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1.
Drug Res (Stuttg) ; 73(9): 513-519, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37935203

ABSTRACT

BACKGROUND: Previous studies indicate the renal vasodilating effects of boldine, an alkaloid found in Peumus boldus. However, its potential to induce diuresis still needs to be studied. METHODS: Wistar rats were used and the urine volume was noted for 8 h and further studied. RESULTS: The acute treatment at 0.1 and 0.3 mg/kg of boldine showed a diuretic, natriuretic, and Ca2+-sparing effect in rats without changing the urinary elimination of K+and Cl-. When boldine was given in combination with hydrochlorothiazide, there was an increase in urinary volume compared to the vehicle group. However, this was not different from the treatments in its isolated form. Urine Ca2+values ​​remained low but were not enhanced by this association. The excretion of Na+and Cl- was significantly increased compared to the group that received only vehicle or boldine. On the other hand, although the association of amiloride plus boldine did not result in a diuretic effect, the increase in Na+and the reduction in K+excretion were significantly potentiated. Furthermore, in the presence of the non-selective muscarinic receptor antagonist atropine, boldine showed reduced capacity to increase urinary volume, maintaining the natriuretic and Ca2+-sparing effect, besides a very evident K+-sparing action. Similar results were obtained in the presence of the non-selective cyclooxygenase inhibitor indomethacin. Furthermore, boldine showed an ex vivo antiurolithiasis activity, reducing calcium oxalate's precipitation and crystallization. CONCLUSIONS: This study reveals the diuretic, natriuretic, Ca2+-sparing, and antiurolithiatic effects of boldine, an action possibly related to muscarinic receptor activation and prostanoid generation.


Subject(s)
Aporphines , Diuretics , Rats , Animals , Diuretics/pharmacology , Calcium , Rats, Wistar , Aporphines/pharmacology , Sodium , Receptors, Muscarinic
2.
Article in English | MEDLINE | ID: mdl-35222671

ABSTRACT

Boldine, 2,9-dihydroxy-1,10-dimethoxyaporphine, is the main alkaloid found in the leaves and bark of Peumus boldus Molina. In recent years, boldine has demonstrated several pharmacological properties that benefit endothelial function, blood pressure control, and reduce damage in kidney diseases. However, the renal vasodilator effects and mechanisms remain unknown. Herein, perfused rat kidneys were used to study the ability of boldine to induce vasodilation of renal arteries. For that, left kidney preparations with and without functional endothelium were contracted with phenylephrine and received 10-300 nmol boldine injections. The preparations were then perfused for 15 min with phenylephrine plus L-NAME, indomethacin, KCl, tetraethylammonium, glibenclamide, apamin, charybdotoxin, or iberiotoxin. In 30, 100, and 300 nmol doses, boldine induced a dose-and endothelium-dependent relaxing effect on the renal vascular bed. No vasodilator effects were observed in preparations lacking functional endothelium. While the inhibition of the cyclooxygenase enzyme through the addition of indomethacin did not cause any change in the vasodilating action of boldine, the nonselective nitric oxide synthase inhibitor L-NAME fully precluded the vasodilatory action of boldine at all doses tested. The perfusion with KCl or tetraethylammonium (nonselective K+ channels blocker) also abolished the vasodilatory effect of boldine, indicating the participation of K+ channels in the renal action of boldine. The perfusion with glibenclamide (selective ATP-sensitive K+ channels blocker), iberiotoxin (selective high-conductance Ca2+-activated K+ channel blocker), and charybdotoxin (selective high- and intermediate-conductance Ca2+-activated K+ channel blocker) did not modify the vasodilatory action of boldine. On the other hand, the perfusion with apamin (selective small-conductance Ca2+-activated K+ channel blocker) completely prevented the vasodilatory action of boldine at all doses tested. Together, the present study showed the renal vasodilatory properties of boldine, an effect dependent on the generation of nitric oxide and the opening of a small-conductance Ca2+-activated K+ channel.

3.
Naunyn Schmiedebergs Arch Pharmacol ; 394(1): 49-57, 2021 01.
Article in English | MEDLINE | ID: mdl-32780226

ABSTRACT

The p-coumaric acid is a phenolic compound present in large quantities in the extract of Baccharis dracunculifolia DC, a Brazilian medicinal plant used to treat gastric ulcer. Given the necessity for finding new chemical components capable of accelerating gastric healing, in this study, the effects of the p-coumaric acid were evaluated in the acetic acid-induced ulcer model in rats, where histological, inflammatory, and oxidative parameters were analyzed. The healing property was also evaluated in the scratch assay on fibroblast cells (L929) and the cytotoxicity of p-coumaric acid was assessed in both L929 and human gastric adenocarcinoma (AGS) cells by MTT assay. The treatment with p-coumaric acid (10 mg/kg, p.o.) for 7 days, twice a day, decreased by 44.6% the acetic acid-induced gastric ulcer compared with the vehicle-treated group. The vehicle control-treated group showed a larger extension of the ulcer base and an extensive damage into the mucosa and submucosa layers, which were mitigated by the treatment with p-coumaric acid. This beneficial effect was also associated with increased levels of mucin and reduced glutathione, decreased amount of lipid hydroperoxides, and increased superoxide dismutase and catalase activities without interfering with the activity of myeloperoxidase in the gastric tissue. The compound promoted the restructuring of the cell monolayer in the scratch test and did not show toxicity in the L929 cell line, while reduced the viability of the AGS, a lineage of human gastric adenocarcinoma. Thus, p-coumaric acid may be considered a natural source for the treatment of gastric ulcers, by reinforcing protective factors of gastric mucosa and by accelerating gastric healing.


Subject(s)
Anti-Ulcer Agents/therapeutic use , Coumaric Acids/therapeutic use , Stomach Ulcer/drug therapy , Acetic Acid , Animals , Anti-Ulcer Agents/pharmacology , Baccharis/chemistry , Catalase/metabolism , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , Coumaric Acids/isolation & purification , Coumaric Acids/pharmacology , Disease Models, Animal , Female , Gastric Mucosa/drug effects , Gastric Mucosa/metabolism , Gastric Mucosa/pathology , Glutathione/metabolism , Humans , Mice , Peroxidase/metabolism , Phytotherapy , Rats , Stomach Ulcer/chemically induced , Stomach Ulcer/metabolism , Stomach Ulcer/pathology , Superoxide Dismutase/metabolism
4.
Phytother Res ; 33(1): 90-106, 2019 Jan.
Article in English | MEDLINE | ID: mdl-30281176

ABSTRACT

This study evaluated the effects of flavonoid-rich fraction from Bauhinia forficata leaves (FRF-BF), against intestinal toxicity induced by irinotecan. The leaves of this plant are used like tea in Brazilian folk medicine, and it is rich in flavonoids, mainly kaempferitrin. First, the chemopreventive effects of FRF-BF and kaempferitrin were evaluated in intestinal cells (IEC-6 cells) exposed to irinotecan. Next, the effects were evaluated against irinotecan-induced mucositis in mice. Lastly, melanoma was induced in C57BL/6 mice to evaluate FRF-BF interference on irinotecan antitumor activity. The results showed that FRF-BF and kaempferitrin exert no cytotoxic effects in IEC-6 cells and confirmed that pretreatment with FRF-BF and kaempferitrin displays chemoprotective effects against cytotoxicity induced by irinotecan. Interestingly, the FRF-BF (100 mg/kg, p.o) reduced the intestinal motility in mice and attenuated parameters linked to irinotecan-induced intestinal mucositis, including diarrhea, histological damage, depletion of duodenal GSH, amount of TNF-α, and MPO activity in the small intestine. Also, FRF-BF does not interfere in the antitumor activity of irinotecan and exerted antitumoral activity in murine melanoma. In conclusion, FRF-BF (100 mg/kg, p.o) presents promising pharmacological potential to prevent and attenuate the severity of intestinal mucositis during chemotherapy treatment, related to the presence of kaempferitrin.


Subject(s)
Bauhinia/chemistry , Flavonoids/chemistry , Irinotecan/adverse effects , Plant Extracts/chemistry , Plant Leaves/chemistry , Animals , Irinotecan/pharmacology , Male , Mice , Mice, Inbred C57BL
5.
Int Immunopharmacol ; 65: 23-28, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30268800

ABSTRACT

The aim of this study was to evaluate the involvement of both B1 and B2 kinins receptors (B1R and B2R) in the fibroblast proliferation induced by the cytokine tumour necrosis factor (TNF) attempting to establish an in vitro model of wound healing. Murine fibroblasts L-929 were cultivated in 24 wells plaque until total confluence (DMEM (Vitrocell®); 5% fetal bovine serum, 5% CO2, 37 °C) and then submitted to the scratch assay. The cells were treated with PBS, TNF (2 ng/mL) and/or mr-TNF antibody (200 µg/mL), or PDTC. The cells received the second set of treatment (3 h later): PBS; 1 µM HOE-140; 1 µM des-Arg9-Leu8-BK (DALBK) or 100 µM PDTC. TNF was able to increase the cell proliferation when compared with the group treated with PBS. The co-treatment with the TNF antibody completely reversed the TNF effect. The TNF-proliferative effect was blocked by B1 (DALBK) and B2 (HOE-140) kinin receptor antagonists administered separately or along, suggesting the involvement of both receptors in the TNF mechanism of action. Furthermore, the treatment with a NF-ĸB inhibitor PDTC completely blocked the cell proliferation. The TNF cell proliferation was incremented with BK (1 µM) treatment, and its effect was totally reversed by HOE-140 treatment. No effect was observed for TNF plus DABK. Eventually, TNF treatment was able to increase TNF level in the growing medium; however, this increase was suppressed by BK treatment. These results suggest that TNF induces cell proliferation and the induced signalling cascade has the B2R participation. All these events seem to be totally dependent on the NF-ĸB activation. These inflammatory mediators can improve the wound healing in the resolution of inflammation.


Subject(s)
Cell Movement/drug effects , Cell Movement/physiology , Cell Proliferation/drug effects , Fibroblasts/metabolism , Kinins/metabolism , Tumor Necrosis Factor-alpha/pharmacology , Animals , Cell Line , Gene Expression Regulation/drug effects , Kinins/genetics , Mice
6.
World J Gastroenterol ; 24(38): 4369-4383, 2018 Oct 14.
Article in English | MEDLINE | ID: mdl-30344421

ABSTRACT

AIM: To evaluate the sex-specific effects of a hydroalcoholic extract from Eugenia punicifolia (HEEP) leaves on gastric ulcer healing. METHODS: In this rat study involving males, intact (cycling) females, and ovariectomized females, gastric ulcers were induced using acetic acid. A vehicle, lansoprazole, or HEEP was administered for 14 d after ulcer induction. Body weight was monitored throughout the treatment period. At the end of treatment, the rats were euthanized and the following in vivo and in vitro investigations were performed: macroscopic examination of the lesion area and organ weights, biochemical analysis, zymography, and evaluation of protein expression levels. Additionally, the concentration-dependent effect of HEEP was evaluated in terms of subacute toxicity and cytotoxicity. RESULTS: Compared to the vehicle, HEEP demonstrated a great healing capacity by substantially reducing the ulcerative lesion area in males (52.44%), intact females (85.22%), and ovariectomized females (65.47%), confirming that HEEP accelerates the healing of acetic acid-induced gastric lesions and suggesting that this effect is modulated by female sex hormones. The antiulcer effect of HEEP was mediated by prostaglandin E2 only in male rats. Overall, the beneficial effect of HEEP was the highest in intact females. Notably, HEEP promoted the expression of vascular endothelial growth factor (intact vs ovariectomized females) and decreased the expression of Caspase-8 and Bcl-2 (intact female vs male or ovariectomized female). Additionally, HEEP enhanced fibroblast proliferation and migration into a wounded area in vitro, confirming its healing effect. Finally, no sign of subacute toxicity or cytotoxicity of HEEP was observed. CONCLUSION: In gastric ulcers, HEEP-induced healing (modulated by female sex hormones; in males, mediated by prostaglandin) involves extracellular matrix remodeling, with gastric mucosa cell proliferation and migration.


Subject(s)
Eugenia/chemistry , Plant Extracts/pharmacology , Re-Epithelialization/drug effects , Stomach Ulcer/drug therapy , Acetic Acid/toxicity , Animals , Disease Models, Animal , Drug Evaluation, Preclinical , Female , Gastric Mucosa/drug effects , Gastric Mucosa/pathology , Humans , Male , Plant Extracts/therapeutic use , Plant Leaves/chemistry , Rats , Rats, Wistar , Sex Factors , Stomach Ulcer/chemically induced , Stomach Ulcer/pathology , Toxicity Tests, Subacute , Treatment Outcome
7.
J Ethnopharmacol ; 209: 294-304, 2017 Sep 14.
Article in English | MEDLINE | ID: mdl-28807848

ABSTRACT

ETHOPHARMACOLOGICAL RELEVANCE: The Persea major (Meisn.) L.E. Kopp (Lauraceae) (botanical synonym: Persea pyrifolia (D. Don) Spreng, Persea pyrifolia Nees and Mart., Persea cordata var. major (Meisn.) Mez and Persea willdenovii Kosterm) is a medicinal plant native in the south of Brazil, where is popularly known as Pau de Andrade, Maçaranduba or Abacate-do-Mato. Its barks are commonly used to prepare an infusion which is administered orally or topically to treat ulcers and wounds, respectively. Thus, this study has been undertaken to contribute to the validation of the popular use of P. major to treat of ulcerative disorders from gastrointestinal system, using different experimental models in rodents. MATERIAL AND METHODS: Firstly, ultra-performance liquid chromatography coupled to a mass spectrophotometer has been performed. Next, the potential gastroprotective of hydroalcoholic extract of P. major barks (HEPM) (30-300mg/kg) has been evaluated in ulcer models acute as: ethanol, ethanol/HCl and indomethacin-induced ulcer. The extract (300mg/kg) has been also tested in acetic acid-induced chronic ulcer model. Histological, toxicological, histochemical, oxidative stress and gastric secretion parameters were analyzed. RESULTS: The main compounds found in HEPM were polyphenols as condensed tannins, flavonoids heterosides derivatives from quercetin and kaempferol. HEPM (300mg/kg, p.o) prevented gastric lesions induced by ethanol or indomethacin in rats by 58.98% and 97.48%, respectively, compared to vehicle group (148.00±14.83mm2 and 12.07±1.61mm2, respectively). In acetic acid-induced chronic ulcer model the HEPM (300mg/kg, p.o) reduced the ulcer are by 40.58%, compared to vehicle group (127.90±12.04mm2). The healing effect was confirmed histologically, by an increase in mucin content and by the reduction in oxidative and inflammatory parameters at the ulcer site. Neither significant effect on gastric acid secretion nor toxicological effects and cytotoxicity were provoked by administration of HEPM. CONCLUSIONS: The results allows to conclude that HEPM exerts gastroprotective and gastric cicatrizing effects favoring on protective defenses, but not possess antisecretory effect in contrast to the current antiulcer therapy, besides the extract present good tolerability and absence of cytotoxicity. Moreover, the results presented here contribute to the validation to the popular use of the P. major in the treatment of gastric ulcer.


Subject(s)
Anti-Ulcer Agents/pharmacology , Persea/chemistry , Plant Extracts/pharmacology , Stomach Ulcer/drug therapy , Animals , Anti-Ulcer Agents/chemistry , Male , Phytochemicals , Phytotherapy , Plant Extracts/chemistry , Plants, Medicinal , Protective Factors , Rats
8.
J Pharm Pharmacol ; 69(11): 1615-1624, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28744880

ABSTRACT

OBJECTIVES: Some species of the genus Mimosa showed promising results in previous investigations, which include diuretic effect; however, no chemical analyses or animal model has been conducted so far to evaluate the biological properties of M. bimucronata. METHODS: Male Wistar rats received the oral treatment with vehicle; hydrochlorothiazide; methanolic extract from M. bimucronata (MEMB), dichloromethane (DCM) and ethyl acetate (EA) fractions or methyl gallate (MG). The cumulative urine volume, electrolytes excretion, pH and osmolality were determined at the end of the experiment. KEY FINDINGS: The chemical studies demonstrated that the phenolic compounds are the majorities in the plant, with the MG being the main substance identified. We showed that MEMB and EA fraction, but not DCM, exhibited diuretic and saluretic effects. Similarly, the MG also revealed diuretic, natriuretic and kaliuretic properties to both normotensive and spontaneously hypertensive rats. Atropine, a muscarinic receptor antagonist, fully prevented MG-induced diuresis and saluresis. In addition, MG did not alter the viability of A7r5 and L929 cell lines and neither stimulated nitric oxide generation. CONCLUSIONS: These findings suggest that M. bimucronata extracts and its majority compound MG present diuretic, natriuretic and kaliuretic properties, which was dependent on the activation of muscarinic acetylcholine receptor.


Subject(s)
Diuretics/pharmacology , Mimosa/chemistry , Natriuretic Agents/pharmacology , Plant Extracts/pharmacology , Administration, Oral , Animals , Atropine/pharmacology , Cell Line , Disease Models, Animal , Diuretics/isolation & purification , Gallic Acid/analogs & derivatives , Gallic Acid/isolation & purification , Gallic Acid/pharmacology , Hydrochlorothiazide/pharmacology , Hypertension , Male , Mice , Natriuretic Agents/isolation & purification , Plant Extracts/chemistry , Plant Leaves , Rats , Rats, Inbred SHR , Rats, Wistar , Receptors, Muscarinic/metabolism
9.
Chem Biol Interact ; 268: 103-110, 2017 Apr 25.
Article in English | MEDLINE | ID: mdl-28284659

ABSTRACT

Active constituents from natural origin have long been used for the treatment of patients suffering from cardiovascular and renal diseases. This study therefore aimed to investigate the diuretic and natriuretic properties of nothofagin, a dihydrochalcone isolated from Leandra dasytricha (A. Gray) Cogn. leaves in normotensive and hypertensive rats. Male Wistar normotensive rats were orally treated with vehicle (1 ml/kg); hydrochlorothiazide (HCTZ; 25 mg/kg); ethyl acetate fraction from L. dasytricha (EALD; 3-30 mg/kg) and nothofagin (NOT; 0.3-3 mg/kg). Spontaneously hypertensive rats (SHR) received NOT (1 mg/kg), HCTZ (25 mg/kg) or vehicle. The cumulative diuretic index, urinary electrolytes excretion (Na+ and K+), pH, density and conductivity were measured at the end of the experiment (after 8 h). A7r5 and L929 cell lines were used to measure cell viability after exposure to NOT. Nitric oxide generation was quantified in A7r5 cell supernatant, and DPPH assay was used for evaluating the antioxidant properties of NOT. The urinary volume of normotensive rats were increased after the treatment with EALD, without any changes in Na+ or K+ excretion. NOT was able to induce diuresis and natriuresis, but not kaliuresis, in both normotensive and hypertensive rats. The reduction in prostanoids generation through cyclooxygenase inhibition, as well as the muscarinic receptor antagonism, fully avoided NOT-induced increases in diuretic index. NOT, which did not interfere with L929 or A7r5 cell viability, was able to stimulate nitric oxide generation in A7r5 cell, besides showing an antioxidant effect in scavenging the free-radical DPPH. Taken together, our study shows, for the first time, the diuretic, natriuretic and potassium-sparing effect of nothofagin in rats, which was associated with prostanoids generation, muscarinic receptor activation and antioxidant properties.


Subject(s)
Antioxidants/therapeutic use , Chalcones/therapeutic use , Diuretics, Potassium Sparing/therapeutic use , Hypertension/drug therapy , Melastomataceae/chemistry , Natriuretic Agents/therapeutic use , Animals , Antioxidants/isolation & purification , Antioxidants/pharmacology , Cell Line , Chalcones/isolation & purification , Chalcones/pharmacology , Diuretics, Potassium Sparing/isolation & purification , Diuretics, Potassium Sparing/pharmacology , Hydrochlorothiazide/pharmacology , Hydrochlorothiazide/therapeutic use , Hypertension/metabolism , Hypokalemia/prevention & control , Male , Mice , Natriuretic Agents/isolation & purification , Natriuretic Agents/pharmacology , Nitric Oxide/metabolism , Nitrites/metabolism , Potassium/urine , Prostaglandins/biosynthesis , Rats, Wistar , Receptors, Muscarinic/metabolism
10.
J Ethnopharmacol ; 175: 75-85, 2015 Dec 04.
Article in English | MEDLINE | ID: mdl-26364940

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Maytenus robusta Reissek (Celastraceae) is traditionally used in Brazilian folk medicine to treat gastric ulcer, as a substitute for M. ilicifolia, which is almost extinct. The gastroprotective properties of M. robusta were demonstrated previously using only preventive approaches, such as acute gastric ulcer models. However, the healing effect of M. robusta in gastric ulcers remains unclear. AIM OF THE STUDY: The current study was carried out to investigate the healing effectiveness of M. robusta hydroalcoholic extract (HEMR) from aerial parts in the acetic acid-induced chronic ulcer model and to determine its effect on cell proliferation, scavenging free radicals, and inflammatory and oxidative damage. MATERIAL AND METHODS: To evaluate the healing properties of HEMR in vivo, chronic gastric ulcer was induced in rats by 80% acid acetic. Next, different groups of animals (n=6) were treated orally with vehicle (water plus 1% tween, 1 ml/kg), omeprazole (20mg/kg), or HEMR (1-10mg/kg), twice daily for 7 days. At the end of the treatment, the total ulcer area (mm(2)) was measured and a sample of gastric tissue was taken for histological and histochemical analysis. Evaluation of GSH and LOOH levels, GST, SOD, CAT and MPO activity was also performed at the site of the lesion. In parallel, radical scavenging activity, cytoprotective effect, and cell proliferation activity in fibroblasts (L929 cells) were determined by in vitro trials. The antisecretory properties were evaluated using the pylorus ligature model in rats, and the anti-Helicobacter pylori activity was determined in vitro. Acute toxicity was evaluated by relative organ weight and biochemical parameters in serum. The prokinetic properties were also evaluated in mice. RESULTS: Oral administration of HEMR (10mg/kg) reduced the gastric ulcer area by 53%, compared to the vehicle group (120.0 ± 8.3mm(2)), the regeneration of gastric mucosa was evidenced in histological analysis. Moreover, HEMR treatment increased gastric mucin content and reduced oxidative stress and inflammatory parameters at the site of the ulcer. In vitro, HEMR (1-1000 µg/ml) was able to scavenge free radical DPPH and promote cytoprotection against H2O2 in fibroblasts at 0.1-100 µg/ml. Moreover, HEMR healing properties also were confirmed by enhancement of proliferation and coverage of scratched wounds in fibroblast monolayer. However, HEMR (10mg/kg) by the intraduodenal route did not promote changes in volume, pH, total acidity or pepsin activity in the pylorus ligature model, and HEMR up to 2000 µg/ml also did not present considerable activity against H. pylori. In relation to gastrointestinal motility, HEMR (10mg/kg, p.o) did not provoke alterations. It is also important to mention that oral administration of HEMR did not produce any sign of acute toxicity in animals. CONCLUSIONS: The data here obtained show that M. robusta has evident ulcer healing potential, mainly through the strengthening of protective factors of gastric mucosa, such as mucus layer, antioxidant defenses and cell proliferation. Taking into account the advantages of cultivation and harvesting of M. robusta compared to M. ilicifolia, and the evidence presented here, it is plausible to conclude that hydroalcoholic extract obtained from aerial parts of M. robusta is an interesting source for the development of a phytotherapeutic formulation to treat gastric ulcer.


Subject(s)
Anti-Ulcer Agents/therapeutic use , Maytenus , Plant Extracts/therapeutic use , Stomach Ulcer/drug therapy , Acetic Acid , Animals , Anti-Ulcer Agents/pharmacology , Brazil , Catalase/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Female , Fibroblasts/drug effects , Gastric Mucosa/drug effects , Gastric Mucosa/metabolism , Gastric Mucosa/pathology , Glutathione/metabolism , Glutathione Transferase/metabolism , Helicobacter pylori/drug effects , Medicine, Traditional , Mice , Peroxidase/metabolism , Phytotherapy , Plant Components, Aerial , Plant Extracts/pharmacology , Rats, Wistar , Stomach Ulcer/chemically induced , Stomach Ulcer/pathology , Superoxide Dismutase/metabolism
11.
Pharmacol Biochem Behav ; 136: 55-63, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26196245

ABSTRACT

Olfactory bulbectomy (OB) is an animal model of depression that can mimic symptoms that are characteristic of depressive patients, such as behavioral, neurochemical and neuromorphological changes. Quercetin decreased the immobility time in the forced swimming test and tail suspension test. With the open field test, quercetin did not alter the locomotor activity of mice and in the splash test, quercetin increased the time spent grooming. The repeated treatment with quercetin (25mg/kg, for 14days) reversed the behavioral hyperactivity induced by OB in the open field test and was able to prevent depressant-like effects in the forced swimming test and tail suspension test. Regarding oxidative stress, OB reduced the levels of glutathione and increase the activity of superoxide dismutase and lipid hydroperoxide content (LOOH) in the hippocampus. Only the increase in LOOH levels was reversed by treatment with quercetin. In a further series of experiments with non-bulbectomized mice, the antidepressant effect of quercetin in the tail suspension test was reversed by the pretreatment of mice with NMDA, l-arginine or sildenafil. The administration of methylene blue and 7-nitroindazole, in combination with an underactive dose of quercetin (5mg/kg, p.o.), decreased the immobility time in the tail suspension test compared with the use of drug alone. There was no significant change in locomotor activity in the open field test. Our results suggest that the antidepressant effect of quercetin is dependent on the inhibition of the NMDA receptors and/or synthesis of nitric oxide. In addition, considering the reduction of LOOH levels on the hippocampus, we verify that the antioxidant effects of quercetin also contribute to its antidepressive potential. These data contribute to the understanding of the mechanisms involved in the antidepressant effect of quercetin and reinforce the involvement of the NMDA receptors and the nitric oxide on the pathophysiology of depression.


Subject(s)
Antioxidants/metabolism , N-Methylaspartate/pharmacology , Olfactory Bulb/surgery , Oxidative Stress/drug effects , Quercetin/pharmacology , Signal Transduction/drug effects , Animals , Antidepressive Agents/pharmacology , Antioxidants/pharmacology , Arginine/pharmacology , Behavior, Animal/drug effects , Disease Models, Animal , Drug Synergism , Fluoxetine/pharmacology , Hippocampus/drug effects , Hippocampus/metabolism , Indazoles/pharmacology , Male , Methylene Blue/pharmacology , Mice , Quercetin/antagonists & inhibitors , Sildenafil Citrate/pharmacology
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