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Biochemically and histopathologically comparative review of thiamine's and thiamine pyrophosphate's oxidative stress effects generated with methotrexate in rat liver

Summary Background Oxidative liver injury occurring with methotrexate restricts its use in the desired dose. Therefore, whether or not thiamine and thiamine pyrophosphate, whose antioxidant activity is known, have protective effects on oxidative liver injury generated with methotrexate was comparatively researched in rats using biochemical and histopathological approaches. Material/Methods Thiamine pyrophosphate+methotrexate, thiamine+methotrexate, and methotrexate were injected intraperitoneally in rats for 7 days. After this period, all animals’ livers were excised, killing them with high-dose anesthesia, and histopathologic and biochemical investigations were made. Result Biochemical results demonstrated a significant elevation in level of oxidant parameters such as MDA and MPO, and a reduction in antioxidant parameters such as GSH and SOD in the liver tissue of the methotrexate group. Also, the quantity of 8-OHdG/dG, a DNA injury product, was higher in the methotrexate group with high oxidant levels and low antioxidant levels, and the quantity of 8-OHdG/dG was in the thiamine pyrophosphate group with low oxidant levels and high antioxidant levels. In the thiamine and control groups, the 8-OHdG/dG rate was 1.48±0.35 pmol/L (P>0.05) and 0.55±0.1 pmol/L (P<0.0001). Thiamine pyrophosphate significantly decreased blood AST, ALT and LDH, but methotrexate and thiamine did not decrease the blood levels of AST, ALT and LDH. Histopathologically, although centrilobular necrosis, apoptotic bodies and inflammation were monitored in the methotrexate group, the findings in the thiamine pyrophosphate group were almost the same as in the control group. Conclusions Thiamine pyrophosphate was found to be effective in methotrexate hepatotoxicity, but thiamine was ineffective.

The Effect of Mirtazapine on Cisplatin-Induced Oxidative Damage and Infertility in Rat Ovaries

Cisplatin causes infertility due to ovarian toxicity. The toxicity mechanism is unknown, but evidence suggests oxidative stress. In this study, the effect of mirtazapine on cisplatin-induced infertility and oxidative stress in rats was investigated. 64 female rats were divided into 4 groups of 16. Except for the controls that received physiologic saline only, all were administered with cisplatin (5 mg/kg i.p.) and mirtazapine (15 mg/kg p.o.) or mirtazapine (30 mg/kg p.o.) for 10 days. After this period, six rats from each group were randomly selected, and malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NO), total gluthatione (tGSH), gluthatione peroxidase (GPx), superoxide dismutase (SOD), and 8-hydroxy-2 deoxyguanine (8-OH Gua) levels were measured in their ovarian tissues. Reproductive functions of the remaining rats were examined for 6 months. The MDA, MPO, NO groups and 8-OH Gua levels were higher in the cisplatin-treated groups than the controls, which was not observed in the mirtazapine and cisplatin groups. GSH, GPx, and SOD levels were reduced by cisplatin, which was prevented by mirtazapine. Cisplatin caused infertility by 70%. The infertility rates were, respectively, 40% and 10% for the 15 and 30 mg/kg mirtazapine administered groups. In conclusion, oxidative stress induced by cisplatin in the rat ovary tissue causes infertility in the female rats. Mirtazapine reverses this in a dose-dependent manner.

The relationship of PON1 QR 192 and LM 55 polymorphisms with serum paraoxonase activities of Turkish diabetic patients.

Paraoxonase (PON1) is a serum esterase responsible for the protection against xenobiotics toxicity such as paraoxon. Alterations in PON1 concentrations have been reported in a variety of diseases including diabetes mellitus (DM). It has been shown that the serum PON1 concentration and activity are decreased in patients with both type 1 and type 2 DM. This study aimed to investigate the lipid profiles and the relationship between PON1 activity and PON1, QR192 and LM55 polymorphisms in Turkish type 2 diabetic patients and non-diabetic control subjects. According to our results, RR variant had significantly higher PON activity than QQ and QR variants (p < 0.01) and LL variant had significantly higher PON activity than MM variant in both control and patient groups (p < 0.05). In conclusion, we found that PON1 192RR and 55LL genotypes are associated with higher PON activity than QQ and MM genotypes. This may be more protective to lipid peroxidation.

The Effect of Etoricoxib on Hepatic Ischemia-Reperfusion Injury in Rats

Ischemia-reperfusion (I/R) damage is known to be a pathological process which continues with the increase of oxidants and expands with the inflammatory response. There is not any study about protective effect of etoricoxib on the liver I/R damage in literature. Objective. This study investigates the effect of etoricoxib on oxidative stress induced by I/R of the rat liver. Material and Methods. Experimental animals were divided into four groups as liver I/R control (LIRC), 50 mg/kg etoricoxib + liver I/R (ETO-50), 100 mg/kg etoricoxib + liver I/R (ETO-100), and healthy group (HG). ETO-50 and ETO-100 groups were administered etoricoxib, while LIRC and HG groups were orally given distilled water by gavage. Hepatic artery was clamped for one hour to provide ischemia, and then reperfusion was provided for 6 hours. Oxidant, antioxidant, and COX-2 gene expressions were studied in the liver tissues. ALT and AST were measured. Results. Etoricoxib in 50 and 100 mg/kg doses changed the levels of oxidant/antioxidant parameters such as MDA, MPO, tGSH, GSHRd, GST, SOD, NO, and 8-OH/Gua in favour of antioxidants. Furthermore, etoricoxib prevented increase of COX-2 gene expression and ALT and AST levels. This important protective effect of etoricoxib on the rat liver I/R can be tested in the clinical setting.

The Ocular Endothelin System: A Novel Target for the Treatment of Endotoxin-Induced Uveitis With Bosentan

PURPOSE We compared the anti-inflammatory effects of bosentan and dexamethasone in endotoxin-induced uveitis (EIU). METHODS Endotoxin-induced uveitis was induced by subcutaneous injection of lipopolysaccharide (LPS, 200 μg) in Wistar rats. Rats were divided randomly into 10 groups (n = 6). Bosentan at doses of 50 and 100 mg/kg were administered orally 1 hour before and 12 hours after LPS injection, and dexamethasone was administered by intraperitoneally 30 minutes before and 30 minutes after LPS injection at a dose of 1 mg/kg. Data were collected at two time points for each control and treatment; animals were killed at either 3 or 24 hours after LPS injection. Histopathologic evaluation and aqueous humour measurements of TNF-α level were performed, and endothelin-1 (ET-1), inducible nitric oxide synthase (iNOS), and endothelin receptor A and B (EDNRA and B) expression were analyzed. RESULTS The group treated with 100 mg/kg bosentan at 24 hours displayed significantly milder uveitis and fewer inflammatory cells compared to LPS-injected animals, and there were similar findings in the dexamethasone-treated group at 24 hours. The TNF-α levels in the dexamethasone treatment group were lower than those in the LPS-induced uveitis control group (P < 0.05); however, there was no difference between the dexamethasone and bosentan treatment groups at 3 and 24 hours after LPS administration. Bosentan treatment at doses of 50 and 100 mg/kg significantly decreased iNOS expression compared to LPS-injected animals (P < 0.001). The ET-1 expression was suppressed significantly by bosentan and dexamethasone at 3 and 24 hours after LPS administration (P < 0.001). The EDNRA expression in the bosentan treatment groups was statistically significantly lower than that in the LPS-induced uveitis control group at 3 and 24 hours after LPS administration (P < 0.05). CONCLUSIONS Bosentan reduces intraocular inflammation and has similar effects as dexamethasone in a rat model of EIU.

Reversal of Rocuronium-Induced Neuromuscular Block with Sugammadex and Resulting Histopathological Effects in Rat Kidneys

Background: This study investigated the effect of injection of rocuronium or sugammadex alone and rocuronium + sugammadex on urea, creatinine, electrolyte levels, and histopathological findings in rats. Methods: Thirty-six Sprague-Dawley male rats were divided to receive intravenously 16 or 96 mg/kg sugammadex, 1 mg/kg rocuronium, 1 mg/kg rocuronium + 16 mg/kg sugammadex, or 1 mg/kg rocuronium + 96 mg/kg sugammadex. The control group received an equal volume of physiological serum. Rats receiving rocuronium were ventilated until resumption of spontaneous ventilation and followed for 72 h. Blood samples were withdrawn from the tail vein to measure urea, creatinine, and electrolyte values; then both kidneys were excised, and the tissues were used for histopathological examination. Results: Rats receiving rocuronium and high doses of sugammadex (96 mg/kg) showed increased glomerular vacuolation, tubular dilatation, vascular vacuolation and hypertrophy, lymphocyte infiltration, and tubular cell sloughing compared to the control group (p = 0.002). Biochemical markers of renal function were not significantly altered after treatment with high doses of sugammadex. Conclusion: The elimination half-life of the rocuronium–sugammadex complex was found to be greater than that of free rocuronium or sugammadex, which led to marginal histopathological changes in the kidney without affecting any renal functions.

A Comparative Investigation of the Analgesic Effects of Metamizole and Paracetamol in Rats

ABSTRACT Background: This study investigated the effects of metamizole and paracetamol on pain and oxidative stress induced by scalpel incision and carrageenan in rats. Materials and methods: Total of 144 rats were divided into groups of 12 animals. Six groups each were used for scalpel incision and carrageenan tests. Pain was inflicted by applying a scalpel incision or carrageenan. Pain-created groups by scalpel incision received metamizole (SIM) or paracetamol (SIP) at doses of 250 or 500 mg/kg. Pain-created groups by carrageenan received metamizole (CAM) or paracetamol (CAP) at doses of 250 or 500 mg/kg. Analgesic activity was determined by Basile Algesimeter. The COX-2 and MPO gene expressions were determined, and malondialdehyde and tGSH were measured in rat paws. Results: In the scalpel incision test, pain was reduced in groups of SIM-250 and SIM-500 in the first hour by 65.2% and 91.3%, respectively, and in the third hour by 51.9% and 77.8%, respectively, compared with the SIC group. In SIP-250 and SIP-500 groups, pain was reduced in the first hour by 43% and 74%, respectively, and by 33.4% and 59.3%, respectively, in the third hour compared with the SIC group. In the carrageenan test, in groups CAM-250 and CAM-500, pain was reduced in the first hour by 72.3% and 86.1%, respectively, and by 65.8% and 71.4%, respectively, in the third hour compared with the CCG group. In groups CAP-250 and CAP-500, pain was reduced in the first hour by 52.8% and 69.4%, respectively, and by 28.6% and 25.8%, respectively, in the third hour compared with the CCG group. Metamizole inhibited COX-2 gene expression at a dose of 500 mg/kg in the carrageenan test. At doses of 250 and 500 mg/kg, metamizole reduced COX-2 and MPO gene expressions and oxidative stress induced by scalpel incision or carrageenan. But both doses of paracetamol were unable to suppress that parameters. Conclusions: Our results show that metamizole is more effective than paracetamol for treating surgical trauma-related pain, inflammation, and oxidative stress and hence may be a preferential drug to paracetamol.

Effect of thiamine pyrophosphate on ischemia-reperfusion induced oxidative damage in rat kidney.

Objectives: The biochemical effects of thiamine pyrophosphate on ischemia-reperfusion (IR) induced oxidative damage and DNA mutation in rat kidney tissue were investigated, and compared to thiamine. Materials and Methods: Rats were divided into four groups: Renal ischemia-reperfusion (RIR); thiamine pyrophosphate + RIR (TPRIR); thiamine + RIR (TRIR); and sham group (SG). Results: The results of biochemical experiments have shown that malondialdehyde (MDA) levels in rat kidney tissue after TRIR and TPRIR treatment were 7.2 ± 0.5 (P > 0.05) and 3.3 ± 0.3 (P < 0.0001) μmol/g protein, respectively. The MDA levels in the SG rat kidney tissue and in RIR group were 3.6 ± 0.2 (P < 0.0001) and 7.6 ± 0.6 μmol/g protein, respectively. Total glutathione (tGSH) levels in TRIR, TPRIR, SG, and RIR animal groups were 2.2 ± 0.3 (P > 0.05), 5.8 ± 0.4 (P < 0.0001), 6.2 ± 0.2 (P < 0.0001), and 1.7 ± 0.2 nmol/g protein, respectively. In the TRIR, TPRIR, SG, and RIR animal groups; 8-hydroxyguanine (8-OHGua)/Gua levels, which indicate mutagenic DNA, were 1.75 ± 0.12 (P > 0.05), 0.93 ± 0.1 (P < 0.0001), 0.85 ± 0.08 (P < 0.0001), and 1.93 ± 0.24 pmol/L, respectively. Conclusions: It has been shown that thiamine pyrophosphate prevents increase in mutagenic DNA in IR induced oxidative damage, whereas thiamine does not have this effect.

Effect of etoricoxib on experimental oxidative testicular ischemia-reperfusion damage in rats induced with torsion-detorsion

Etoricoxib features antioxidant and anti-inflammatory properties concomitantly, suggesting that it may be beneficial in testicular ischemia reperfusion (I/R) damage. Our aim is to investigate the effects of etoricoxib on testicular I/R damage induced with torsion-detorsion (TD). The etoricoxib + torsion-detorsion (ETD) groups of animals were given etoricoxib in 50 and 100 mg/kg of body weight (ETD-50 and ETD-100), while the testes torsion-detorsion (TTD) and sham operation rat group (SOG) animals were given single oral doses of distilled water as a solvent. TTD, ETD-50 and ETD-100 groups were subjected to 720° degrees torsion for four hours, and detorsion for four hours. The SOG group was not subjected to this procedure. Biochemical, gene expression and histopathological analyses were carried out on the testicular tissues. The levels of malondialdehyde (MDA), myeloperoxidase (MPO), interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) were significantly higher, and the levels of total glutathione (tGSH) and glutathione reductase (GSHRd) were significantly lower in the TTD group, compared to the ETD-50, ETD-100 and SOG groups. Etoricoxib at a dose of 100 mg/kg better prevented I/R damage than the 50 mg/kg dose. Etoricoxib may be useful in clinical practice in the reduction of I/R damage on testes caused by torsion-detorsion.

The effects of ketamine and thiopental used alone or in combination on the brain, heart, and bronchial tissues of rats

Introduction We compared the side effects of ketamine and thiopental used alone and of a ketamine/thiopental combination dose on the brain,heart, and bronchial tissues of rats. Material and methods Three groups received intraperitoneal injections of 30 mg/kg ketamine (K-30); 15 mg/kg thiopental (T-15); or of both in combination (KTSA). These doses were doubled in another set of study groups (K-60, T-30, and KTA groups, respectively). Optimal anesthesia duration was examined in all groups. Results Anesthesia did not occur with 30 mg/kg ketamine or 15 mg/kg thiopental. However, when used alone ketamine and thiopental led to oxidative stress in the striatum, heart, and bronchial tissues. Conversely, combined administration of anesthetics and subanesthetic doses were found not to create oxidative stress in any of these areas. The highest level of adrenaline in blood samples collected from the tail veins was measured in the KTA-60, and the lowest amount in the T-30. Creatine kinase activity was highest in the KTA-60 group (p < 0.001). When we compared for all 5 groups to untreated control group; the creatine kinase-MB activities were significiantly different in K-30, T-15 and T-30 (p < 0.001). Conclusions The studied doses of ketamine led to oxidative stress by increasing the amount of adrenaline. Thiopental increased oxidative stress with decreases in adrenaline. A longer anesthetic effect with minimal adverse events may be achieved by ketamine and thiopental in combination.