Anionic diketopiperazine induces osteogenic differentiation and supports osteogenesis in a 3D cryogel microenvironment.

Bioactive molecules that enhance or induce osteogenic potential of bone precursor cells have shown vital roles in bone tissue engineering. Herein, we report the design and synthesis of a novel diketopiperazine (DT) that induces osteoblastic differentiation of pre-osteoblasts and bone-marrow-derived stem cells in vitro and enhances the osteogenic potential of cryogel matrix. Such functional diketopiperazines can serve as potential scaffolds for bone healing and regeneration.

Bone microstructure of mice after prolonged taurine treatment.

Taurine, a sulphur - containing amino acid, has been termed a functional nutrient. Its synthetic form is a common ingredient in supplements and energy drinks. There is no information concerning taurine impact on bone microstructure after prolonged supplemental use. Also, differences in bone parameters of mice following taurine exposure are unknown. In this study, a detailed microstructure of compact and trabecular bone tissues of mice subchronically exposed to taurine was determined. Animals (n=12) were segregated into three groups: E1 group - mice received 20 mg/kg b.w. of taurine per day during 8 weeks; E2 group - mice were fed by taurine at a dose of 40 mg/kg b.w. for 8 weeks and a control (C) group. Decreased density of secondary osteons, increased sizes of primary osteon's vascular canals (P<0.05) were observed in taurine - treated animals. Cortical bone thickness, trabecular thickness were decreased (P<0.05) in E1 group, and relative volume of trabecular bone was lower (P<0.05) in E2 group as compared to C group. According to our results, prolonged taurine exposure at the doses used in this study can negatively affect both compact and trabecular bone tissues microstructure.

The nephroprotective properties of taurine in colistin-treated mice is mediated through the regulation of mitochondrial function and mitigation of oxidative stress.

Colistin (COL) belongs to the polymixin class of antibiotics used as the last line antibiotic against drug-resistant infections. However, nephrotoxicity is the major deleterious and dose-limiting side effect associated with COL therapy. Oxidative stress and mitochondrial impairment are suspected mechanisms involved in COL-induced nephrotoxicity. Taurine is one of the most abundant amino acids in the human body with antioxidant and mitochondria protecting properties. The current study was designed to evaluate the potential nephroprotective properties of taurine against COL-associated nephrotoxicity. Mice were treated with COL (15 mg/kg/day, i.v, for 7 consecutive days) alone or in combination with taurine (500 and 1000 mg/kg, i.p). Plasma biomarkers of nephrotoxicity in addition of kidney tissue markers of oxidative stress were evaluated. Additionally, kidney mitochondria were isolated, and several mitochondrial indices were assessed. The COL-associated renal injury was evident by a significant increase in plasma markers of renal injury including creatinine (Cr), and blood urine nitrogen (BUN). COL treatment also caused a significant increase in kidney reactive oxygen species (ROS) and lipid peroxidation (LPO). Renal GSH reservoirs and antioxidant capacity were also decreased in COL-treated animals. Mitochondrial parameters including mitochondrial dehydrogenase activity, membrane potential, GSH, and ATP were significantly decreased while mitochondrial LPO, permeabilization, and GSSG content were increased in the kidney of COL-treated mice. It was found that taurine (500 and 1000 mg/kg, i.p) treatment alleviated COL-induced oxidative stress and mitochondrial dysfunction in the kidney tissue. The data obtained from the current study suggest mitochondrial dysfunction and oxidative stress as fundamental mechanisms of renal injury induced by COL. On the other hand, taurine supplementation protected kidney through decreasing oxidative stress and regulating mitochondrial function.

[Effect of the taurine on striatum tissue cell cycle and apoptosis in manganese exposed rats].

Objective: To elucidate the effect of taurine on neurotoxicity induced by Mn by investigating cell cycle and apoptosis in manganese exposed rats. Methods: 156 healthy male SD rats were randomly divided into 1 control group, 3 manganese exposure groups (10, 15, and 20 mg/kg respectively) , and 9 intervened groups based on orthogonal design, with 12 rats in each group. After 12 weeks of exposure, all rats were decapitated and striatums were removed, cell cycle was analyzed by flow cytometry, the apoptosis was detected by TUNEL, level of Mn was determined. Results: The striatum apoptosis index of the 3 dose groups exposed to Mn were significantly higher than control group (P<0.05) . The striatum apoptosis index of the 9 intervened groups were significantly higher than control group (P<0.05) . 150 and 200 mg/kg of taurine could decrease apoptosis index of the group exposed to 10、15、20 mg/kg of Mn (P<0.05) . The striatum Mn content of the 3 dose groups exposed to Mn were significantly higher than that of the control group (P<0.05) . The G0/G1 proportion of the 3 dose groups exposed to Mn were significantly lower than that of the control group (P<0.05) , the S proportion of the 3 dose groups exposed to Mn were significantly higher than that of the control group (P<0.05) . Conclusion: Mn could cause cell cycle arrest to S, increase level of apoptosis in striatum, to a certain extent, taurine can protect neurons from apoptosis induced by Mn.

Energy drink and alcohol combination leads to kidney and liver alterations in rats.

The aim of this study was to evaluate the acute toxicity of the association of energy drink and alcohol in male Wistar rats. Animals were treated by oral gavage with 10 ml/kg distilled water (control); 10 ml/kg energy drink (ED10); 3.2 mg/kg caffeine + 40 mg/kg taurine; 2 g/kg alcohol 20%; 2 g/kg alcohol 20% + ED10; and 2 g/kg alcohol 20% + 3.2 mg/kg caffeine + 40 mg/kg taurine. Behavioral alterations were observed for 6 h after treatment. Animals presented significant differences in the frequency of rearing, ambulation, grooming, wakefulness and tachypnea along time. Caffeine + taurine increased the levels of TBARS and total thiols in kidneys. ED10 increased lipoperoxidation in liver. The association of ED10 + alcohol induced nephrotoxicity observed by the increase of urinary N-acetyl-ß-d-glucosaminidase (NAG) activity. Histopathological analysis showed the presence of congestion and hydropic and hyaline degenerations in the livers of ED10 + alcohol treated rats, and hemorrhage in the liver of alcohol + caffeine + taurine group. In kidneys, hyaline degeneration was observed in ED10; ED10 + alcohol; caffeine + taurine; and alcohol + caffeine + taurine. Hemorrhage was present in the kidneys of all groups. The combination of energy drinks and alcohol is not safe for the consumers. Therefore, precautionary measures should be disseminated among risk populations, especially the teenagers.

Comparison of Toxicity of Taurine and GABA in Combination with Alcohol in 7-Day-Old Mice.

Previously, we described the combined toxicity of taurine and alcohol, and assumed hypoglycemia to be one reason of this toxicity. To understand whether taurine-ethanol combined toxicity is exclusively connected to taurine or whether other inhibitory amino acids may have similar effects when combined with ethanol, we tested different doses of gamma-aminobutyric acid (GABA) in combination with ethanol in 7-day-old mice. The minimal dose of GABA in combination with 5 g/kg ethanol which could kill a mouse was 2 g/kg. GABA combined with ethanol at doses of 3 g/kg, 4 g/kg, 6 g/kg induced lethality of 30%, 90% and 100%, correspondingly. Taurine at the doses of 4 and 6 g/kg combined with ethanol induced death in 60 and 100% of mice. Ethanol (5 g/kg), taurine (6 g/kg), GABA (4 g/kg) administered alone and the combination of ethanol (5 g/kg) with taurine (3 g/kg) have no lethal effects. GABA (6 g/kg) applied alone induced 90% lethality. Taurine or GABA alone decreased blood glucose in a dose-depending manner. Ethanol potentiated GABA- and taurine-induced decrease in blood glucose and in some animals it dropped from 8.8 (intact) to a hypoglycemic level 3.1-3.3 mmol/L (GABA 4 g/kg, taurine 6 g/kg), but this may not be considered a single reason of death. We conclude that the combination of GABA and ethanol has a lethal effect and this is stronger than the combined toxicity of ethanol and taurine.

Short-term treatment with taurolidine is associated with liver injury.

BACKGROUND: Taurolidine has been used for peritonitis, oncological and catheter-lock treatment because of its anti-inflammatory properties. It has been suggested that taurolidine has no severe side-effects, but after long-term use morphological and functional changes of the liver were reported. The aim of this study was to investigate the effect of short-term use of taurolidine on the liver. METHODS: In HepaRG cell cultures and on a novel liver biochip dose-dependent effects of taurolidine treatment on hepatocyte adherence and cell viability was investigated. Furthermore, liver enzymes and interleukin- (IL-) 6 were measured in supernatants. Male rats were treated with low- or high-dose taurolidine, respectively, and compared to controls with physiological saline solution administration regarding blood serum parameters and histology. RESULTS: In HepaRG cell cultures, hepatocyte adherence was significantly decreased, cell death and cleaved caspase-3 were significantly increased after administration of taurolidine in a dose-dependent manner. High-dose application of taurolidine led to elevated liver enzymes and IL-6 secretion in hepatic organoid. After 24 h a significant increase of serum GLDH and ASAT was observed in rats treated with high-dose taurolidine treatment. CONCLUSIONS: Our results suggest that taurolidine caused liver injury after short-term use in in vitro and in vivo models probably due to direct toxic effects on hepatocytes. Therefore, the taurolidine dose should be titrated in further investigations regarding liver injury and inflammation.

Arachidonic acid with taurine enhances pulmonary absorption of macromolecules without any serious histopathological damages.

Therapeutic peptides and protein are being used in several indications; however, their poor permeability still remains to be solved. This study focused on the pulmonary route of macromolecules. First, the effects of arachidonic acid (AA) as an absorption enhancer on drug serum concentration, after intratracheal administration, were investigated in rats. Second, the safety of AA was assessed in rats in an acute toxicity study for 7days. AA enhanced the exposure of both interferon-α (IFN-α) and fluorescein isothiocyanate 4000 (FD-4). In addition, the histopathological analysis indicated that AA caused alveolitis and bronchitis in rats. In combination with Taurine (Tau), these lung injuries were prevented through the histopathological analysis. The combined use of Tau with AA did not show any changes in the pharmacokinetics of FD-4. From these results, we suggest the combined use of AA with Tau as a novel formulation on the pulmonary route of macromolecule drugs. This formulation could improve the bioavailability of macromolecule drugs without any serious local damage to the lungs.

The effects of taurine on vigabatrin, high light intensity and mydriasis induced retinal toxicity in the pigmented rat.

The overall purpose of this study was to establish a model that may be used for examining the effect of Vigabatrin-induced retinal toxicity in pigmented rats, and subsequently examine the possible effects of taurine on the retinal toxicity. In the first part of the study, pigmented Long Evans rats were subjected to combinations of induced mydriasis, low/high light intensities (40/2000 lx) and oral administration of near-MTD (Maximum Tolerated Dose) doses (200 mg/kg/day) of Vigabatrin for up to 6 weeks. The combination of mydriasis and high light intensity applied to Long Evans rats resulted in retinal damage that was increased by the administration of Vigabatrin. In the second part of the study Long Evans rats were subjected to combinations of induced mydriasis and high/low light intensity (40/2000 lx) while being orally administered low (30 mg/kg/day) or high (200 mg/kg/day) doses of Vigabatrin for up to 6 weeks. In addition, selected groups of animals were administered taurine via the drinking water (20 mg/ml), resulting in systemic taurine concentrations of approximately threefold the endogenous concentration. The combined results of the studies demonstrate that retinal damage can be induced in pigmented animals when combining mydriasis and high light intensity. Retinal damage was functionally evaluated by electroretinography (ERG), then confirmed by histopathology. While depending on mydriasis and high light intensity, administration of Vigabatrin increased the retinal toxicity and resulted in the formation of rosette-like structures in the retina in a dose-related manner. Administration of taurine did not alleviate the Vigabatrin-induced retinal toxicity, as demonstrated either functionally by ERG or morphologically, although systemic concentrations of 3-fold the endogenous levels were reached, and it was thus not possible to demonstrate a protective effect of taurine in these pigmented animals.

Possible contribution of taurine to distorted glucagon secretion in intra-islet insulin deficiency: a metabolome analysis using a novel α-cell model of insulin-deficient diabetes.

Glycemic instability is a serious problem in patients with insulin-deficient diabetes, and it may be due in part to abnormal endogenous glucagon secretion. However, the intracellular metabolic mechanism(s) involved in the aberrant glucagon response under the condition of insulin deficiency has not yet been elucidated. To investigate the metabolic traits that underlie the distortion of glucagon secretion under insulin deficient conditions, we generated an αTC1-6 cell line with stable knockdown of the insulin receptor (IRKD), i.e., an in vitro α-cell model for insulin-deficient diabetes, which exhibits an abnormal glucagon response to glucose. A comprehensive metabolomic analysis of the IRKD αTC1-6 cells (IRKD cells) revealed some candidate metabolites whose levels differed markedly compared to those in control αTC1-6 cells, but also which could affect the glucagon release in IRKD cells. Of these candidates, taurine was remarkably increased in the IRKD cells and was identified as a stimulator of glucagon in αTC1-6 cells. Taurine also paradoxically exaggerated the glucagon secretion at a high glucose concentration in IRKD cells and islets with IRKD. These results indicate that the metabolic alterations induced by IRKD in α-cells, especially the increase of taurine, may lead to the distorted glucagon response in IRKD cells, suggesting the importance of taurine in the paradoxical glucagon response and the resultant glucose instability in insulin-deficient diabetes.

Lethality of taurine and alcohol coadministration in mice.

Alcohol consumption by mothers during pregnancy causes a fetal alcohol syndrome associated with massive neuronal apoptosis. We have recently shown that taurine at a dose of 2 g/kg saves about 50% of dying cerebellar neurons from ethanol-induced apoptosis in 7-day-old mice. However, a further increase in the taurine dose to ethanol-treated mice had a toxic and in some cases lethal effect. In the present work we studied the toxic effects of taurine and ethanol coadministration in three age groups: 7-day-old, adult (5 to 6 months old), and old (12 to 13 months old) mice. Taurine and ethanol were injected in two half-doses: taurine at 0 and 4 h and ethanol at 1 and 3 h. The minimal 100% lethal doses in coadministration of taurine and ethanol were the following: 7-day-old mice-6 g/kg taurine + 5 g/kg ethanol, adult mice-10 g/kg of taurine + 8 g/kg of ethanol, and old mice-above 6 g/kg of taurine + 6 g/kg of ethanol. All mice treated with taurine or ethanol alone survived. The adult and old mice dying from the combined toxicity of taurine and ethanol showed a marked fall in blood glucose, which may be one reason for lethality. A comparison of the lethal doses of taurine and ethanol coadministration in different age groups allows us to conclude that the adverse effect of the combined toxicity of taurine and ethanol is age dependent.

N-chlorotaurine and its analogues N,N-dichloro-2,2-dimethyltaurine and N-monochloro-2,2-dimethyltaurine are safe and effective bactericidal agents in ex vivo corneal infection models.

PURPOSE: N-chlorotaurine (NCT) and its analogues N-monochloro-2,2-dimethyltaurine (NVC-612) and N-dichloro-2,2-dimethyltaurine (NVC-422) are new anti-infectives for topical treatment for conjunctivitis. The aim of this study was to show that these compounds are safe in an EpiOcular model and effective in corneas infected ex vivo. METHODS: Corneal buttons were excised from porcine eyes. In 183 of the 229 corneas, erosion and artificial superficial stromal incision were induced. They were bathed in suspensions of Pseudomonas aeruginosa or Staphylococcus aureus for 24 hr at 37°C and incubated in solutions of the test substances at 37°C and pH 7.1. Subsequently, they were subjected to histology (n = 20) or homogenized followed by quantitative bacterial cultures (n = 209). Ocular irritation was tested using the EpiOcular™ tissue system (MatTek Corporation). RESULTS: Bacterial accumulations were detected histologically both on the corneal surface and also in the anterior third of the stroma of incised corneal buttons. All three test compounds at a concentration of 55 mm (equals 1% NCT) reduced the bacterial counts of P. aeruginosa and S. aureus by approximately 5 log10 after 60- and 120-min incubation, respectively. Significant killing was observed as early as after 5-min incubation. Also intrastromal bacteria were inactivated. In the EpiOcular™ tissue model, NCT, NVC-422 and NVC-612 had no or very low potential to irritate corneal tissue. CONCLUSION: N-chlorotaurine, NVC-422 and NVC-612 are non-irritating in cornea and kill P. aeruginosa and S. aureus, even following penetration into the deeper corneal stromal layers.

Decrease of calbindin-d28k, calretinin, and parvalbumin by taurine treatment does not induce a major susceptibility to kainic acid.

Taurine, 2-aminoethanesulfonic acid, is present at high concentrations in many invertebrate and vertebrate systems, and it has several biological functions. In addition, it has been related to a neuroprotective role against several diseases, such as epilepsy. It has been reported that taurine induces a decrease of calbindin-D28k, calretinin, and parvalbumin protein levels in the hippocampus 3 days after administration. In the present work we hypothesized that the decrease of these proteins could alter the action of kainic acid (KA) and make mice more susceptible to excitotoxicity. Therefore, we treated mice with taurine and after 3 days treated them with KA. The results showed that taurine pretreatment did not induce a major susceptibility to KA. Moreover, neurodegeneration was reduced in pretreated mice. However, astrogliosis was similar to that observed in mice treated only with KA. The immunohistochemistries for calbindin-D28k, calretinin, and parvalbumin showed that these proteins were reduced as a consequence of KA treatment and of taurine treatment. However, mice pretreated with taurine prior to KA administration presented the same reduction in these proteins as mice treated with only taurine or only KA.

Toxicity of antiseptics against chondrocytes: what is best for the cartilage in septic joint surgery?

In septic joint surgery, the most frequently used antiseptics are polyhexanide, hydrogen peroxide and taurolidine. The aim of this study was to examine the effects of these antiseptics on viability of human chondrocytes. Our hypothesis was that antiseptics and supplemental irrigation with sodium chloride lavage are less toxic on human chondrocytes than treatment with antiseptics only. Primary human chondrocytes were isolated and cultured from six donated human knee joints. Polyhexanide, hydrogen peroxide or taurolidine were added to the cultures. Toxicity analysis was performed by visualisation of cell structure using light microscopy and LDH activity. The determination of vital cells and total cell numbers of chondrocytes treated with antiseptics partly followed by irrigation with sodium chloride solution was performed by using Casy Cell-Counter. Light microscopic data revealed a defect in cell structure after addition of antiseptics. We showed a significant increase of LDH enzyme activity after the treatment with polyhexanide or taurolidine. After treatment with antiseptics followed by sodium chloride solution a significant increase of vital and total cell numbers resulted in comparison with the chondrocytes that were only treated with antiseptics. The data show that treatment with polyhexanid, hydrogen peroxide or taurolidine induces cell death of human chondroctes in vitro. The application of sodium chloride solution after the treatment with polyhexanide and hydrogen peroxide possibly has a protective effect on chondrocyte viability.

Divergent effects of taurolidine as potential anti-neoplastic agent: inhibition of bladder carcinoma cells in vitro and promotion of bladder tumor in vivo.

We investigated taurolidine (TRD) against various human bladder cell lines and the AY-27 rat bladder carcinoma cells. In vitro we tested the effect of TRD in ascending concentrations depending on different incubation times on cell proliferation by the XTT-test. Taurolidine had an inhibitory effect on all tested cell lines. Increasing concentrations and longer incubation times decreased the proliferation depending on the primary quantities of cells. For in vivo studies, an orthotopic rat bladder carcinoma was used. The animals were treated intravenously or intravesically and the tumors were harvested and weighted after the study. In contrast to other authors we could not find any anti-proliferative effect, we actually showed that instillation into the rat urinary bladder enhanced tumor growth.

Risk assessment for the amino acids taurine, L-glutamine and L-arginine.

Taurine, glutamine and arginine are examples of amino acids which have become increasingly popular as ingredients in dietary supplements and functional foods and beverages. Animal and human clinical research suggests that oral supplementation of these amino acids provides additional health and/or performance benefits beyond those observed from normal intake of dietary protein. The increased consumer awareness and use of these amino acids as ingredients in dietary supplements and functional foods warrant a comprehensive review of their safety through quantitative risk assessment, and identification of a potential safe upper level of intake. The absence of a systematic pattern of adverse effects in humans in response to orally administered taurine (Tau), l-glutamine (Gln) and l-arginine (Arg) precluded the selection of a no observed adverse effect level (NOAEL) or lowest observed adverse effect level (LOAEL). Therefore, by definition, the usual approach to risk assessment for identification of a tolerable upper level of intake (UL) could not be used. Instead, the newer method described as the Observed Safe Level (OSL) or Highest Observed Intake (HOI) was utilized. The OSL risk assessments indicate that based on the available published human clinical trial data, the evidence for the absence of adverse effects is strong for Tau at supplemental intakes up to 3 g/d, Gln at intakes up to 14 g/d and Arg at intakes up to 20 g/d, and these levels are identified as the respective OSLs for normal healthy adults. Although much higher levels of each of these amino acids have been tested without adverse effects and may be safe, the data for intakes above these levels are not sufficient for a confident conclusion of long-term safety, and therefore these values are not selected as the OSLs.

Taurine and ethanol interactions: behavioral effects in mice.

Taurine is an abundant amino acid in the brain that shares pharmacological effects and similar potency with ethanol. Recently, taurine-containing beverages have been reported to enhance the euphoric effects of ethanol, though the extent of this effect and the role of taurine remain speculative. The present study was designed to explore interactions between taurine and ethanol on several behaviors including locomotion, ataxia, and loss of righting. Two strains of mice, C57BL/6J and DBA/2J mice, were used to examine potential strain differences. In the first experiment, effects of various doses of taurine (0.3-3.0 g/kg), ethanol (1.0-4.2 g/kg), or taurine in combination with ethanol were assessed in a within-subjects design. Although taurine did not appear to alter effects of ethanol on any measure in either strain, the development of tolerance to locomotor effects and sensitization to ataxic effects of ethanol in DBA/2J mice complicated interpretation of these results. In a second experiment, drug-naïve mice were assigned to one of four treatment groups: saline+saline, saline+ethanol (1.78 g/kg), taurine (1.78 g/kg)+saline, or ethanol+taurine. In this experiment, taurine pretreatment significantly attenuated the locomotor-stimulating effect of ethanol in both strains (but to a greater extent in C57BL/6J mice) and appeared to reduce the ataxic effects of ethanol in C57BL/6J mice. In conclusion, the interaction between taurine and ethanol is subtle. Further, results are inconsistent with the notion that taurine plays a major role in the locomotor, ataxic, or loss of righting effects of ethanol.

Rapid analysis of taurine in energy drinks using amino acid analyzer and Fourier transform infrared (FTIR) spectroscopy as basis for toxicological evaluation.

So-called energy drinks with very high amounts of taurine (up to 4000 mg/l are usually granted by certificates of exemption) are increasingly offered on the market. To control the currently valid maximum limits of taurine in energy drinks, a simple and rapid analytical method is required to use it routinely in food monitoring. In this article, we describe a fast and efficient analytical method (FTIR-spectroscopy) that is able to reliably characterize and quantify taurine in energy drinks. The determination of taurine in energy drinks by FTIR was compared with amino acid analyzer (ion chromatography with ninhydrin-postcolumn derivatization). During analysis of 80 energy drinks, a median concentration of 3180 mg/l was found in alcohol-free products, 314 mg/l in energy drinks with spirits, 151 mg/l in beer-containing drinks and 305 mg/l in beverages with wine. Risk analysis of these products is difficult due to the lack of valid toxicological information about taurine and its interferences with other ingredients of energy drinks (for example caffeine and alcohol). So far, the high taurine concentrations of energy drinks in comparison to the rest of the diet are scientifically doubtful, as the advertised physiological effects and the value of supplemented taurine are unproven.

Cytotoxicity of taurine metabolites depends on the cell type.

We report that the effect of Tau-Cl on the cell fate strongly depends on the cellular context. In leukemic Jurkat cells Tau-Cl (> 200 microM) triggers mitochondrial, p53-independent apoptosis and amplifies PCD induced by anti-Fas treatment. In contrast, Tau-Cl affects RA FLS in a dose-dependent manner. At the noncytotoxic (200-400 microM) concentrations it induces: (i) p53-dependent growth arrest (Kontny et al., 2005), and (ii) Bax translocation and caspase 9 activity. Although the last events are characteristic for apoptotic state, there is not execution of RA FLS apoptosis, probably due to simultaneous inhibition of caspase 3 activity and prevention of PARP degradation. The last two events suggest an excessive ATP deprivation in Tau-Cl-treated RA FLS. At sufficiently high concentrations (> or = 500 microM) Tau-Cl causes therefore necrosis of these cells. Altogether our results suggest that Tau-Cl is able to eliminate the cells with both functional (RA FLS) and mutated (Jurkat) p53 tumor suppressor. This observation is clinically relevant because Tau-Cl is used in many animal inflammatory models and its sodium salt (used in this study) has been introduced to human therapy (Gottardi and Nagl, 2002; Teuchner et al., 2005).