56-60) including three age groups with PCM (8-9, 14-15 and 56-60 weeks old) were used. Plasma and urinary salicylates were assayed by h.p.l.c. Plasma t1/2 was longer and Clp smaller in pups than in weanling and young rats and comparable to values for old rats; Vd of salicylate in pups was larger than in any other group of rats. Plasma t1/2 was longer and Clp as well as Vd of salicylate were smaller in adult females than in males of comparable age. Relative to nonpregnant adult females, Vd of salicylate in pregnant rats was larger but plasma t1/2 and Clp were unchanged. In all groups of rats studied, PCM decreased the plasma t1/2 and increased the Clp of salicylate; Vd was unchanged. Changes in salicylate pharmacokinetics were not due to any differences in serum protein-salicylate binding or to serum testosterone levels. Ovariectomy decreased the plasma t1/2 of salicylate but castration of male rats had no significant effect. Administration of testosterone to ovariectomized female rats exerted no significant effect on salicylate pharmacokinetics. It is concluded that the physiological state and the nutritional status can modify salicylate pharmacokinetics; in so far as the rat model reflects the human situation, these variables should be taken into account for a rational salicylate therapy.

The influence of maternal protein deficiency on the placental transfer of salicylate in rats.

1 The influence of a low protein diet (5% as compared with a control 21% protein diet) on the placental transfer of sodium salicylate was investigated in Sprague-Dawley rats on day 20 of gestation. 2 Maternal plasma salicylate concentrations (assayed by high pressure liquid chromatography) were generally lower in protein-deficient than in control animals at a wide range of times (0.25 - 12 h) and dose levels (2 - 250 mg/kg, i.v.); however, foetal plasma salicylate levels in the two groups of animals did not differ. 3 The placental transfer of salicylate as indicated by the ratio of foetal plasma or foetal liver to maternal plasma salicylic acid concentration was consistently and significantly greater in the protein-deficient group than in the control group of animals following the administration of the drug to the mother as well as to the foetus. 4 A decrease in calorie without a concomitant decrease in protein intake (pair-fed controls) did not alter the placental transfer of salicylate. 5 The increased placental transfer of salicylate in protein-deficient animals could not be attributed to changes in serum protein-salicylate binding. 6 It is suggested that the pharmacokinetic factors responsible for maintaining a lower level of salicylate in the foetus than in the mother are impaired by maternal malnutrition, and this may increase the foetal effects of maternally ingested salicylate.

Prevention of ethanol and aspirin-induced gastric mucosal lesions by paracetamol and salicylate in rats: role of endogenous prostaglandins.

Paracetamol or sodium salicylate given intragastrically 30 minutes before the administration of absolute ethanol or acidified aspirin dose-dependently reduced the formation of mucosal lesions. The generation of gastric mucosal prostaglandin-like activity increased with ethanol and was completely suppressed by acidified aspirin. Paracetamol or sodium salicylate given alone increased the generation of mucosal prostaglandin-like material. Indomethacin, the prostaglandin synthesis inhibitor, suppressed this effect and inhibited the protective influence of paracetamol or sodium salicylate on the production of gastric lesions.

Effect of heparin injection on plasma protein binding of 1-anilino-8-naphthalenesulfonate and salicylate in rats.

After intravenous injection of heparin, the plasma protein binding of 1-anilino-8-naphthalenesulfonate (ANS) was remarkably decreased in rats. This effect occurred within one min after the injection of 1000 units/kg of heparin and lasted for about 30 min. The change in the binding of ANS was closely related to the plasma concentration of free acids (FFA), which was suggested as one of the heparin-induced inhibitors. The free fatty fraction of salicylate in plasma after the intravenous injection of heparin, has a pronounced variation, and also had a statistically significantly correlation with the plasma free fraction of ANS. It was suggested that ANS might be useful for the prediction of the heparin-induced changes in the plasma protein binding of acidic drugs.

Effect of Heparin Injection on Plasma Protein Binding of Bilirubin and Salicylate in Rats

Intravenous heparin injection significantly increased the free bilirubin and salicylate fractions in the plasma of rats. This effect occurred within 2min after injection of 500 U of heparin/kg and lasted for 15–45min (bilirubin) or for >45min (salicylate). In vitro addition of heparin to plasma had no quantitatively significant effect on the protein binding of bilirubin and salicylate. The in vivo effect of heparin on protein binding was reversible by treating the plasma with activated charcoal, a procedure known to remove fatty acids from albumin. Since protein binding affects the pharmacokinetic characteristics and the pharmacological activity of drugs, the heparin-drug interaction may have significant clinical implications. Use of heparinized plasma for exchange transfusion in the treatment of neonatal jaundice may be hazardous.

Studies on closure of the ductus arteriosus. XII. [formula omitted] effect of indomethacin and sodium salicylate in rats and rabbits

Administration of prostaglandin synthetase inhibitors to pregnant does and dams in late gestation was followed by in utero contraction of the fetal ductus arteriosus when studied by the whole-body freezing method. In the rat this contraction was well established within 6 h and persisted up to 36 h following 15 mg/kg indomethacin p.o. No effect was observed in the 18 d rat fetus but fetuses at 20 d and 22 d of gestation responded significantly to indomethacin. Doses of indomethacin approaching clinical usage (2.5 mg/kg) also caused a positive response in utero . The rat was found to be sensitive also to sodium salicylate and in the rabbit both indomethacin and sodium salicylate were effective. Exposure in utero to prostaglandin synthetase inhibitors with resulting contraction of the ductus may seriously disturb cardiac function in the fetus.

Short-term toxicity of isoamyl salicylate in rats

Isoamyl salicylate was given to groups of 15 male and 15 female rats at dietary concentrations of 0 (control), 50, 500 or 5000 ppm for 13 wk. There was a decrease in weight gain at the highest dietary level accompanied by a reduced food intake, but a paired-feeding study showed that this was due to the diet's unpalatability. The females given the highest dietary level drank more water than the controls and produced slightly greater volumes of more dilute urine. The relative kidney weight was increased in rats on the 500 and 5000 ppm levels without any histopathological changes. It is concluded that isoamyl salicylate was exerting a mildly nephrotoxic effect. The relative liver weight was increased at the highest level of feeding but there were no other effects attributable to treatment. The no-untoward-effect level from this study was 50 ppm of the diet, providing a mean intake of approximately 4·7 mg/kg/day.

Hypothalamic and septal neuronal responses to iontophoretic application of salicylate in rats

Iontophoretic application of sodium salicylate to neurones in the septum and preoptic/ anterior hypothalamic area in afebrile rats resulted in excitation of the majority of drug-sensitive cells tested. The excitatory and inhibitory responses of neurones to salicylate were similar to those produced by comparable application of acetylcholine, 5-hydroxytryptamine, and norepinephrine. Tests with preoptic/anterior hypothalamic temperature-sensitive neurones showed that the majority of warm-sensitive cells was excited by salicylate. The responses of these presumed thermoregulatory neurones to salicylate are compatible with, and may therefore be involved in producing, the augmented heat-loss which is characteristic of salicylate-induced defervescence from pyrogen fever.

Modification of drug absorption by bacterial toxins—I: The influence of staphylococcal alpha toxin and Shigella dysenteriae toxin on resorption of sodium salicylate

The effect of staphylococcal alpha toxin and Shigella dysenteriae toxin on intestinal absorption of sodium salicylate in rats was investigated. Shortly after intravenous (i.v.) administration, staphylococcal alpha toxin induced in the intestinal villi pathological changes which resulted in impaired absorption of orally administered sodium salicylate, lower levels being found in blood of intoxicated animals in comparison to control animals. When sodium salicylate was administered intraperitoneally (i.p.), the toxin did not induce any changes in the blood level of the drug. The effect of Shigella dysenteriae toxin reached its peak 72 hr after toxin injection, at which time the salicylate blood levels in intoxicated animals are significantly lower than in controls and the histological changes are most apparent.