Protective effect of gallic acid on doxorubicin-induced ovarian toxicity in mouse.

The aims of the present study were to evaluate the protective effects of gallic acid against doxorubicin-induced ovarian toxicity in mice, and to verify the possible involvement of PI3K and mTOR signaling pathway members (PTEN, Akt, FOXO3a and rpS6) in the gallic acid protective actions. Mice were pretreated with NaCl (0.15 M, p.o.) (control and doxorubicin groups) or gallic acid (50, 100 or 200 mg/kg body weight, p.o.) once daily, for 5 days, and on the third day of treatment, after 1 h of treatment administration, the mice received saline solution (i.p.) (control group) or doxorubicin (10 mg/kg of body weight, i.p.). Next, the ovaries were harvested for histological (follicular morphology and activation), fluorescence (GSH and mitochondrial activity), and immunohistochemical (PCNA, cleaved caspase-3, TNF-α, p-PTEN, Akt, p-Akt, p-rpS6 and p-FOXO3a) analyses. The results showed that cotreatment with 50 mg/kg gallic acid plus doxorubicin preserved the percentage of normal follicles and cell proliferation, reduced the percentage of cleaved caspase-3 follicles, prevented inflammation, and increased GSH concentrations and mitochondrial activity compared to doxorubicin treatment alone. Furthermore, cotreatment 50 mg/kg gallic acid plus doxorrubicin increased expression of Akt, p-Akt, p-rpS6 and p-FOXO3a compared to the doxorubicin alone. In conclusion, 50 mg/kg gallic acid protects the mouse ovary against doxorubicin-induced damage by improving GSH concentrations and mitochondrial activity and cellular proliferation, inhibiting inflammation and apoptosis, and regulating PI3K and mTOR signaling pathway.

Involvement of MT2 receptors in protective effects of melatonin against cisplatin-induced gastrointestinal damage in mice

Abstract Melatonin (MLT) reportedly reduces side effects associated with certain antineoplastic agents. Accordingly, we investigated the effect of MLT on cisplatin (CP)-induced gastric emptying (GE) delay. Mice were intraperitoneally pretreated with vehicle (ethanol 5%; control group), MLT (5, 10, or 20 mg/kg), or N-acetylcysteine (NAC; 150 mg/kg), followed by CP treatment (5 mg/kg). Pharmacological modulation was analyzed using relevant receptor antagonists (luzindole: non-selective MT1/MT2 antagonist; 5 mg/kg or 4-P-PDOT: selective MT2 antagonist; 4 mg/kg) before treatment with MLT plus CP. All treatments were performed once daily for three days. GE was assessed using phenol red. Gut morphology was examined using scanning electron microscopy and optical microscopy. Compared with the control, CP decreased GE. Pretreatment with NAC and MLT (5 and 10 mg/kg) did not prevent CP-induced gastric dysmotility; however, pretreatment with 20 mg/kg MLT prevented this effect. In addition, luzindole and 4-P-PDOT suppressed MLT-mediated gastroprotection against cytotoxic effects of CP. CP caused degeneration of the gut mucosa, which was attenuated by MLT treatment. Thus, 20 mg/kg MLT prevented the GE delay and decreased CP-induced adverse effects on the gut mucosa. In addition, the gastroprotective activity was mediated via the MT2 receptor.

Moderate Physical Exercise Activates ATR2 Receptors, Improving Inflammation and Oxidative Stress in the Duodenum of 2K1C Hypertensive Rats.

Background: In addition to the cardiovascular and renal systems, the gastrointestinal tract also contains angiotensin ATR1a, ATR1b, and ATR2. We previously observed that the 2Kidney-1Clip hypertension model elicits physical exercise and gastrointestinal dysmotility, which is prevented by renin-angiotensin system blockers. Here, we investigate the effect of physical exercise on inflammation, stress biomarkers, and angiotensin II receptors in the duodenum of 2K1C rats. Methods: Arterial hypertension was induced by the 2K1C surgical model. The rats were allocated in Sham, 2K1C, or 2K1C+Exercise groups. One week after surgery, they were submitted to a physical exercise protocol (running 5x/week, 60min/day). Next, we assessed their intestinal contractility, cytokine levels (TNF-α, IL-1ß, and IL-6), oxidative stress levels (MPO, GSH, MDA, and SOD), and the gene expression of angiotensin receptors (ATR1A, ATR1B, and ATR2). Results: In comparison with the Sham group, the 2K1C arterial hypertension decreased (p<0.05) the intestinal contractility. In comparison with 2K1C, the 2K1C+Exercise group exhibited lower (p<0.05) MPO activity (22.04±5.90 vs. 78.95±18.09 UMPO/mg tissue) and higher (p<0.05) GSH concentrations in intestinal tissues (67.63±7.85 vs. 31.85±5.90mg NPSH/mg tissue). The 2K1C+Exercise group showed lower (p<0.05) cytokine levels in the intestine than 2K1C rats. In comparison with the Sham group, the 2K1C+Exercise rats showed higher (p<0.05) gene expression of ATR2 in the duodenum. Conclusion: 2K-1C hypertension elicits an oxidative stress and inflammation process in the duodenum. Physical exercise modulates the expression twice as much of ATR2 receptors, suggesting possible anti-inflammatory and antioxidant effects induced by exercise.

Role of cholecystokinin and oxytocin in slower gastric emptying induced by physical exercise in rats.

Vigorous exercise can induce gastrointestinal disorders such decreased gastric emptying pace, while low-intensity exercise can accelerate gastric motility. However, the mechanisms of these effects are still unknown. We investigated the possible neurohumoral mechanisms involved in these phenomena. In sedentary (Sed) and acute exercise (Ex) groups of rats, we assessed the activation of c-Fos in NTS and DVMN and the plasma levels of CCK and OXT. Separate groups received pretreatment with the oxytocin antagonist atosiban (AT), the cholecystokinin antagonist devazepide (DVZ), or the TRPV1 receptor inhibitor capsazepine (CAPZ). AT, DVZ and CAPZ treatments prevented (p<0.05) slower gastric emptying induced by acute exercise. The gene expression of OXT decreased (P<0.05) while that of CCK increased (P<0.05) in the gastric fundus and pylorus of the Ex group, while the plasma levels of OXT rose (p<0.05) and of CCK declined (p<5.05). We also observed activation (p<0.05) of c-Fos-sensitive neurons in the NTS and DVMN of exercised rats. In conclusion, acute exercise slowed gastric emptying by the vagal afferent pathway, which involved activation of CCK1/OXT/TRPV1 sensitivity.

Exercise and pyridostigmine prevents gastric emptying delay and increase blood pressure and cisplatin-induced baroreflex sensitivity in rats.

Cisplatin treatment induces an autonomic dysfunction and gastrointestinal and cardiovascular disorders. Physical exercise as well as pyridostigmine treatment induces improves in the autonomic nervous system. In the current study, we investigated the effect of physical exercise and pyridostigmine treatment on gastrointestinal and cardiovascular changes in cisplatin-treated rats. Rats were divided into groups: Saline (S), Cisplatin (Cis), Exercise (Ex), Cisplatin+Exercise (Cis+Ex), Pyridostigmine (Pyr), and Cisplatin+Pyridostigmine (Cis+Pyr). We induced gastrointestinal dysmotility by administering 3 mg kg-1 of cisplatin once week for 5 weeks. The Ex was swimming (1 h per day/5 days per week for 5 weeks with 5% b.w.). GE was evaluated through the colorimetric method of fractional red phenol recovery 10 min after feeding. Pyr groups received 1.5 mg kg-1, p.o. or concomitant Cis treatment. Moreover, gastric contraction in vitro and hemodynamic parameters such as MAP, HR, and evoked baroreflex sensitivity were assessed, as well as sympathetic and parasympathetic tone and intrinsic heart rate (IHR). Cis decrease GE vs. saline (p<0.05). Cis+Ex or Cis+Pyr prevented (p<0.05) decrease in GE vs. Cis rats. Cis decreased (p<0.05) gastric responsiveness in vitro vs. saline. Cis+Ex or Cis+Pyr prevented this phenomenon. Cis treatment increase MAP and decrease in HR (p<0.05) vs saline. Cis+Ex or Cis+Pyr attenuated (p<0.05) both alterations. Cis increased sympathetic tone and decreased vagal tone and IHR (p<0.05) vs. the saline. Cis+Ex or Cis+Pyr prevented those effects vs. the Cis group. In conclusion, physical exercise and pyridostigmine treatment improves autonomic dysfunction and prevented GE delay and changes in hemodynamic parameters, baroreflex sensitivity, and cardiac autonomic control in cisplatin-treated rats.

Inhibitory effects of Morus nigra L. (Moraceae) against local paw edema and mechanical hypernociception induced by Bothrops jararacussu snake venom in mice.

BACKGROUND: Bothropic venoms cause intense local damage, pain, edema, and myonecrosis. Morus nigra L. (Moraceae) has several uses in folk medicine and can be a promising candidate for the treatment of several inflammatory disorders. HYPOTHESIS/PURPOSE: The present study aims to evaluate the anti-inflammatory and antinociceptive effects of the ethanolic extract of Morus nigra L. (Mn-EtOH) on paw lesions induced by Bothrops jararacussu snake venom (BjcuV) in mice. METHODS: UV-vis absorption of BjcuV was evaluated. A phytochemical study was performed, which led to the isolation and characterization of three compounds. These compounds were identified using spectrometric methods, namely LC-MS and NMR (1D and 2D), followed by the validation of their spectra with the data available in the literature. Further, the flavonoids i.e. rutin and quercetin (chemical markers of M. nigra), Mn-EtOH or Mn-EtOH-encapsulated electrospun fibers of Eudragit L100 (FB/Mn-EtOH), and Mn-EtOH-encapsulated microparticles of Eudragit L100 (MP/Mn-EtOH) were evaluated, in paw edema test induced by BjcuV. RESULTS: UV-vis spectra showed the presence of phospholipases A2 as component of BjcuV. The chemical examination resulted in the isolation of ß-sitosterol, quercetin-3-O-glucopyranoside, and kaempferol-3-O-glucopyranoside. Mn-EtOH, FB/Mn-EtOH, MP/Mn-EtOH, rutin, and quercetin reduced the local edema induced by BjcuV. The Mn-EtOH also prevented edema provoked by serotonin and bradykinin. Moreover, it reduced paw edema and peritoneal leukocyte infiltration induced by carrageenan, and decreased the mechanical hypernociception of BjcuV. Mn-EtOH exerted anti-inflammatory and antinociceptive effects, possibly by the inhibition of leukocyte migration and the modulation of serotonin and bradykinin actions. This anti-inflammatory activity was maintained even upon incorporation of the M. nigra extract into the drug delivery systems (i.e., Mn-EtOH-encapsulated FBs and MPs of Eudragit L100). CONCLUSION: These results reinforce the therapeutic potential of M. nigra in the treatment of inflammatory conditions, in addition to, its role as a complementary treatment of snakebites.

The participation of the nitrergic pathway in increased rate of transitory relaxation of lower esophageal sphincter induced by rectal distension in dogs.

CONTEXT: The rectal distension in dogs increases the rate of transitory lower esophageal sphincter relaxation considered the main factor causing gastroesophageal reflux. OBJECTIVES: The aim of this study was evaluate the participation of the nitrergic pathway in the increased transitory lower esophageal sphincter relaxation rate induced by rectal distension in anesthetized dogs. METHODS: Male mongrel dogs (n = 21), weighing 10-15 kg, were fasted for 12 hours, with water ad libitum. Thereafter, they were anesthetized (ketamine 10 mg.Kg-1 + xylazine 20 mg.Kg-1), so as to carry out the esophageal motility evaluation protocol during 120 min. After a 30-minute basal period, the animals were randomly intravenous treated whith: saline solution 0.15M (1ml.Kg-1), L-NAME (3 mg.Kg-1), L-NAME (3 mg.Kg-1) + L-Arginine (200 mg.Kg-1), glibenclamide (1 mg.Kg-1) or methylene blue (3 mg.Kg-1). Forty-five min after these pre-treatments, the rectum was distended (rectal distension, 5 mL.Kg-1) or not (control) with a latex balloon, with changes in the esophageal motility recorded over 45 min. Data were analyzed using ANOVA followed by Student Newman-Keuls test. RESULTS: In comparison to the respective control group, rectal distension induces an increase in transitory lower esophageal sphincter relaxation. Pre-treatment with L-NAME or methylene blue prevents (P<0.05) this phenomenon, which is reversible by L-Arginine plus L-NAME. However, pretreating with glibenclamide failed to abolish this process. CONCLUSIONS: Therefore, these experiments suggested, that rectal distension increases transitory lower esophageal sphincter relaxation in dogs via through nitrergic pathways.

The participatinn of the nitrergic pathway in icreased rate of transitory relaaxation of lower esophageal sphincter induced by rectal distension in dogs / A participação da via nitrérgica no aumento da taxa de relaxamento transitório do esfíncter esofágico inferior induzida pela distensão retal em cães

Context The rectal distension in dogs increases the rate of transitory lower esophageal sphincter relaxation considered the main factor causing gastroesophageal reflux. Objectives The aim of this study was evaluate the participation of the nitrergic pathway in the increased transitory lower esophageal sphincter relaxation rate induced by rectal distension in anesthetized dogs. Methods Male mongrel dogs (n = 21), weighing 10-15 kg, were fasted for 12 hours, with water ad libitum. Thereafter, they were anesthetized (ketamine 10 mg.Kg-1 + xylazine 20 mg.Kg-1), so as to carry out the esophageal motility evaluation protocol during 120 min. After a 30-minute basal period, the animals were randomly intravenous treated whith: saline solution 0.15M (1ml.Kg-1), L-NAME (3 mg.Kg-1), L-NAME (3 mg.Kg-1) + L-Arginine (200 mg.Kg-1), glibenclamide (1 mg.Kg-1) or methylene blue (3 mg.Kg-1). Forty-five min after these pre-treatments, the rectum was distended (rectal distension, 5 mL.Kg-1) or not (control) with a latex balloon, with changes in the esophageal motility recorded over 45 min. Data were analyzed using ANOVA followed by Student Newman-Keuls test. Results In comparison to the respective control group, rectal distension induces an increase in transitory lower esophageal sphincter relaxation. Pre-treatment with L-NAME or methylene blue prevents (P<0.05) this phenomenon, which is reversible by L-Arginine plus L-NAME. However, pretreating with glibenclamide failed to abolish this process. Conclusions Therefore, these experiments suggested, that rectal distension increases transitory lower esophageal sphincter relaxation in dogs via through nitrergic pathways. .

Contexto A distensão retal aumenta a taxa de relaxamento transitório do esfíncter esofágico inferior em cães, sendo o relaxamento transitório do esfíncter esofágico inferior considerado o principal fator responsável pelo refluxo gastroesofágico. Objetivos Avaliar a participação da via nitrérgica no aumento da taxa relaxamento transitório do esfíncter esofágico inferior induzida por distensão retal em cães anestesiados. Métodos Cães sem raça definida, machos (n = 21), pesando entre 10-15 kg, foram mantidos em jejum durante 12 horas, no entanto, com água ad libitum. Depois disso, eles foram anestesiados (cetamina 10 mg.Kg-1 + xilazina 20 mg.Kg-1), para a realização do protocolo de avaliação da motilidade esofágica durante 120 minutos. Após um período basal de 30 minutos, os animais foram aleatoriamente tratados intravenosa com: solução salina 0,15 (1 ml.Kg-1), L-NAME (3 mg.Kg-1), L-NAME (3 mg.Kg-1) + L-arginina (200 mg.Kg-1), glibenclamida (1 mg.Kg-1) e azul de metileno (3 mg.Kg-1). Quarenta e cinco minutos após os pré-tratamentos, o reto foi distendido com um balão de látex (DR, 5 mg.Kg-1) ou não (grupo controle), e as variações da motilidade esofágica foram registradas e gravadas ao longo dos 45 minutos seguintes. Os dados foram analisados utilizando-se ANOVA seguido pelo teste de Student Newman-Keuls. Resultados Em comparação com o respectivo grupo controle, a distensão retal demonstrou induzir um aumento na taxa de relaxamento transitório do esfíncter esofágico inferior. O pré-tratamento com L -NAME ou azul de metileno impediu (P<0,05) este fenômeno, que foi reversível após a administração de L-Arginina + L-NAME. No entanto, o pré-tratamento com a glibenclamida não ...

Repeated cisplatin treatments inhibit gastrointestinal motility and induces baroreflex changes and mechanical hyperalgesia in rats.

Cisplatin is a chemotherapy agent known for its neurotoxicity. We evaluated the effect of cisplatin on the gastric emptying (GE), gastrointestinal (GI) transit of liquid, baroreflex function, thermal, and mechanical withdrawal latencies in rats. Cisplatin increased the GE of liquid with doses ≥ 2 mg.kg(-1) by 59.7-77.4%. This GE delay was not present two weeks after the treatment with five doses of cisplatin at 1 mg.kg(-1). Cisplatin also enhanced baroreflex gain possibly by increasing sympathetic activity. Our results demonstrated that cisplatin (2-10 mg.kg(-1)) causes autonomic neuropathy with GI and baroreflex changes and mechanical but not thermal hyperalgesia in rats.

The essential oil of Eucalyptus tereticornis and its constituents, α- and ß-pinene, show accelerative properties on rat gastrointestinal transit.

The essential oil of Eucalyptus tereticornis (EOET) has pharmacological activities but their effects on the gastrointestinal tract are yet unknown. It possesses α- and ß-pinene as minor constituents, isomers largely used as food or drink additives. In this work, we studied their actions on gut motility. After feeding with a liquid test meal, conscious rats received perorally EOET, α-, or ß-pinene, and the fractional dye retention was determined. EOET and its constituents decreased the gastric retention. In anesthetized rats, pinenes increased gastric tonus, while enhancing the meal progression in the small intestine of conscious rats. Both α- and ß-pinene contracted gastric strips IN VITRO but relaxed the duodenum. Conversely, EOET relaxed both the gastric and duodenal strips. In conclusion, EOET accelerates the gastric emptying of liquid, and part of its action is attributed to the contrasting effects induced by α- and ß-pinene on the gut.

Caracterização das vias neuro-humorais no retarde do esvaziamento gástrico de líquidos advindo da distensão mecânica atrial direta em ratos acordados [manuscrito] / Characterization of neurohumoral pathways in the delay gastric emptying of liquids arising from direct mechanical atrial distension in awake rats [manuscript]

A distensão mecânica do átrio direito (DA) aumenta a motilidade gástrica em ratos anestesiados (Palheta et al., 2010). Resolvemos avaliar o efeito da DA sobre o esvaziamento gástrico (EG) de líquido em ratos acordados e as eventuais vias neuro-humorais relacionadas ao fenômeno. Utilizamos ratos albinos machos (n = 361, 250 - 280 g) que receberam um balão de silicone posicionado no átrio direito. Decorridos 24 h, monitoramos a pressão venosa central (PVC), frequência cardíaca (FC) e a pressão arterial média (PAM) e após os 20-min iniciais os animais foram aleatoriamente pré-tratados com: Salina (S, 0,1 ml/100g, i.v.), Atropina (A, 0,5 mg/kg, i.v.), Guanetidina (GT, 10 mg/kg, i.p.), Hexametônio (H, 10mg/kg, i.v.), L-NAME (3mg/kg,i.v.), L-Arg (100 mg/kg, i.v.) + L-NAME (3mg/kg,i.v.), Azul de metileno (MB,3mg/kg, i.v.), Glibenclamida (GB, 1mg/kg, i.p.) ou Glibenclamida + Diazóxido (3mg/kg, i.v.) [GB + D], Dexametasona (DEX, 1mg/kg, i.p.), Anantin (ANT, 5μg, i.v.) ou Atosibana (AT, 40μg/kg/h, i.v.). Além disto, em grupos separados realizamos 72h antes da DA a vagotomia (V), ou esplancnotomia + gangliectomia celíaca (SC) ou denervação cardíaca aferente com capsaicina (ACD). Em outro conjunto de animais realizamos aurilectomia direita uma semana antes da DA (AX). Em seguida ao tratamento farmacológico realizamos protocolo de falsa DA (controle) ou DA com 50 μL do balão intra-atrial durante...