Rosa Ribeiro-do-valle | Universidade Federal de Santa Catarina - UFSC (Federal University of Santa Catarina) (original) (raw)

Papers by Rosa Ribeiro-do-valle

Research paper thumbnail of Antinociceptive effect of proanthocyanidins from <I>Croton celtidifolius</I> bark

Journal of Pharmacy and Pharmacology, 2005

The chemical composition of the chromatography 63 subfraction (63SF) from the ethyl acetate solub... more The chemical composition of the chromatography 63 subfraction (63SF) from the ethyl acetate soluble fraction of the crude extract of Croton celtidifolius bark presented a high content of total proanthocyanidins (75.0¯AE 2.3%). HPLC analysis of 63SF revealed a dimeric profile (e.g. catechin-(4?8)-catechin and gallocatechin-(4?8)-catechin) and polymeric proanthocyanidins. In pharmacological investigations, 63SF administered intraperitoneally exhibited dose-dependent antinociceptive activity against several chemical stimuli, including the intraperitoneal injection of acetic acid (ID50 (the dose of 63SF which was able to reduce the nociceptive response by 50% relative to the control value) ¼ 0.9 (0.5-1.6)) and the intraplantar injection of capsaicin (ID50 ¼ 13.0 (10.0-17.0)), glutamate (ID50 ¼ 4.0 (2.0-7.0)) and formalin (ID50 first phase ¼ 36.0 (24.0-53.0) and late phase ¼ 11.0 (8.0-14.0)). 63SF administered orally exhibited an antinociceptive effect in the formalin test (ID50 first phase ¼ 125.0 (89.0-177.0) and late phase ¼ 65.0 (33.0-95.0)). In the same test, 63SF was effective when given soon after the first phase, as well as exhibiting therapeutic activity. Furthermore, 63SF was effective in models of thermal nociception including tail-flick and hot-plate tests. When the mice were treated in the neonatal period with capsaicin, the antinociceptive effect of 63SF in the first phase of the formalin test was abolished, but pretreatment with naltrexone did not change the antinociceptive effect of 63SF. Together, these results provide evidence that 63SF exerted a pronounced systemic antinociception against chemical (acetic acid, formalin, glutamate and capsaicin tests) and thermal (hot-plate and tail-flick tests) nociceptive models of pain in mice at a dose that did not interfere with the locomotor activity. The mechanism by which this sub-fraction produced antinociception remains unclear, but it is unlikely to involve the activation of the opioid system. However, unmyelinated C-fibres sensitive to treatment with capsaicin are likely to participate in antinociception caused by 63SF.

Research paper thumbnail of The important discrepancy between the apparent affinity observed in Ca2+ mobilization studies and the Kd measured in binding studies is a consequence of the quantal process by which inositol 1,4,5-trisphosphate releases Ca2+ from bovine adrenal cortex microsomes

Cell Calcium, 1994

lnositol 1,4,&trisphosphate (InsPs) is a second messenger responsible for Ca*' release from a non... more lnositol 1,4,&trisphosphate (InsPs) is a second messenger responsible for Ca*' release from a non-mitochondrial intracellular store. An impoftant discrepancy has been observed between the affinity measured in binding studies (Kd) and the apparent afftnity obtained in Ca*+ mobilization studfes (EQo). It has been proposed that this dfscrepancy could be due to different experimental conditions used for Ca*+ mobilization studies and for InsP3 binding studies. With the fluorescent indicator Fura-2, we studied InsPs-induced Ca*+ release activp at 7-C and at 37*C, in bovine adrenal cortex microsomes. Under both conditions, the Ca ' releasing effect of lnsPs (1 m was completed within about 2 s, as a result of the quanta1 process of InsPs receptor action. The apparent afftnity (EC50) observed for InsPs-induced Ca*' rdease at 7% and at 37% were 0.64 f 0.2 w and 0.g f 0.2 jNl respectively. lnsP3 degradation studies, at 37X, indicated that less than 1096 of [SH]-InsPa was degraded within the first 10 s of incubation. InsP association rates were evaluated, at low temperature, with increasing concentrations of E HI&&%. These kinetic studies revealed a direct relationship between the initial rate of association (Vi) and InsPs concentration. From this relationship, we evaluated that the concentration of InsPs needed to occupy half of the binding sites within the first second of incubation was 271 nM. We conclude that the discrepancy between Kd and EC50 is related to a kinetic con&mint dictated by the quanta1 process by which InsPa releases Ca*+.

Research paper thumbnail of Activation of endothelial nitric oxide synthase by proanthocyanidin-rich fraction from Croton celtidifolius (Euphorbiaceae): involvement of extracellular calcium influx in rat thoracic aorta

Journal of pharmacological sciences, 2008

The present study investigates the mechanisms related to the endogenous nitric oxide synthase (eN... more The present study investigates the mechanisms related to the endogenous nitric oxide synthase (eNOS) activation in the relaxant effects of a proanthocyanidin-rich fraction (PRF), obtained from Croton celtidifolius Baill barks, in rat thoracic aorta rings with endothelium. In vessels pre-contracted with phenylephrine (Phe), PRF (0.1 - 100 microg/mL) induced a concentration-dependent relaxation. This effect was significantly reduced by endothelium denudation, by N(omega)-nitro-L-arginine, and by 1H[1,2,3]oxadiazolo[4,3-alpha]quinoxalin. However, the vasorelaxant effect was not altered by indomethacin, atropine, tetraethylammonium, and charybdotoxin plus apamin. In thoracic aorta rings pre-contracted with phorbol-12,13-dibuyrate, PRF also induced a concentration-dependent relaxation. The PRF-induced relaxation disappeared in the absence of extracellular calcium in the medium and decreased significantly in the presence of lanthanum. A sulfhydryl alkylating agent, N-ethylmaleimide, and a...

Research paper thumbnail of Effects of valeryl salicylate, a COX-1 inhibitor, on models of acute inflammation in mice

Pharmacological research : the official journal of the Italian Pharmacological Society, 2003

The effect of valeryl salicylate (VS), an inhibitor of cyclooxygenase-1 (COX-1), was evaluated in... more The effect of valeryl salicylate (VS), an inhibitor of cyclooxygenase-1 (COX-1), was evaluated in arachidonic acid or croton oil-induced ear oedema and carrageenan-induced paw oedema in mice. Ear oedema was induced by topical administration of arachidonic acid (2mg per ear; 20 microliters) or croton oil (1mg per ear; 20 microliters) to the inner surface of the left ear and the change in the ear's thickness was measured with a precision micrometer (Fisher, USA). VS significantly inhibited the arachidonic acid ear oedema after lh at doses of 1.5-45 micrograms per ear; however, only at the dose of 45 micrograms per ear was it able to significantly reduce the croton oil-induced oedema at 6h. Paw oedema was induced by the injection of 25 microliters of 1% carrageenan into the plantar aponeurosis of the right hind paw. The oedema was evaluated at 0.5, 1, 2, 4, 24, 48 and 72h. Previously in our experiments, we observed two peaks in paw oedema formation: one at 2h, in the early phase (0...

Research paper thumbnail of Antiangiogenic and antitumoral properties of a polysaccharide isolated from the seaweed Sargassum stenophyllum

The potential antiangiogenic and antitumoral properties of SargA, a polysaccharide extracted from... more The potential antiangiogenic and antitumoral properties of SargA, a polysaccharide extracted from the brown marine alga Sargassum stenophyllum, were studied in assays carried out in chick embryos and mice. Gelfoam plugs containing SargA (2-1500 lg/ plug) implanted in vivo into fertilized 6-day-old chicken eggs induced dose-related antiangiogenic activity in the chorioallantoic membrane (CAM). By day 8, the highest dose of SargA alone decreased the vessel number in the CAM by 64%, but coadminis-tered with hydrocortisone (156 lg/plug, which alone caused 30% inhibition) failed to potentiate its antiangiogenic effect. Combined with basic fibroblast growth factor (50 ng/plug), SargA (1500 lg/plug) abolished angiogenesis stimulated by this factor in both chick embryo CAM and in subcutaneous (s.c.) Gelfoam plugs implanted in the dorsal skin of Swiss mice (measured as plug hemoglobin content). Repeated s.c. injections of SargA (1.5 or 150 lg per animal per day for 3 days) close to B16F10 melanoma cell tumors in the dorsal skin of mice markedly decreased tumor growth in a dose-related fashion (by 40% and 80% at 2 weeks after the first injection, respectively), without evident signs of toxicity. SargA caused graded inhibitions of migration and viability of cultured B16F10 cells and also displayed antithrombotic activity in human plasma (5 mg/ml increased thrombin time 2.5-fold relative to saline). Thus, SargA exhibits pronounced antiangiogenic as well as antitumoral properties. Although the latter action of SargA might be related to the inhibition of angiogenesis, the polysaccharide also exerts cytotoxic effects on tumor cells. Because of its chemical characteristics and polyanionic constituents, we postulate that the polysaccharide SargA might modulate the activity of heparin-binding angiogenic growth factors.

Research paper thumbnail of Manipulation of chemical composition and architecture of non-biodegradable poly(ethylene terephthalate)/chitosan fibrous scaffolds and their effects on L929 cell behavior

Materials science & engineering. C, Materials for biological applications, 2013

Microporous, non-woven fibrous scaffolds made of poly(ethylene terephthalate) and chitosan were p... more Microporous, non-woven fibrous scaffolds made of poly(ethylene terephthalate) and chitosan were produced by electrospinning. Fiber morphology, diameter, pore size, and wettability were manipulated by varying the chemical composition of the electrospinning solution, i.e. chitosan concentration and molecular weight, and by post-electrospinning treatment with glutaraldehyde. In vitro studies were conducted using a fibroblast cell line toward a comprehensive understanding of how scaffolds characteristics can modulate the cell behavior, i.e. viability, adhesion, proliferation, extracellular matrix secretion, and three-dimensional colonization. Substantial differences were found as a result of scaffold morphological changes. Higher levels of adhesion, spreading, and superficial proliferation were achieved for scaffolds with smaller fiber and pore diameters while cell penetration and internal colonization were enhanced for scaffolds with larger pores. Additionally, the available area for c...

Research paper thumbnail of High performance liquid chromatography determination of cucurbitacins in the roots of Wilbrandia ebracteata Cogn

Revista Brasileira de Farmacognosia, 2009

A sensitive and selective method is presented for the determination of Zn-Bacitracin in adulterat... more A sensitive and selective method is presented for the determination of Zn-Bacitracin in adulterated animal feed by reversed-phase ion-pair high-performance liquid chromatography and post-column derivatization with o-phthalaldehyde prior 21 to fluorescence detection. The calibration function was estimated to be between 8.0 and 65.0 mg l of Zn-BC. The detection 21 and quantification limits of the chromatographic method were 2.5 and 7.5 mg l , respectively. Using the extraction procedure of Zn-Bacitracin from the feedstuff that we recently proposed and applying this new chromatographic method, it 21 was possible to detect this antibiotic at levels below 5 mg kg in different kinds of feedstuffs with a standard deviation less than 6.0%.

Research paper thumbnail of Foreign body reaction associated with PET and PET/chitosan electrospun nanofibrous abdominal meshes

PloS one, 2014

Electrospun materials have been widely explored for biomedical applications because of their adva... more Electrospun materials have been widely explored for biomedical applications because of their advantageous characteristics, i.e., tridimensional nanofibrous structure with high surface-to-volume ratio, high porosity, and pore interconnectivity. Furthermore, considering the similarities between the nanofiber networks and the extracellular matrix (ECM), as well as the accepted role of changes in ECM for hernia repair, electrospun polymer fiber assemblies have emerged as potential materials for incisional hernia repair. In this work, we describe the application of electrospun non-absorbable mats based on poly(ethylene terephthalate) (PET) in the repair of abdominal defects, comparing the performance of these meshes with that of a commercial polypropylene mesh and a multifilament PET mesh. PET and PET/chitosan electrospun meshes revealed good performance during incisional hernia surgery, post-operative period, and no evidence of intestinal adhesion was found. The electrospun meshes were ...

Research paper thumbnail of Diphenyl diselenide protects endothelial cells against oxidized low density lipoprotein-induced injury: Involvement of mitochondrial function

Biochimie, 2014

Elevated levels of oxidized low density lipoprotein (oxLDL) are considered to be one of the major... more Elevated levels of oxidized low density lipoprotein (oxLDL) are considered to be one of the major risk factors for atherosclerosis and cardiovascular morbidity. The early stages of atherosclerosis are initiated by the accumulation of oxLDL and the induction of toxic effects on endothelial cells, resulting in endothelial dysfunction. The aim of this study was to investigate how diphenyl diselenide (DD), an organoselenium compound, protect vascular endothelial cells against the toxic effects of oxLDL in vitro. Our data showed that the treatment of bovine endothelial aortic cells (BAEC) with DD (0.1-1 μM) for 24 h protected from oxLDL-induced reactive species (RS) production and reduced glutathione (GSH) depletion. Moreover, DD (1 μM) per se improved the maximal mitochondrial respiratory capacity and prevented oxLDL-induced mitochondrial damage. In addition, DD could prevent apoptosis induced by oxLDL in BAEC. Results from this study may provide insight into a possible molecular mechan...

Research paper thumbnail of Anti-inflammatory and antioxidant effects of Croton celtidifolius bark

Phytomedicine, 2003

19SF, 35SF and 63SF that contained a mixture of proanthocyanidins and were derived from the EAF f... more 19SF, 35SF and 63SF that contained a mixture of proanthocyanidins and were derived from the EAF fraction. The CE, AqF, EAF, BuF, catechin and sub-fractions 35SF and 63SF reduced paw edema induced by carrageenan. The CE, fractions, sub-fractions and isolated compounds showed antioxidant properties in vitro, all were able to scavenge superoxide anions at a concentration of 100 µg·ml -1 . The EAF, catechin and gallocatechin were most effective in the deoxyribose assay, IC50 0.69 (0.44-1.06), 0.20 (0.11-0.39), 0.55 (0.28-1.08) µg·ml -1 respectively. The CE and other fractions and sub-fractions inhibited deoxyribose degradation up to 1 µg·ml -1 . In the hydrophobic system only AqF did not show lipid peroxidation inhibition. The CE, other fractions, sub-fractions and isolated compounds inhibited lipidid peroxidation only at a concentration of 100 µg·ml -1 . In summary, this study demonstrates that Croton celtidifolius bark has significant anti-inflammatory and antioxidant activity.

Research paper thumbnail of Antinociceptive effect of proanthocyanidins from Croton celtidifolius bark

Journal of Pharmacy and Pharmacology, 2005

The chemical composition of the chromatography 63 subfraction (63SF) from the ethyl acetate solub... more The chemical composition of the chromatography 63 subfraction (63SF) from the ethyl acetate soluble fraction of the crude extract of Croton celtidifolius bark presented a high content of total proanthocyanidins (75.0¯AE 2.3%). HPLC analysis of 63SF revealed a dimeric profile (e.g. catechin-(4?8)-catechin and gallocatechin-(4?8)-catechin) and polymeric proanthocyanidins. In pharmacological investigations, 63SF administered intraperitoneally exhibited dose-dependent antinociceptive activity against several chemical stimuli, including the intraperitoneal injection of acetic acid (ID50 (the dose of 63SF which was able to reduce the nociceptive response by 50% relative to the control value) ¼ 0.9 (0.5-1.6)) and the intraplantar injection of capsaicin (ID50 ¼ 13.0 (10.0-17.0)), glutamate (ID50 ¼ 4.0 (2.0-7.0)) and formalin (ID50 first phase ¼ 36.0 (24.0-53.0) and late phase ¼ 11.0 (8.0-14.0)). 63SF administered orally exhibited an antinociceptive effect in the formalin test (ID50 first phase ¼ 125.0 (89.0-177.0) and late phase ¼ 65.0 (33.0-95.0)). In the same test, 63SF was effective when given soon after the first phase, as well as exhibiting therapeutic activity. Furthermore, 63SF was effective in models of thermal nociception including tail-flick and hot-plate tests. When the mice were treated in the neonatal period with capsaicin, the antinociceptive effect of 63SF in the first phase of the formalin test was abolished, but pretreatment with naltrexone did not change the antinociceptive effect of 63SF. Together, these results provide evidence that 63SF exerted a pronounced systemic antinociception against chemical (acetic acid, formalin, glutamate and capsaicin tests) and thermal (hot-plate and tail-flick tests) nociceptive models of pain in mice at a dose that did not interfere with the locomotor activity. The mechanism by which this sub-fraction produced antinociception remains unclear, but it is unlikely to involve the activation of the opioid system. However, unmyelinated C-fibres sensitive to treatment with capsaicin are likely to participate in antinociception caused by 63SF.

Research paper thumbnail of An ethyl acetate fraction obtained from a Southern Brazilian red wine relaxes rat mesenteric arterial bed through hyperpolarization and NO-cGMP pathway

Vascular Pharmacology, 2005

A number of studies suggest that moderate consumption of red wine may be more effective than othe... more A number of studies suggest that moderate consumption of red wine may be more effective than other alcoholic beverages in decreasing the risk of coronary heart disease (CAD). In this study, we investigated the effect of a crude extract (CE), as well as an ethyl acetate fraction (EAF) obtained from a Brazilian red wine in the mesenteric arterial bed (MAB) from rats.

Research paper thumbnail of Antioxidant capacity of phenolic and related compounds: correlation among electrochemical, visible spectroscopy methods and structure–antioxidant activity

Redox Report, 2001

We investigated the antioxidant activity of phenylpropionic acids--caffeic (CAF), ferulic (FER), ... more We investigated the antioxidant activity of phenylpropionic acids--caffeic (CAF), ferulic (FER), para-coumaric (COU) and cinnamic (CIN)--and phenolic acids and related compounds--gallic (GAL), methyl gallate (meGAL), vanillic (VAN) and gentisic (GEN)--using visible spectroscopy, inhibition of nitroblue tetrazolium (NBT) reduction, and electrochemical methods including cyclic voltammetry and potentiometry. In the spectroscopic assays, only CAF, GAL and meGAL were able to inhibit NBT reduction. The same compounds showed the lowest oxidation potentials (Epa) and the highest redox potentials deltaE) in the cyclic voltammetric and potentiometric studies, respectively. In addition, it was observed that the greater the number of hydroxyls linked to the aromatic ring, the greater was the antioxidant activity of the analysed compounds. The correlations of Spermann--used to compare the methods between themselves and the methods with the relationship structure-antioxidant activity--were r = -0.9762 for the cyclic voltammetric-potentiometric methods. r = 0.8333 for the inhibition of NBT reduction-potentiometric methods and r = -0.8095 for the inhibition of NBT reduction-cyclic voltammetric methods. The correlations for cyclic voltammetric, potentiometric and inhibition of NBT reduction methods-number of hydroxyls linked to the aromatic ring were r = -0.9636, 0.9636 and 0.9142, respectively. These findings indicate that the electrochemical methods together with spectroscopic studies are a good tool to evaluate the antioxidant activity of substances.

Research paper thumbnail of Anti-Inflammatory and Analgesic Effects of Cucurbitacins from Wilbrandia ebracteata

Planta Medica, 1997

The anti-inflammatory and antinociceptive actions of the CH2Cl2 extract and semipurified fraction... more The anti-inflammatory and antinociceptive actions of the CH2Cl2 extract and semipurified fraction (F-III) from roots of Wilbrandia ebracteata Cogn. have been investigated in rats and mice. The CH2Cl2 extract (1-10 mg/kg, i.p.; ID50 5 mg/kg) and (3-30 mg/kg, p.o.; ID50 15 mg/kg) inhibited, in a dose-related manner, carrageenan-induced paw edema in rats. The subfraction (F-III) from CH2Cl2 extract and compounds isolated as cucurbitacin B and E also inhibited carrageenan-induced edema. The CH2Cl2 extract and F-III also exhibited significant analgesic action in acetic acid-induced pain in mice. In the formalin test, the CH2Cl2 extract (0.3-10 mg/kg, i.p.) and (3-30 mg/kg, p.o.) caused inhibition of the neurogenic (first phase) and inflammatory phase (second phase) of formalin-induced pain. However, the CH2Cl2 extract was more effective in relation to the second phase than in inhibition of the formalin-induced edema. These findings suggest that CH2Cl2 extract has potent anti-inflammatory and analgesic action and that F-III and cucurbitacin B and E may account for these actions.

Research paper thumbnail of Effect of quercetin on tachykinin-induced plasma extravasation in rat urinary bladder

Phytotherapy Research, 2001

The effect of quercetin on substance P-induced plasma extravasation in rat urinary bladder and it... more The effect of quercetin on substance P-induced plasma extravasation in rat urinary bladder and its modulation by endogenous peptidases in conscious rats was studied. Plasma protein extravasation (PE) was assayed by measurement of extravasated Evans blue dye (microg/g dry tissue). Intravenous injection of substance P (SP, 10 nmol/kg) significantly increased PE in the urinary bladder. PE evoked by SP was increased significantly by quercetin (20 mg/kg, p.o.) pretreatment in the urinary bladder (73.5 +/- 4.9 to 152.2 +/- 9.9). Pretreatment with captopril, an angiotensin-converting enzyme (ACE) inhibitor (10 nmol/kg, i.v.), or with phosphoramidon, a neutral endopeptidase (NEP) inhibitor (2.5 micromol/kg, i.v.) also potentiated the SP-induced PE in urinary bladder, 286.2 +/- 20.4 and 323.3 +/- 34.0, respectively. Quercetin did not show any effect on neurokinin-A (NKA, 10 nmol/kg, i.v.) -induced plasma extravasation. The present study demonstrates that quercetin potentiates the PE induced by substance P in the urinary bladder. These effects suggest that this flavonoid might cause inhibition of NEP and/or ACE.

Research paper thumbnail of Involvement of 5-HT receptors in the antinociceptive effect of

Pharmacology Biochemistry and Behavior, 2005

Uncaria tomentosa (Willd.) DC (Rubiaceae) is a vine that grows in the Amazon rainforest. Its bark... more Uncaria tomentosa (Willd.) DC (Rubiaceae) is a vine that grows in the Amazon rainforest. Its bark decoctions are used by Peruvian Indians to treat several diseases. Chemically, it consists mainly of oxindole alkaloids. An industrial fraction of U. tomentosa (UT fraction), containing 95% oxindole alkaloids, was used in this study in order to characterize its antinociceptive activity in chemical (acetic acid-induced abdominal writhing, formalin and capsaicin tests) and thermal (tail-flick and hot-plate tests) models of nociception in mice. UT fraction given by the i.p. route dose-dependently suppressed the behavioural response to the chemical stimuli in the models indicated and increased latencies in the thermal stimuli models. The antinociception caused by UT fraction in the formalin test was significantly attenuated by i.p. treatment of mice with ketanserin (5-HT2 receptor antagonist), but was not affected by naltrexone (opioid receptor antagonist), atropine (a nonselective muscarinic antagonist), l-arginine (precursor of nitric oxide), prazosin (a1-adrenoceptor antagonist), yohimbine (a2adrenoceptor antagonist), and reserpine (a monoamine depleter). Together, these results indicate that UT fraction produces dose-related antinociception in several models of chemical and thermal pain through mechanisms that involve an interaction with 5-HT2 receptors. D

Research paper thumbnail of Antinociceptive Effects of Peripheral Benzodiazepine Receptors

Pharmacology, 2004

Pretreatment of mice with Ro5-4864 or PK11195 inhibited the first-and second-phase responses in t... more Pretreatment of mice with Ro5-4864 or PK11195 inhibited the first-and second-phase responses in the formalin test and this effect was significantly reversed by aminoglutethimide, an inhibitor of pregnenolone synthesis, suggesting that the antinociceptive effect of the peripheral-type benzodiazepine receptor ligands is dependent on steroid formation. Doses of Ro5-4864 that did not produce an antinociceptive effect when injected by the intraperitoneal route presented an analgesic effect, if infected by the intracerebroventricular, intrathecal or intraplantar routes. PK11195 pretreatments with intrathecal, intracerebroventricular or intraplantar doses had no effect in the formalin test. These results suggest that the antinociceptive effect of Ro5-4864 reflects the influence of this ligand on steroid production not only in many nonneuronal peripheral tissues but also in the nervous system, while the antinociceptive action of PK11195 may be due to the stimulation of steroid synthesis only in nonnervous tissues.

Research paper thumbnail of Positive correlation between elevated plasma cholesterol levels and cognitive impairments in LDL receptor knockout mice: relevance of cortico-cerebral mitochondrial dysfunction and oxidative stress

Neuroscience, 2011

Convergent epidemiological, clinical, and experimental findings indicate that hypercholesterolemi... more Convergent epidemiological, clinical, and experimental findings indicate that hypercholesterolemia contributes to the onset of Alzheimer's disease (AD)-like dementia, but the exact underlying mechanisms remains unknown. In this study, we evaluated the cognitive performance of mice submitted to a model of hypercholesterolemia, as well as its relationship with mitochondrial dysfunction and oxidative stress, two key events involved in AD pathogenesis. Wildtype C57bl/6 or low density lipoprotein receptor (LDLr)-deficient mice were fed with either standard or cholesterol-enriched diet for a 4-week period and tested for spatial learning and memory in the object location task. LDLr ؊/؊ mice displayed spatial learning and memory impairments regardless of diet. Moreover, LDLr ؊/؊ mice fed cholesterol-enriched diet presented a significant decrease in the mitochondrial complexes I and II activities in the cerebral cortex, which were negatively correlated with respective blood cholesterol levels. Additionally, hypercholesterolemic LDLr ؊/؊ mice presented a significant decrease in glutathione levels, about 40% increase in the thiobarbituric acid-reactive substances levels, as well as an imbalance between the peroxide-removing-related enzymes glutathione peroxidase/glutathione reductase activities in the cerebral cortex. These findings indicate a significant relationship between hypercholesterolemia, cognitive impairment, and cortico-cerebral mitochondrial dysfunctional/oxidative stress. Because of the involvement of such alterations in AD patients, our data render this mouse model of hypercholesterolemia a useful approach to comprehend the molecular events mediating AD pathogenesis. . R.P.; M.F.; R.M.R.V.; A.L., and A.B. are productivity fellows from the CNPq. Scholarships to J.O. (CAPES) and V.G. (FAPESC) are also acknowledged. M.A.H. is a PNPD/CAPES posdoctoral grantee. The authors are grateful to Ms. Renate Schinke, an English professor, for checking the language of this manuscript.

Research paper thumbnail of Diphenyl Diselenide Prevents Cortico-cerebral Mitochondrial Dysfunction and Oxidative Stress Induced by Hypercholesterolemia in LDL Receptor Knockout Mice

Neurochemical Research

Recent studies have indicated a causal link between high dietary cholesterol intake and brain oxi... more Recent studies have indicated a causal link between high dietary cholesterol intake and brain oxidative stress. In particular, we have previously shown a positive correlation between elevated plasma cholesterol levels, cortico-cerebral oxidative stress and mitochondrial dysfunction in low density lipoprotein receptor knockout (LDLr(-/-)) mice, a mouse model of familial hypercholesterolemia. Here we show that the organoselenium compound diphenyl diselenide (PhSe)2 (1 mg/kg; o.g., once a day for 30 days) significantly blunted the cortico-cerebral oxidative stress and mitochondrial dysfunction induced by a hypercholesterolemic diet in LDLr(-/-) mice. (PhSe)2 effectively prevented the inhibition of complex I and II activities, significantly increased the reduced glutathione (GSH) content and reduced lipoperoxidation in the cerebral cortex of hypercholesterolemic LDLr(-/-) mice. Overall, (PhSe)2 may be a promising molecule to protect against hypercholesterolemia-induced effects on the ce...

Research paper thumbnail of Anti-inflammatory effects of a triterpenoid isolated from Wilbrandia ebracteata Cogn

Life Sciences, 2007

Wilbrandia ebracteata (WE), a Brazilian medicinal plant used in folk medicine for the treatment o... more Wilbrandia ebracteata (WE), a Brazilian medicinal plant used in folk medicine for the treatment of rheumatic diseases, displays antiinflammatory properties and constitutes a rich source of cucurbitacins and cucurbitacin-related compounds. The current study investigated the potential anti-inflammatory properties of Dihydrocucurbitacin B (DHCB), a cucurbitacin-derived compound isolated from roots of WE, in some in vivo and in vitro experimental models. Intraperitoneal treatment of mice with DHCB reduced both carrageenan-induced paw edema (0.3, 1 and 3 mg/kg caused inhibitions of 26, 44 and 56 % at 2 h after stimulation, respectively) and pleurisy (10 mg/kg inhibited leukocyte numbers and LTB 4 levels in the pleural fluid by 51 and 75% at 6 h after cavity challenge, respectively). In vitro, DHCB (up to 10 μg/mL) failed to modify LTB 4 production by human neutrophils or PGE 2 production by COS-7 cells transfected with COX-1, but PGE 2 production by COX-2 transfected COS-7 cells was markedly inhibited (by 72%). The levels of COX-1 or COX-2 proteins in IL-1α-stimulated NIH3T3 cells were unaffected by DHCB. The results corroborate the potential anti-inflammatory properties ascribed to W. ebracteata Cogn. in folk medicine and suggest that they might be attributed, at least in part, to the capacity of one of this plants main constituents, DHCB, to inhibit COX-2 activity (but not its expression) during inflammation.

Research paper thumbnail of Antinociceptive effect of proanthocyanidins from <I>Croton celtidifolius</I> bark

Journal of Pharmacy and Pharmacology, 2005

The chemical composition of the chromatography 63 subfraction (63SF) from the ethyl acetate solub... more The chemical composition of the chromatography 63 subfraction (63SF) from the ethyl acetate soluble fraction of the crude extract of Croton celtidifolius bark presented a high content of total proanthocyanidins (75.0¯AE 2.3%). HPLC analysis of 63SF revealed a dimeric profile (e.g. catechin-(4?8)-catechin and gallocatechin-(4?8)-catechin) and polymeric proanthocyanidins. In pharmacological investigations, 63SF administered intraperitoneally exhibited dose-dependent antinociceptive activity against several chemical stimuli, including the intraperitoneal injection of acetic acid (ID50 (the dose of 63SF which was able to reduce the nociceptive response by 50% relative to the control value) ¼ 0.9 (0.5-1.6)) and the intraplantar injection of capsaicin (ID50 ¼ 13.0 (10.0-17.0)), glutamate (ID50 ¼ 4.0 (2.0-7.0)) and formalin (ID50 first phase ¼ 36.0 (24.0-53.0) and late phase ¼ 11.0 (8.0-14.0)). 63SF administered orally exhibited an antinociceptive effect in the formalin test (ID50 first phase ¼ 125.0 (89.0-177.0) and late phase ¼ 65.0 (33.0-95.0)). In the same test, 63SF was effective when given soon after the first phase, as well as exhibiting therapeutic activity. Furthermore, 63SF was effective in models of thermal nociception including tail-flick and hot-plate tests. When the mice were treated in the neonatal period with capsaicin, the antinociceptive effect of 63SF in the first phase of the formalin test was abolished, but pretreatment with naltrexone did not change the antinociceptive effect of 63SF. Together, these results provide evidence that 63SF exerted a pronounced systemic antinociception against chemical (acetic acid, formalin, glutamate and capsaicin tests) and thermal (hot-plate and tail-flick tests) nociceptive models of pain in mice at a dose that did not interfere with the locomotor activity. The mechanism by which this sub-fraction produced antinociception remains unclear, but it is unlikely to involve the activation of the opioid system. However, unmyelinated C-fibres sensitive to treatment with capsaicin are likely to participate in antinociception caused by 63SF.

Research paper thumbnail of The important discrepancy between the apparent affinity observed in Ca2+ mobilization studies and the Kd measured in binding studies is a consequence of the quantal process by which inositol 1,4,5-trisphosphate releases Ca2+ from bovine adrenal cortex microsomes

Cell Calcium, 1994

lnositol 1,4,&trisphosphate (InsPs) is a second messenger responsible for Ca*' release from a non... more lnositol 1,4,&trisphosphate (InsPs) is a second messenger responsible for Ca*' release from a non-mitochondrial intracellular store. An impoftant discrepancy has been observed between the affinity measured in binding studies (Kd) and the apparent afftnity obtained in Ca*+ mobilization studfes (EQo). It has been proposed that this dfscrepancy could be due to different experimental conditions used for Ca*+ mobilization studies and for InsP3 binding studies. With the fluorescent indicator Fura-2, we studied InsPs-induced Ca*+ release activp at 7-C and at 37*C, in bovine adrenal cortex microsomes. Under both conditions, the Ca ' releasing effect of lnsPs (1 m was completed within about 2 s, as a result of the quanta1 process of InsPs receptor action. The apparent afftnity (EC50) observed for InsPs-induced Ca*' rdease at 7% and at 37% were 0.64 f 0.2 w and 0.g f 0.2 jNl respectively. lnsP3 degradation studies, at 37X, indicated that less than 1096 of [SH]-InsPa was degraded within the first 10 s of incubation. InsP association rates were evaluated, at low temperature, with increasing concentrations of E HI&&%. These kinetic studies revealed a direct relationship between the initial rate of association (Vi) and InsPs concentration. From this relationship, we evaluated that the concentration of InsPs needed to occupy half of the binding sites within the first second of incubation was 271 nM. We conclude that the discrepancy between Kd and EC50 is related to a kinetic con&mint dictated by the quanta1 process by which InsPa releases Ca*+.

Research paper thumbnail of Activation of endothelial nitric oxide synthase by proanthocyanidin-rich fraction from Croton celtidifolius (Euphorbiaceae): involvement of extracellular calcium influx in rat thoracic aorta

Journal of pharmacological sciences, 2008

The present study investigates the mechanisms related to the endogenous nitric oxide synthase (eN... more The present study investigates the mechanisms related to the endogenous nitric oxide synthase (eNOS) activation in the relaxant effects of a proanthocyanidin-rich fraction (PRF), obtained from Croton celtidifolius Baill barks, in rat thoracic aorta rings with endothelium. In vessels pre-contracted with phenylephrine (Phe), PRF (0.1 - 100 microg/mL) induced a concentration-dependent relaxation. This effect was significantly reduced by endothelium denudation, by N(omega)-nitro-L-arginine, and by 1H[1,2,3]oxadiazolo[4,3-alpha]quinoxalin. However, the vasorelaxant effect was not altered by indomethacin, atropine, tetraethylammonium, and charybdotoxin plus apamin. In thoracic aorta rings pre-contracted with phorbol-12,13-dibuyrate, PRF also induced a concentration-dependent relaxation. The PRF-induced relaxation disappeared in the absence of extracellular calcium in the medium and decreased significantly in the presence of lanthanum. A sulfhydryl alkylating agent, N-ethylmaleimide, and a...

Research paper thumbnail of Effects of valeryl salicylate, a COX-1 inhibitor, on models of acute inflammation in mice

Pharmacological research : the official journal of the Italian Pharmacological Society, 2003

The effect of valeryl salicylate (VS), an inhibitor of cyclooxygenase-1 (COX-1), was evaluated in... more The effect of valeryl salicylate (VS), an inhibitor of cyclooxygenase-1 (COX-1), was evaluated in arachidonic acid or croton oil-induced ear oedema and carrageenan-induced paw oedema in mice. Ear oedema was induced by topical administration of arachidonic acid (2mg per ear; 20 microliters) or croton oil (1mg per ear; 20 microliters) to the inner surface of the left ear and the change in the ear's thickness was measured with a precision micrometer (Fisher, USA). VS significantly inhibited the arachidonic acid ear oedema after lh at doses of 1.5-45 micrograms per ear; however, only at the dose of 45 micrograms per ear was it able to significantly reduce the croton oil-induced oedema at 6h. Paw oedema was induced by the injection of 25 microliters of 1% carrageenan into the plantar aponeurosis of the right hind paw. The oedema was evaluated at 0.5, 1, 2, 4, 24, 48 and 72h. Previously in our experiments, we observed two peaks in paw oedema formation: one at 2h, in the early phase (0...

Research paper thumbnail of Antiangiogenic and antitumoral properties of a polysaccharide isolated from the seaweed Sargassum stenophyllum

The potential antiangiogenic and antitumoral properties of SargA, a polysaccharide extracted from... more The potential antiangiogenic and antitumoral properties of SargA, a polysaccharide extracted from the brown marine alga Sargassum stenophyllum, were studied in assays carried out in chick embryos and mice. Gelfoam plugs containing SargA (2-1500 lg/ plug) implanted in vivo into fertilized 6-day-old chicken eggs induced dose-related antiangiogenic activity in the chorioallantoic membrane (CAM). By day 8, the highest dose of SargA alone decreased the vessel number in the CAM by 64%, but coadminis-tered with hydrocortisone (156 lg/plug, which alone caused 30% inhibition) failed to potentiate its antiangiogenic effect. Combined with basic fibroblast growth factor (50 ng/plug), SargA (1500 lg/plug) abolished angiogenesis stimulated by this factor in both chick embryo CAM and in subcutaneous (s.c.) Gelfoam plugs implanted in the dorsal skin of Swiss mice (measured as plug hemoglobin content). Repeated s.c. injections of SargA (1.5 or 150 lg per animal per day for 3 days) close to B16F10 melanoma cell tumors in the dorsal skin of mice markedly decreased tumor growth in a dose-related fashion (by 40% and 80% at 2 weeks after the first injection, respectively), without evident signs of toxicity. SargA caused graded inhibitions of migration and viability of cultured B16F10 cells and also displayed antithrombotic activity in human plasma (5 mg/ml increased thrombin time 2.5-fold relative to saline). Thus, SargA exhibits pronounced antiangiogenic as well as antitumoral properties. Although the latter action of SargA might be related to the inhibition of angiogenesis, the polysaccharide also exerts cytotoxic effects on tumor cells. Because of its chemical characteristics and polyanionic constituents, we postulate that the polysaccharide SargA might modulate the activity of heparin-binding angiogenic growth factors.

Research paper thumbnail of Manipulation of chemical composition and architecture of non-biodegradable poly(ethylene terephthalate)/chitosan fibrous scaffolds and their effects on L929 cell behavior

Materials science & engineering. C, Materials for biological applications, 2013

Microporous, non-woven fibrous scaffolds made of poly(ethylene terephthalate) and chitosan were p... more Microporous, non-woven fibrous scaffolds made of poly(ethylene terephthalate) and chitosan were produced by electrospinning. Fiber morphology, diameter, pore size, and wettability were manipulated by varying the chemical composition of the electrospinning solution, i.e. chitosan concentration and molecular weight, and by post-electrospinning treatment with glutaraldehyde. In vitro studies were conducted using a fibroblast cell line toward a comprehensive understanding of how scaffolds characteristics can modulate the cell behavior, i.e. viability, adhesion, proliferation, extracellular matrix secretion, and three-dimensional colonization. Substantial differences were found as a result of scaffold morphological changes. Higher levels of adhesion, spreading, and superficial proliferation were achieved for scaffolds with smaller fiber and pore diameters while cell penetration and internal colonization were enhanced for scaffolds with larger pores. Additionally, the available area for c...

Research paper thumbnail of High performance liquid chromatography determination of cucurbitacins in the roots of Wilbrandia ebracteata Cogn

Revista Brasileira de Farmacognosia, 2009

A sensitive and selective method is presented for the determination of Zn-Bacitracin in adulterat... more A sensitive and selective method is presented for the determination of Zn-Bacitracin in adulterated animal feed by reversed-phase ion-pair high-performance liquid chromatography and post-column derivatization with o-phthalaldehyde prior 21 to fluorescence detection. The calibration function was estimated to be between 8.0 and 65.0 mg l of Zn-BC. The detection 21 and quantification limits of the chromatographic method were 2.5 and 7.5 mg l , respectively. Using the extraction procedure of Zn-Bacitracin from the feedstuff that we recently proposed and applying this new chromatographic method, it 21 was possible to detect this antibiotic at levels below 5 mg kg in different kinds of feedstuffs with a standard deviation less than 6.0%.

Research paper thumbnail of Foreign body reaction associated with PET and PET/chitosan electrospun nanofibrous abdominal meshes

PloS one, 2014

Electrospun materials have been widely explored for biomedical applications because of their adva... more Electrospun materials have been widely explored for biomedical applications because of their advantageous characteristics, i.e., tridimensional nanofibrous structure with high surface-to-volume ratio, high porosity, and pore interconnectivity. Furthermore, considering the similarities between the nanofiber networks and the extracellular matrix (ECM), as well as the accepted role of changes in ECM for hernia repair, electrospun polymer fiber assemblies have emerged as potential materials for incisional hernia repair. In this work, we describe the application of electrospun non-absorbable mats based on poly(ethylene terephthalate) (PET) in the repair of abdominal defects, comparing the performance of these meshes with that of a commercial polypropylene mesh and a multifilament PET mesh. PET and PET/chitosan electrospun meshes revealed good performance during incisional hernia surgery, post-operative period, and no evidence of intestinal adhesion was found. The electrospun meshes were ...

Research paper thumbnail of Diphenyl diselenide protects endothelial cells against oxidized low density lipoprotein-induced injury: Involvement of mitochondrial function

Biochimie, 2014

Elevated levels of oxidized low density lipoprotein (oxLDL) are considered to be one of the major... more Elevated levels of oxidized low density lipoprotein (oxLDL) are considered to be one of the major risk factors for atherosclerosis and cardiovascular morbidity. The early stages of atherosclerosis are initiated by the accumulation of oxLDL and the induction of toxic effects on endothelial cells, resulting in endothelial dysfunction. The aim of this study was to investigate how diphenyl diselenide (DD), an organoselenium compound, protect vascular endothelial cells against the toxic effects of oxLDL in vitro. Our data showed that the treatment of bovine endothelial aortic cells (BAEC) with DD (0.1-1 μM) for 24 h protected from oxLDL-induced reactive species (RS) production and reduced glutathione (GSH) depletion. Moreover, DD (1 μM) per se improved the maximal mitochondrial respiratory capacity and prevented oxLDL-induced mitochondrial damage. In addition, DD could prevent apoptosis induced by oxLDL in BAEC. Results from this study may provide insight into a possible molecular mechan...

Research paper thumbnail of Anti-inflammatory and antioxidant effects of Croton celtidifolius bark

Phytomedicine, 2003

19SF, 35SF and 63SF that contained a mixture of proanthocyanidins and were derived from the EAF f... more 19SF, 35SF and 63SF that contained a mixture of proanthocyanidins and were derived from the EAF fraction. The CE, AqF, EAF, BuF, catechin and sub-fractions 35SF and 63SF reduced paw edema induced by carrageenan. The CE, fractions, sub-fractions and isolated compounds showed antioxidant properties in vitro, all were able to scavenge superoxide anions at a concentration of 100 µg·ml -1 . The EAF, catechin and gallocatechin were most effective in the deoxyribose assay, IC50 0.69 (0.44-1.06), 0.20 (0.11-0.39), 0.55 (0.28-1.08) µg·ml -1 respectively. The CE and other fractions and sub-fractions inhibited deoxyribose degradation up to 1 µg·ml -1 . In the hydrophobic system only AqF did not show lipid peroxidation inhibition. The CE, other fractions, sub-fractions and isolated compounds inhibited lipidid peroxidation only at a concentration of 100 µg·ml -1 . In summary, this study demonstrates that Croton celtidifolius bark has significant anti-inflammatory and antioxidant activity.

Research paper thumbnail of Antinociceptive effect of proanthocyanidins from Croton celtidifolius bark

Journal of Pharmacy and Pharmacology, 2005

The chemical composition of the chromatography 63 subfraction (63SF) from the ethyl acetate solub... more The chemical composition of the chromatography 63 subfraction (63SF) from the ethyl acetate soluble fraction of the crude extract of Croton celtidifolius bark presented a high content of total proanthocyanidins (75.0¯AE 2.3%). HPLC analysis of 63SF revealed a dimeric profile (e.g. catechin-(4?8)-catechin and gallocatechin-(4?8)-catechin) and polymeric proanthocyanidins. In pharmacological investigations, 63SF administered intraperitoneally exhibited dose-dependent antinociceptive activity against several chemical stimuli, including the intraperitoneal injection of acetic acid (ID50 (the dose of 63SF which was able to reduce the nociceptive response by 50% relative to the control value) ¼ 0.9 (0.5-1.6)) and the intraplantar injection of capsaicin (ID50 ¼ 13.0 (10.0-17.0)), glutamate (ID50 ¼ 4.0 (2.0-7.0)) and formalin (ID50 first phase ¼ 36.0 (24.0-53.0) and late phase ¼ 11.0 (8.0-14.0)). 63SF administered orally exhibited an antinociceptive effect in the formalin test (ID50 first phase ¼ 125.0 (89.0-177.0) and late phase ¼ 65.0 (33.0-95.0)). In the same test, 63SF was effective when given soon after the first phase, as well as exhibiting therapeutic activity. Furthermore, 63SF was effective in models of thermal nociception including tail-flick and hot-plate tests. When the mice were treated in the neonatal period with capsaicin, the antinociceptive effect of 63SF in the first phase of the formalin test was abolished, but pretreatment with naltrexone did not change the antinociceptive effect of 63SF. Together, these results provide evidence that 63SF exerted a pronounced systemic antinociception against chemical (acetic acid, formalin, glutamate and capsaicin tests) and thermal (hot-plate and tail-flick tests) nociceptive models of pain in mice at a dose that did not interfere with the locomotor activity. The mechanism by which this sub-fraction produced antinociception remains unclear, but it is unlikely to involve the activation of the opioid system. However, unmyelinated C-fibres sensitive to treatment with capsaicin are likely to participate in antinociception caused by 63SF.

Research paper thumbnail of An ethyl acetate fraction obtained from a Southern Brazilian red wine relaxes rat mesenteric arterial bed through hyperpolarization and NO-cGMP pathway

Vascular Pharmacology, 2005

A number of studies suggest that moderate consumption of red wine may be more effective than othe... more A number of studies suggest that moderate consumption of red wine may be more effective than other alcoholic beverages in decreasing the risk of coronary heart disease (CAD). In this study, we investigated the effect of a crude extract (CE), as well as an ethyl acetate fraction (EAF) obtained from a Brazilian red wine in the mesenteric arterial bed (MAB) from rats.

Research paper thumbnail of Antioxidant capacity of phenolic and related compounds: correlation among electrochemical, visible spectroscopy methods and structure–antioxidant activity

Redox Report, 2001

We investigated the antioxidant activity of phenylpropionic acids--caffeic (CAF), ferulic (FER), ... more We investigated the antioxidant activity of phenylpropionic acids--caffeic (CAF), ferulic (FER), para-coumaric (COU) and cinnamic (CIN)--and phenolic acids and related compounds--gallic (GAL), methyl gallate (meGAL), vanillic (VAN) and gentisic (GEN)--using visible spectroscopy, inhibition of nitroblue tetrazolium (NBT) reduction, and electrochemical methods including cyclic voltammetry and potentiometry. In the spectroscopic assays, only CAF, GAL and meGAL were able to inhibit NBT reduction. The same compounds showed the lowest oxidation potentials (Epa) and the highest redox potentials deltaE) in the cyclic voltammetric and potentiometric studies, respectively. In addition, it was observed that the greater the number of hydroxyls linked to the aromatic ring, the greater was the antioxidant activity of the analysed compounds. The correlations of Spermann--used to compare the methods between themselves and the methods with the relationship structure-antioxidant activity--were r = -0.9762 for the cyclic voltammetric-potentiometric methods. r = 0.8333 for the inhibition of NBT reduction-potentiometric methods and r = -0.8095 for the inhibition of NBT reduction-cyclic voltammetric methods. The correlations for cyclic voltammetric, potentiometric and inhibition of NBT reduction methods-number of hydroxyls linked to the aromatic ring were r = -0.9636, 0.9636 and 0.9142, respectively. These findings indicate that the electrochemical methods together with spectroscopic studies are a good tool to evaluate the antioxidant activity of substances.

Research paper thumbnail of Anti-Inflammatory and Analgesic Effects of Cucurbitacins from Wilbrandia ebracteata

Planta Medica, 1997

The anti-inflammatory and antinociceptive actions of the CH2Cl2 extract and semipurified fraction... more The anti-inflammatory and antinociceptive actions of the CH2Cl2 extract and semipurified fraction (F-III) from roots of Wilbrandia ebracteata Cogn. have been investigated in rats and mice. The CH2Cl2 extract (1-10 mg/kg, i.p.; ID50 5 mg/kg) and (3-30 mg/kg, p.o.; ID50 15 mg/kg) inhibited, in a dose-related manner, carrageenan-induced paw edema in rats. The subfraction (F-III) from CH2Cl2 extract and compounds isolated as cucurbitacin B and E also inhibited carrageenan-induced edema. The CH2Cl2 extract and F-III also exhibited significant analgesic action in acetic acid-induced pain in mice. In the formalin test, the CH2Cl2 extract (0.3-10 mg/kg, i.p.) and (3-30 mg/kg, p.o.) caused inhibition of the neurogenic (first phase) and inflammatory phase (second phase) of formalin-induced pain. However, the CH2Cl2 extract was more effective in relation to the second phase than in inhibition of the formalin-induced edema. These findings suggest that CH2Cl2 extract has potent anti-inflammatory and analgesic action and that F-III and cucurbitacin B and E may account for these actions.

Research paper thumbnail of Effect of quercetin on tachykinin-induced plasma extravasation in rat urinary bladder

Phytotherapy Research, 2001

The effect of quercetin on substance P-induced plasma extravasation in rat urinary bladder and it... more The effect of quercetin on substance P-induced plasma extravasation in rat urinary bladder and its modulation by endogenous peptidases in conscious rats was studied. Plasma protein extravasation (PE) was assayed by measurement of extravasated Evans blue dye (microg/g dry tissue). Intravenous injection of substance P (SP, 10 nmol/kg) significantly increased PE in the urinary bladder. PE evoked by SP was increased significantly by quercetin (20 mg/kg, p.o.) pretreatment in the urinary bladder (73.5 +/- 4.9 to 152.2 +/- 9.9). Pretreatment with captopril, an angiotensin-converting enzyme (ACE) inhibitor (10 nmol/kg, i.v.), or with phosphoramidon, a neutral endopeptidase (NEP) inhibitor (2.5 micromol/kg, i.v.) also potentiated the SP-induced PE in urinary bladder, 286.2 +/- 20.4 and 323.3 +/- 34.0, respectively. Quercetin did not show any effect on neurokinin-A (NKA, 10 nmol/kg, i.v.) -induced plasma extravasation. The present study demonstrates that quercetin potentiates the PE induced by substance P in the urinary bladder. These effects suggest that this flavonoid might cause inhibition of NEP and/or ACE.

Research paper thumbnail of Involvement of 5-HT receptors in the antinociceptive effect of

Pharmacology Biochemistry and Behavior, 2005

Uncaria tomentosa (Willd.) DC (Rubiaceae) is a vine that grows in the Amazon rainforest. Its bark... more Uncaria tomentosa (Willd.) DC (Rubiaceae) is a vine that grows in the Amazon rainforest. Its bark decoctions are used by Peruvian Indians to treat several diseases. Chemically, it consists mainly of oxindole alkaloids. An industrial fraction of U. tomentosa (UT fraction), containing 95% oxindole alkaloids, was used in this study in order to characterize its antinociceptive activity in chemical (acetic acid-induced abdominal writhing, formalin and capsaicin tests) and thermal (tail-flick and hot-plate tests) models of nociception in mice. UT fraction given by the i.p. route dose-dependently suppressed the behavioural response to the chemical stimuli in the models indicated and increased latencies in the thermal stimuli models. The antinociception caused by UT fraction in the formalin test was significantly attenuated by i.p. treatment of mice with ketanserin (5-HT2 receptor antagonist), but was not affected by naltrexone (opioid receptor antagonist), atropine (a nonselective muscarinic antagonist), l-arginine (precursor of nitric oxide), prazosin (a1-adrenoceptor antagonist), yohimbine (a2adrenoceptor antagonist), and reserpine (a monoamine depleter). Together, these results indicate that UT fraction produces dose-related antinociception in several models of chemical and thermal pain through mechanisms that involve an interaction with 5-HT2 receptors. D

Research paper thumbnail of Antinociceptive Effects of Peripheral Benzodiazepine Receptors

Pharmacology, 2004

Pretreatment of mice with Ro5-4864 or PK11195 inhibited the first-and second-phase responses in t... more Pretreatment of mice with Ro5-4864 or PK11195 inhibited the first-and second-phase responses in the formalin test and this effect was significantly reversed by aminoglutethimide, an inhibitor of pregnenolone synthesis, suggesting that the antinociceptive effect of the peripheral-type benzodiazepine receptor ligands is dependent on steroid formation. Doses of Ro5-4864 that did not produce an antinociceptive effect when injected by the intraperitoneal route presented an analgesic effect, if infected by the intracerebroventricular, intrathecal or intraplantar routes. PK11195 pretreatments with intrathecal, intracerebroventricular or intraplantar doses had no effect in the formalin test. These results suggest that the antinociceptive effect of Ro5-4864 reflects the influence of this ligand on steroid production not only in many nonneuronal peripheral tissues but also in the nervous system, while the antinociceptive action of PK11195 may be due to the stimulation of steroid synthesis only in nonnervous tissues.

Research paper thumbnail of Positive correlation between elevated plasma cholesterol levels and cognitive impairments in LDL receptor knockout mice: relevance of cortico-cerebral mitochondrial dysfunction and oxidative stress

Neuroscience, 2011

Convergent epidemiological, clinical, and experimental findings indicate that hypercholesterolemi... more Convergent epidemiological, clinical, and experimental findings indicate that hypercholesterolemia contributes to the onset of Alzheimer's disease (AD)-like dementia, but the exact underlying mechanisms remains unknown. In this study, we evaluated the cognitive performance of mice submitted to a model of hypercholesterolemia, as well as its relationship with mitochondrial dysfunction and oxidative stress, two key events involved in AD pathogenesis. Wildtype C57bl/6 or low density lipoprotein receptor (LDLr)-deficient mice were fed with either standard or cholesterol-enriched diet for a 4-week period and tested for spatial learning and memory in the object location task. LDLr ؊/؊ mice displayed spatial learning and memory impairments regardless of diet. Moreover, LDLr ؊/؊ mice fed cholesterol-enriched diet presented a significant decrease in the mitochondrial complexes I and II activities in the cerebral cortex, which were negatively correlated with respective blood cholesterol levels. Additionally, hypercholesterolemic LDLr ؊/؊ mice presented a significant decrease in glutathione levels, about 40% increase in the thiobarbituric acid-reactive substances levels, as well as an imbalance between the peroxide-removing-related enzymes glutathione peroxidase/glutathione reductase activities in the cerebral cortex. These findings indicate a significant relationship between hypercholesterolemia, cognitive impairment, and cortico-cerebral mitochondrial dysfunctional/oxidative stress. Because of the involvement of such alterations in AD patients, our data render this mouse model of hypercholesterolemia a useful approach to comprehend the molecular events mediating AD pathogenesis. . R.P.; M.F.; R.M.R.V.; A.L., and A.B. are productivity fellows from the CNPq. Scholarships to J.O. (CAPES) and V.G. (FAPESC) are also acknowledged. M.A.H. is a PNPD/CAPES posdoctoral grantee. The authors are grateful to Ms. Renate Schinke, an English professor, for checking the language of this manuscript.

Research paper thumbnail of Diphenyl Diselenide Prevents Cortico-cerebral Mitochondrial Dysfunction and Oxidative Stress Induced by Hypercholesterolemia in LDL Receptor Knockout Mice

Neurochemical Research

Recent studies have indicated a causal link between high dietary cholesterol intake and brain oxi... more Recent studies have indicated a causal link between high dietary cholesterol intake and brain oxidative stress. In particular, we have previously shown a positive correlation between elevated plasma cholesterol levels, cortico-cerebral oxidative stress and mitochondrial dysfunction in low density lipoprotein receptor knockout (LDLr(-/-)) mice, a mouse model of familial hypercholesterolemia. Here we show that the organoselenium compound diphenyl diselenide (PhSe)2 (1 mg/kg; o.g., once a day for 30 days) significantly blunted the cortico-cerebral oxidative stress and mitochondrial dysfunction induced by a hypercholesterolemic diet in LDLr(-/-) mice. (PhSe)2 effectively prevented the inhibition of complex I and II activities, significantly increased the reduced glutathione (GSH) content and reduced lipoperoxidation in the cerebral cortex of hypercholesterolemic LDLr(-/-) mice. Overall, (PhSe)2 may be a promising molecule to protect against hypercholesterolemia-induced effects on the ce...

Research paper thumbnail of Anti-inflammatory effects of a triterpenoid isolated from Wilbrandia ebracteata Cogn

Life Sciences, 2007

Wilbrandia ebracteata (WE), a Brazilian medicinal plant used in folk medicine for the treatment o... more Wilbrandia ebracteata (WE), a Brazilian medicinal plant used in folk medicine for the treatment of rheumatic diseases, displays antiinflammatory properties and constitutes a rich source of cucurbitacins and cucurbitacin-related compounds. The current study investigated the potential anti-inflammatory properties of Dihydrocucurbitacin B (DHCB), a cucurbitacin-derived compound isolated from roots of WE, in some in vivo and in vitro experimental models. Intraperitoneal treatment of mice with DHCB reduced both carrageenan-induced paw edema (0.3, 1 and 3 mg/kg caused inhibitions of 26, 44 and 56 % at 2 h after stimulation, respectively) and pleurisy (10 mg/kg inhibited leukocyte numbers and LTB 4 levels in the pleural fluid by 51 and 75% at 6 h after cavity challenge, respectively). In vitro, DHCB (up to 10 μg/mL) failed to modify LTB 4 production by human neutrophils or PGE 2 production by COS-7 cells transfected with COX-1, but PGE 2 production by COX-2 transfected COS-7 cells was markedly inhibited (by 72%). The levels of COX-1 or COX-2 proteins in IL-1α-stimulated NIH3T3 cells were unaffected by DHCB. The results corroborate the potential anti-inflammatory properties ascribed to W. ebracteata Cogn. in folk medicine and suggest that they might be attributed, at least in part, to the capacity of one of this plants main constituents, DHCB, to inhibit COX-2 activity (but not its expression) during inflammation.