Intranasal in situ gelling liquid crystal for delivery of resveratrol ameliorates memory and neuroinflammation in Alzheimer's disease.

Alzheimer's disease (AD) is an illness that affects people aged 65 or older and affects around 6.5 million in the United States. Resveratrol is a chemical obtained from natural products and it exhibits biological activity based on inhibiting the formation, depolymerization of the amyloid, and decreasing neuroinflammation. Due to the insolubility of this compound; its incorporation in surfactant-based systems was proposed to design an intranasal formulation. A range of systems has been produced by mixing oleic acid, CETETH-20 and water. Polarised light microscopy (PLM), small angle x-ray scattering (SAXS) and transmission electron microscopy (TEM) confirm the initial liquid formulation (F) presented as microemulsion (ME). After dilution, the gelled systems were characterized as hexagonal mesophase and they showed feasibility proprieties. Pharmacological assays performed after intranasal administration showed the ability to improve learning and memory in animals, as well as remission of neuroinflammation via inhibition of interleukin.

Geraniol accelerates the gastric healing, minimizes ulcers recurrence, and reduces anxiolytic-like behavior in ulcerated rodents by oral or inhaled route.

BACKGROUND: Geraniol (GE) is dietary acyclic monoterpene alcohol found in essential oils from aromatic plants with therapeutic value against gastric ulcers already described. HYPOTHESIS/PURPOSE: To assess whether oral GE accelerates gastric healing or prevents ulcer recurrence, and to evaluate the hypothesis that GE promotes antiulcer effects by the inhaled route and that promotes changes in the behavior of ulcerated rodents. METHODS: Gastric healing effects, underlining mechanisms, and behavioral changes were measured in80% acetic acid-induced gastric ulcer model in rats receiving GE by oral (30 mg/kg) or inhaled route (1 mg/L of air/min); whereas the effects of GE to avoid ulcer recurrence was evaluated in mice submitted to 10% acetic acid plus IL-1ß ulcer. RESULTS: GE administered by both routes accelerates gastric healing, increasing mucin and GSH levels, CAT, and GST activities, and reducing MPO activity. Moreover, oral, and inhaled GE minimized ulcer recurrence reducing gastric TNF and IL-6 levels and preserving mucin levels. Interestingly, the inhalation or oral intake of GE promotes anxiolytic-like effects in ulcerated rats. CONCLUSION: Data altogether suggest that the GE accelerates gastric healing through the strengthening of protective factors of the gastric mucosa, promoting a quality healing that reduces the recurrence of the lesion. Besides, the anxiolytic-like effect of GE may also contribute to its gastric healing action since anxiety is recognized as one of the etiologic agents of ulcers.

Phytochemical Analysis and Antinociceptive Properties of Hydroalcoholic Extracts of Aleurites moluccanus Bark.

Aleurites moluccanus is used in folk medicine to treat many diseases including pain and inflammatory processes in general. Considering the potential of the leaf extract, evidenced in a previous study, the present study investigates the antinociceptive and anti-inflammatory properties of the hydroethanolic extract of A. moluccanus bark and isolated compounds in animal models of pain. The antinociceptive and anti-inflammatory activities of A. moluccanus bark were evaluated through hyperalgesia induced by carrageenan, PGE2, cytokines, bradykinin, epinephrine, Freund's complete adjuvant, and lipopolysaccharide. Five compounds were isolated from the dichloromethane bark extract: acetyl aleuritolic acid, atraric acid, spruceanol, (5ß,10α)-12-hydroxy-13-methoxy-8,11,13-podocarpatrien-3-one and sonderianol. To optimize the extraction conditions, ethanol 50, 70, and 90°GL were used as extracting solvent, in a 1 : 20 (w/v) drug : solvent ratio, under stirring at room temperature for 4 h. The extracts were named AMC50, AMC70, and AMC90, respectively. These extracts were administered to mice (250 mg/kg, p. o.) with reduced mechanical hyperalgesia activity in the carrageenan test. Of these, AMC90 showed the best results. Pure (5ß,10α)-12-hydroxy-13-methoxy-8,11,13-podocarpatrien-3-one showed a beneficial effect for up to 48 hours after the administration of carrageenan, while acetyl aleuritolic acid was effective only in the first hour. AMC90 was able to reverse the analgesia induced only by prostaglandin E2 and tumor necrosis factor. We also induced hyperalgesia using the lipopolysaccharide and Freund's complete adjuvant models, with positive results. These results support the antinociceptive and anti-inflammatory activity of A. moluccanus bark extract. The observed effects are partly due to the presence of acetyl aleuritolic acid, atraric acid, and (5ß,10α)-12-hydroxy-13-methoxy-8,11,13-podocarpatrien-3-one.

Epidemiology of HIV, syphilis, and hepatitis B and C among manual cane cutters in low-income regions of Brazil.

BACKGROUND: In recent decades the epidemic of asymptomatic sexually transmitted infections has extended deep into Brazil, including small towns and rural areas. The purpose of this study was to investigate the epidemiology of HIV, syphilis, and hepatitis B (HBV) and hepatitis C viruses (HCV), and to evaluate immunization coverage against hepatitis B in a group of rural workers in Brazil. METHODS: In 2016, a cross-sectional study was conducted with 937 manual sugarcane cutters of the Midwest and Northeast Regions of Brazil. All individuals were interviewed and screened for HIV, syphilis, HBV and HCV. Correlating factors with lifetime HBV infection were investigated using logistic regression. Positive Predictive Values, Negative Predictive Values, sensitivity and specificity were also calculated relative to vaccination against Hepatitis B, comparing anti-HBs titers to vaccination reports. RESULTS: Most reported previous hospitalization (55%), occupational injuries (54%), sharing of personal items (45.8%), alcohol consumption (77.2%), multiple sexual partners in previous 12 months (39.8%), and no condom use during sexual intercourse in last 12 months (46.5%). Only 0.2% reported using injection drugs. Anti-HIV-1 was detected in three individuals (0.3%). Serological markers of lifetime syphilis (treponemal test) were detected in 2.5% (95% CI: 1.6-3.6) of participants, and active syphilis (treponemal test and VDRL) present in 1.2%. No samples were positive for anti-HCV. The prevalence of lifetime HBV infection (current or past infection) was 15.9%, and 0.7% (95% CI 0.4 to 1.5) were HBsAg-positive. Previous hospitalization (OR 1.53, CI 1.05-2.24, p < 0.01) and multiple sexual partners in the last 12 months (OR 1.80, CI 1.25-2.60, p < 0.01) were predictors for lifetime HBV infection. Although 46.7% (95% CI 43.4-49.9) of individuals reported having been vaccinated against hepatitis B, only 20.6% (95% CI 18.1-23.3) showed serological evidence of previous hepatitis B vaccination (positive for anti-HBs alone). CONCLUSIONS: The high prevalence of syphilis and HBV compared to the general population and the high frequency of risk behaviors show the potential for sexual and parenteral dissemination of these agents in this rural population. In addition, the low frequency of hepatitis B vaccinated individuals suggests a need for improved vaccination services.

Neuropharmacological and acute toxicological evaluation of ethanolic extract of Allamanda cathartica L. flowers and plumieride.

Psychiatric diseases affect more than 350 million people all over the world, and medicinal plants have been considered the basis for pharmacological research. The study investigates the anticonvulsant and antidepressant-like activities and acute toxicological effects of ethanolic extract of Allamanda cathartica flowers, and plumieride. The extract was analyzed by HPLC and plumieride was isolated. Toxicity studies were carried out on females Wistar rats (2000 mg/kg). Toxicity was evaluated by measuring biochemical parameters and conducting histopathological analysis. For pharmacological evaluation different doses of the extract (100, 150 and 300 mg/kg, p.o.) and plumieride (0.5, 1 and 2 µg/kg, i.p.) were administered before the Forced-Swimming Test (FST), pentylenetetrazole seizure test (PTZT) or Tail-Suspension Test (TST) in mice. Furthermore, hemolytic activity, cytotoxicity and micronucleus test were performed. In addition, mutagenicity and reproductive/developmental toxicity were estimated by TEST-software analysis. Data show that both treatments induce significant antidepressive-like effect in FST and TST, but not anticonvulsant effect. The effect of plumieride last up to 4 h after treatment. No signs of toxicity, mutagenicity, cytotoxicity or hemolytic activity were observed. The TEST-software demonstrated that plumieride present reproductive/developmental toxicity. Together, the data obtained show that the flowers extract and plumieride present antidepressant-like effect and did not present signals of acute toxicity.

DYRK1A Inhibitors and Perspectives for the Treatment of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disease and the most common form of dementia, especially in the elderly. Due to the increase in life expectancy, in recent years, there has been an excessive growth in the number of people affected by this disease, causing serious problems for health systems. In recent years, research has been intensified to find new therapeutic approaches that prevent the progression of the disease. In this sense, recent studies indicate that the dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) gene, which is located on chromosome 21q22.2 and overexpressed in Down syndrome (DS), may play a significant role in developmental brain disorders and early onset neurodegeneration, neuronal loss and dementia in DS and AD. Inhibiting DYRK1A may serve to stop the phenotypic effects of its overexpression and, therefore, is a potential treatment strategy for the prevention of ageassociated neurodegeneration, including Alzheimer-type pathology. OBJECTIVE: In this review, we investigate the contribution of DYRK1A inhibitors as potential anti-AD agents. METHODS: A search in the literature to compile an in vitro dataset including IC50 values involving DYRK1A was performed from 2014 to the present day. In addition, we carried out structure-activity relationship studies based on in vitro and in silico data. RESULTS: molecular modeling and enzyme kinetics studies indicate that DYRK1A may contribute to AD pathology through its proteolytic process, reducing its kinase specificity. CONCLUSION: further evaluation of DYRK1A inhibitors may contribute to new therapeutic approaches for AD.

Antihyperalgesic effects of myrsinoic acid B in pain-like behavior induced by inflammatory and neuropathic pain models in mice.

BACKGROUND: Myrsinoic acid B (MAB) is a diprenylated benzoic acid widely found in the vegetal kingdom. Recent studies demonstrate that MAB has important antinociceptive effects in models of chemically or thermally induced nociception in mice. METHODS: In the present study we evaluated the effect of MAB in different models of inflammatory and neuropathic hypersensitivity in mice. RESULTS: This study demonstrates that the pretreatment with MAB, given orally (8.4 to 83.8 µmol/kg), inhibited carrageenan- and complete Freund adjuvant-induced mechanical hypersensitivity. When administered after the induction of hypersensitivity, MAB also reduced the mechanical hypersensitivity in the ipsilateral and in the contralateral hindpaws of mice injected with complete Freund adjuvant, interfering with a signaling cascade already established. MAB reversed the hypersensitivity (mechanical and thermal) of operated animals, with similar results to those observed with gabapentin. MAB activity was evident when administered either systemically (PO or IV) or intrathecally, suggesting interference in the central pathways of pain control. Furthermore, MAB seems to present an antiinflammatory effect evidenced by the interference in both the neutrophil migration and in the increase of interleukin-1ß levels after carrageenan injection. Of note, MAB treatment did not interfere with mechanical or thermal sensitivity in healthy mice, a frequent characteristic of commonly used analgesics, such as morphine or gabapentin. Side effects including interference in locomotor activity, motor performance, and body temperature in animals treated with MAB were absent. CONCLUSIONS: MAB reduced mechanical and thermal hypersensitivity in mice submitted to models of inflammatory and neuropathic pain, showing excellent potential for treating persistent pain in humans.

Baccharis dracunculifolia DC Hydroalcoholic Extract Improves Intestinal and Hippocampal Inflammation and Decreases Behavioral Changes of Colitis Mice.

The hydroalcoholic extract of B. dracunculifolia (HEBD) and its major compound p-coumaric acid were evaluated against the severity of intestinal inflammation and behavioral changes like depressive and anxious behavior in colitis mice. Colitis was induced in Swiss mice by oral dextran sulfate sodium (DSS) administration for five days. The mice received vehicle (10 ml/kg), HEBD (3, 30, or 300 mg/kg), or p-coumaric acid (15 mg/kg) orally, once a day for twelve days. Behavioral tests were performed on the 11th and 12th days after the beginning of the treatments. Moreover, the colon, cortex, and hippocampus were collected to analyze oxidative and inflammatory parameters. The treatment with HEBD (300 mg/Kg), but not p-coumaric acid, showed decreased disease activity index (DAI) values compared to the vehicle group and partially preserved the villi architecture and mucin levels. Furthermore, the HEBD increased the antioxidant defenses in the colon and hippocampus and reduced the myeloperoxidase activity and IL-6 levels in the colon from colitis mice. Colitis mice treated with HEBD did not show depressive-like behavior in the tail suspension test. HEBD reduced colon inflammation, while it maintains antioxidant defenses and mucin levels in this tissue. It may reduce neuropsychiatric comorbidities associated with colitis through its antioxidant effects.

Synthesis and antidepressant-like activity evaluation of sulphonamides and sulphonyl-hydrazones.

In this study a series of sulphonamides and sulphonyl hydrazones of maleimide, naphthalimide and phthalimide derivatives was synthesized. The antidepressant effect of these compounds was evaluated by the forced-swimming test in mice. The behavioural parameter observed in this test is a reduction in the immobility time, which is indicative of antidepressant activity. All compounds, except 8, 11 and 24, were active as antidepressants. The most active compound was the sulphonyl-hydrazone 10 which showed an activity of around 72.02% at 60 mg/kg, it thus being more active than imipramine (10mg/kg, ip), a commercial antidepressant. Other important results were obtained for the benzylnaphthalimide derivatives, the sulphonamides 21 and 22 showing activity of 64% at 10mg/kg, also being more active than imipramine. These results indicate that the sulphonamides and sulphonyl-hydrazone cyclic imide derivatives are potential compounds for use in the designing of new candidates for the treatment of depression.

Evaluation of Behavioral and Pharmacological Effects of Hydroalcoholic Extract of Valeriana prionophylla Standl. from Guatemala.

There are few studies on the pharmacological properties of Valeriana prionophylla Standl. (VP), known as "Valeriana del monte", and used in Mesoamerican folk medicine to treat sleep disorders. This study examines the pharmacological effects of the hydroalcoholic extract of the dry rhizome using the open field, rota rod, elevated plus-maze (EPM), forced swimming (FST), strychnine- and pentobarbital-induced sleeping time, PTZ-induced seizures, and the inhibitory avoidance tests. VP did not show any protective effect against PTZ-induced convulsions. In the EPM, exhibited an anxiolytic-like effect through the effective enhancement of the entries (38.5%) and time spent (44.7%) in the open arms, when compared with control group. Time spent and the numbers of entrances into the enclosed arms were decreased, similar to those effects observed with diazepam. In the FST, acute treatment with VP, produced a dose-dependent decrease in immobility time, similarly to imipramine. VP also produced a significant dose-dependent decrease in the latency of sleeping time, while producing an increase in total duration of sleep; influenced memory consolidation of the animals only at lower doses, unlike those that produced anti-depressant and anxiolytic effects. In summary, the results suggest that VP presents several psychopharmacological activities, including anxiolytic, antidepressant, and hypno-sedative effects.

Plumieride exerts anxiolytic-like effect mediated by GABAergic and monoaminergic systems.

Plumieride (PLU), an iridoid isolated from Allamanda cathartica flowers, has been studied by our research group due to its anti-inflammatory potential, antidepressant-like and anxiolytic-like effects. This research investigated the involvement of GABAergic and monoaminergic systems in the anxiolytic-like effect elicited by PLU. Therefore, mice were pre-treated with GABAergic, serotonergic, adrenergic or dopaminergic receptor antagonists (i.p.), and exposed to Elevated Plus-Maze (EPM) and Open-Field Test (OFT). The preliminary results revealed that PLU (p.o.) possibly interacts with the mentioned systems through the GABAA, GABAB, 5-HT1A, 5-HT3, α1, α2, and D2 receptors.

Assessment of mechanisms involved in antinociception caused by myrsinoic acid B.

Myrsinoic acid B (AMB) is a prenylated-benzoic acid derivative isolated from the Rapanea genus. Recent studies suggest that AMB has antihyperalgesic and antinociceptive properties in different animal models. The present study was designed to investigate the mechanisms involved in antinociception elicited by AMB (60 mg/kg) when administered by intraperitonial route (i.p.) in mice. The antinociceptive response of the compound was characterized by a reduction in contractions of the abdominal muscle, together with stretching of the hind limbs in response to i.p. injection of acetic acid (0.6%, 0.45 ml/mouse). The antinociception caused by AMB in the acetic acid test was significantly attenuated by i.p. treatment of mice with nitric oxide precursor, (L-arginine, 600 mg/kg), alpha2 and alpha1-adrenoceptor antagonists (yohimbine, 0.2 mg/kg/prazosin, 0.2 mg/kg), p-chlorophenylalanine (PCPA) an inhibitor of serotonin synthesis (100 mg/kg), 1-(2-methoxyphenyl)-4-(4-phthalimidobutyl)piperazine (NAN 190), a 5-HT1(A) selective receptor antagonist (0.5 mg/kg) and a non-selective cholinergic antagonist (atropine, 10 mg/kg). Its action was also modulated by the adrenal-gland hormones. In contrast, antinociception was not affected by naloxone (non-selective opioid receptor antagonist, 1.0 mg/kg), phaclofen (2.0 mg/kg) and bicuculline (1.0 mg/kg) GABA(B) and GABA(A) receptor antagonists, respectively, ondansetron (0.3 mg/kg) and ketaserin (1.0 mg/kg), (5-HT3 and 5-HT2 receptors, respectively) and haloperidol (0.2 mg/kg), a non-selective dopaminergic receptor. The antinociceptive effects are not related to muscle-relaxant or sedative action. These results indicate that AMB produces antinociception through mechanisms that involve interaction with L-arginine-nitric oxide, the serotonergic and cholinergic systems, as well as interaction with the alpha-adrenoceptors.

Effects of 2',6'-dihydroxy-4'-methoxydihidrochalcone on innate inflammatory response.

Chalcones present potential therapeutic activities reported on literature, which led us to evaluate the anti-inflammatory effects and the acute toxicity of 2',6'-dihydroxy-4'-methoxydihydrochalcone (DHMDC) using in vitro and in vivo models. The anti-inflammatory activity was firstly in vitro investigated using macrophages (RAW 264.7) and neutrophils previously treated with DHMCD activated with lipopolysaccharide (LPS). Nitrite, IL-1ß, and TNF levels were measured in the macrophage culture supernatant, and the adhesion molecule expression (CD62L, CD49D, and CD18) was evaluated in neutrophils. Then, carrageenan-induced inflammation was performed in the subcutaneous tissue of male Swiss mice. Leukocyte migration and histological analysis were performed in the pouches. Toxicological studies were carried out on female Swiss mice (600 mg/kg) through biochemical parameters and histopathological analysis. In vitro, the DHMCD significantly reduced the IL-1ß, TNF, and nitrite levels. The DHMCD was also able to modulate the percentage of positive neutrophils for CD62L, without modifying the expression of CD18 or CD49d. In vivo, DHMCD (3 mg/kg, p.o.) significantly reduced neutrophil migration to inflammatory exudate and subcutaneous tissue. No evidence of toxic effect was observed considering the biochemical parameters and histopathological analysis of liver and kidney. Together, the obtained data shows that DHMCD presents anti-inflammatory activity by modulating the macrophage inflammatory protein secretion and also by blocking the CD62L cleavage in neutrophils. Furthermore, there was not any evidence of toxic effect in acute toxicological analysis.

Antidepressant-like effect of hydroalcoholic extract from barks of Rapanea ferruginea: Role of monoaminergic system and effect of its isolated compounds myrsinoic acid A and B.

Major Depressive Disorder (MDD) is a highly disabling condition and has been linked to increased inflammatory mediators. Hydroalcoholic extract from barks of Rapanea ferruginea (HEBRF) and the majoritary compounds-myrsinoic acid A (MAA) and B (MAB)-have been studied due to their anti-inflammatory potential, but there is no evidence about its antidepressant-like effects. This research investigated the HEBRF, MAA, and MAB antidepressant-like effect, besides the involvement of the monoaminergic system and MAO-A activity in the HEBRF antidepressant-like effect. HEBRF (50-300 mg/kg, p.o.), MAA (5-30 mg/kg, p.o.) or MAB (3-60 mg/kg, p.o.) were administrated to mice, and behavioral parameters were assessed using the tail suspension test (TST), splash test (ST) and open field test (OFT). The involvement of monoaminergic system in the HEBRF antidepressant-like effect was established through the pretreatment of mice with antagonists. The influence triggered by HEBRF in the monoamine oxidase A (MAO-A) activity was evaluated in the hippocampus (HIP) and prefrontal cortex (PFC) of mice. HEBRF (100-300 mg/kg) promoted antidepressant-like effect in the TST and augmented the total time of grooming in the ST, without compromising the locomotor activity. Pretreatment of mice with serotoninergic, dopaminergic, and noradrenergic antagonists, reversed the HEBRF antidepressant-like effect. Besides, HEBRF inhibited the MAO-A activity in the HIP and PFC. Moreover, MAA (5 mg/kg) and MAB (3 mg/kg) also promoted antidepressant-like and anti-anhedonic effects in mice. Data showed that monoaminergic system is involved in the HEBRF antidepressant-like effect, besides MAA and MAB possibly could be responsible for these pharmacological effects.

Structure-activity relationships of sulfonamides derived from carvacrol and their potential for the treatment of Alzheimer's disease.

Five synthetic sulfonamides derived from carvacrol, a natural product and a small molecule with druglike properties, were evaluated with respect to their effects on the cognitive deficits of animals with streptozotocin (STZ)-induced Alzheimer's disease (AD). Memory, ambulation, anxiety and oxidative stress were evaluated. In vitro assays were performed to assess the inhibition of acetylcholinesterase (AChE), and the data were combined with molecular docking for the establishment of structure-activity relationships. The memories of animals treated with the compounds derived from morpholine (1), hydrazine (3) and 2-phenol (5) were improved. Compound 3 was the most promising, yielding excellent results in the inhibitory avoidance test. Moreover, the compounds did not exhibit any deleterious effects on the animals' ambulation in the open field test. Molecular docking confirmed the results obtained in the AChE inhibition assay. In short, compounds 1, 3 and 5 can reduce STZ-induced deficits and show potential for the treatment of Alzheimer's. In addition, these agents produce significant anxiolytic and antioxidant effects.

Antidepressant-like effect and toxicological parameters of extract and withanolides isolated from aerial parts of Solanum capsicoides All. (Solanaceae).

The present work describes the evaluation of the antidepressant-like activity of the extract, fractions, and compounds obtained from the aerial parts of Solanum capsicoides. The methanolic extract (MESC) obtained by conventional maceration was partitioned with solvents of increasing polarities yielding the respective fractions of hexane (HE), dichloromethane (DCM), and ethyl acetate (EA). The dichloromethane and ethyl acetate fractions were submitted to chromatographic and spectroscopic techniques, leading to the isolation and identification of cilistadiol (1), astragalin (2), and cilistol A (3). In relation to the antidepressant activity, the extract was active against the forced swimming test (FST) at a concentration of 300 mg/kg an ED50 (deffective dose that reduces 50% of immobility time) of 120.3 (117.3-123.4) mg/kg. Similar values were observed when evaluated in the tail suspension test (TST). In addition, the results showed no influence on motor behavior when evaluated in the open field test (OFT). Based on the observed profile of the MESC, dichloromethane fraction presenting the best profile, in both FST and TST test. Likewise, the fraction also did not present motor impairment when evaluated by the OFT test. Considering that the dichloromethane fraction was more effective, the isolated compounds cilistadiol and cilistol A were evaluated in the same experimental models. In FST, both compounds had a significant antidepressant-like effect, with ED50 values of 0.22 (0.16-0.28) and 1.03 (0.89-1.18) µmol/kg, respectively. When evaluated in the TST, showed ED50 values of 0.30 (0.18-0.52) and 1.49 (1.27-1.73) µmol/kg, respectively. The isolated compounds also did not present significant differences in the motor behavior when evaluated on OFT test in comparison with the control group. No toxicological parameters were observed until the highest dose of MESC (2000 mg/kg), demonstrating safety in the use of this plant.

Aleurites moluccanus and its main active constituent, the flavonoid 2″-O-rhamnosylswertisin, in experimental model of rheumatoid arthritis.

ETHNOPHARMMACOLOGICAL RELEVANCE: Aleurites moluccana is used in folk medicine to treat pain, fever, asthma, hepatitis, gastric ulcer and inflammatory process in general, and the nut oil had been topically applied to treat arthritis and other joint pain, however the seeds are classified as toxic for oral use. AIM: Faced with the need for new alternative to treat the symptoms and modify rheumatoid arthritis (RA) the aim of this work was to evaluate the effects of A. moluccanus' leaves dried extract in rats and mice submitted to complete Freund adjuvant (CFA)-induced RA. MATERIAL AND METHODS: Wistar Rats and Swiss mice were submitted to CFA-induced RA in the right hindpaw. They received A. moluccanus extract (orally; p.o.), dexamethasone (subcutaneously), 2″-O-rhamnosylswertisin (p.o.) or vehicle (p.o.), from the 14th day after the CFA injection for up to 8 days. The mechanical hypersensitivity was evaluated using the von Frey filaments and the paw-oedema was measured using a plethysmometer. The rats' injected hindpaw was used to perform the histological analysis. RESULTS: A. moluccanus was able to significantly reduce the mechanical hypersensitivity in both ipsi- and contralateral hindpaws of mice injected with CFA, in a dose dependent manner. Furthermore, the paw-oedema was progressively reduced by A. moluccanus. Similar results were obtained for the positive-control drug dexamethasone and the isolated compound 2″-O-rhamnosylswertisin. Besides the effects mentioned above, the extract was also effective to repair the joint damage in CFA-induced RA rats, including reduction of fibrosis, cartilage degradation and bone erosion scores. CONCLUSION: These results together with the literature data reinforce the anti-hypersensitivity and anti-inflammatory activity of A. moluccanus extract. Part of the observed effects is due to the presence of the compound 2″-O-rhamnosylswertisin. The fact that the extract acted as a disease modifier point this herbal product as a promisor and safe tool to treat RA and other associated chronic diseases.

Study of rabbit septal cartilage grafts placed on the nasal dorsum.

OBJECTIVE: To compare the reabsorption characteristics of fresh septal cartilage autografts, preserved homografts, and preserved autografts in the nasal dorsum of rabbits. METHODS: Rabbit nasal dorsum cartilage grafts were placed in 3 groups. The first group used fresh autologous cartilage; the second group, alcohol-preserved homologous cartilage; and the third group, alcohol-preserved autologous cartilage. Each rabbit received 2 grafts, one crushed and another noncrushed. After 16 weeks, the grafts were removed for analysis. RESULTS: No graft calcification occurred in any group. Chondrogenesis was observed in all groups. The fresh autograft group had the best results in the evaluation of the area of graft recovered and chondrocyte viability. The preserved autologous and homologous grafts did not differ in relation to any of the variables analyzed. Crushed grafts had inferior results in the area of graft recovered and chondrocyte viability compared with the noncrushed forms. No significant difference among the 3 groups was noted in the thickness of the fibrous capsule that developed around the graft. CONCLUSIONS: The fresh cartilage autograft was superior to the crushed and uncrushed preserved homografts and autografts; both types of preserved grafts had equivalent histological results. The uncrushed forms were superior to the crushed forms.

Quercetin: further investigation of its antinociceptive properties and mechanisms of action.

The antinociceptive action of quercetin, a common bioactive flavonoid present in many medicinal plants, was assessed in different models of chemical and thermal nociception in mice. Quercetin (10-60 mg/kg, i.p. or 100-500 mg/kg, p.o.) dose-dependently inhibited nociceptive behavior in the acetic acid-induced pain test. Moreover, quercetin (10-60 mg/kg, i.p.) inhibited both phases of formalin-induced pain, with ID50 values of 374.1 (68.0-402.0) mmol/kg and 103.0 (45.0-201.0) mmol/kg, for the neurogenic and inflammatory phases, respectively. Quercetin (10-60 mg/kg) also inhibited the nociception induced by glutamate and capsaicin by 68.2% and 75.5%, respectively. Its analgesic action was significantly reversed by p-chlorophenylalanine methyl ester, katanserin, methysergide, a GABA(A) antagonist (bicuculline), or a GABA(B) antagonists (baclofen). Its action was also modulated by tachykinins, but was not affected by adrenal-gland hormones. Furthermore, the antinociceptive effects did not result from muscle-relaxant or sedative action. Together, these results indicate that quercetin produces dose-related anti-nociception in several models of chemical pain, through mechanisms that involve interaction with L-arginine-nitric oxide, serotonin, and GABAergic systems. These results confirm and extend other investigations on the analgesic effect of quercetin and its mechanisms of action.

Antinociceptive action of limonexic acid obtained from Raulinoa echinata.

The antinociceptive effect of the limonexic acid isolate of Raulinoa echinata Cowan in four models of pain in mice is described. When evaluated against acetic acid-induced abdominal constrictions, limonexic acid (10, 30 and 60 mg kg(-1), i.p.) produced dose-related inhibition of the number of constrictions, with a mean ID50 value of 43 (2.3-79) micromol kg(-1), and was more potent than some standard drugs. In the formalin test, limonexic acid inhibited both the first and second phases of formalin-induced pain. Furthermore, the effect was more pronounced in the second phase, with a mean ID50 value of 13.66 (9.35-19.61) micromol kg(-1), and had a pharmacological profile that was similar to standard drugs such as acetaminophen and acetyl salicylic acid. Limonexic acid also produced dose-related inhibition of glutamate- and capsaicin-induced pain, with mean ID50 values of 11.67 (8.51-16.0) micromol kg(-1) and 47.17 (36.51-60.93) micromol kg(-1), respectively. The mechanism of action is not completely understood, but seems to involve direct interaction with the GABAergic and nitroxidergic pathways.