RESUMEN
PURPOSE: 5'-methoxynobiletin (5'-MeONB), a polymethoxyflavone isolated from A. conyzoides, has shown anti-inflammatory property. Nevertheless, the antinociceptive activity and pre-clinical pharmacokinetics (PK) characteristics of 5'-MeONB remain unknown. Considering the anti-inflammatory potential of the 5'-MeONB, this study aimed to investigate the pre-clinical PK behavior of 5'-MeONB, as well as its time course antinociceptive activity. METHODS: 5'-MeONB plasma concentrations were determined in Wistar rats after intravenous (i.v.) (10 mg/kg) and oral (50 mg/kg) administration, and in Swiss mice after oral administration (100 mg/kg). Plasma samples were deproteinization and 5'-MeONB quantified by a validated UPLC-MS method. Additionally, the antinociceptive activity of 5'-MeONB was evaluated after 15, 30, 60, 180 and 360 min following oral administration on the acute nocifensive behavior of mice induced by formalin. RESULTS: 5'-MeONB rats and mice plasma concentration-time profiles were best one-compartment model. After i.v. administration to rats, a short half-life, a high clearance and moderate volume of distribution at steady state were observed. Similar results were obtained after oral administration. The oral bioavailability ranged from 8 to 11%. Additionally, 5'-MeONB exhibited antinociceptive activity in both formalin phases, especially in the inflammatory phase of the model, inhibiting 68% and 91% of neurogenic and inflammatory responses, respectively, after 30 min of oral administration. CONCLUSIONS: The results described here provide novel insights on 5'-MeONB pharmacokinetics and pharmacodynamic effect, serving as support for future studies to confirm this compound as anti-nociceptive and anti-inflammatory effective agent.
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Ageratum , Administración Oral , Analgésicos/farmacología , Animales , Antiinflamatorios/farmacología , Cromatografía Liquida , Formaldehído , Ratones , Ratas , Ratas Wistar , Espectrometría de Masas en TándemRESUMEN
Adipose tissue accumulation, resulting from the consumption of hypercaloric foods, can cause a dysfunction of the endocrine system. Such endocrine changes can influence the expression of various neurochemicals including brain-derived neurotrophic factor (BDNF) - associated with cognitive and emotional problems. Here, we investigated the effects of a hypercaloric diet on depression- and anxiety-like behaviors in young rats along with concomitant changes in BDNF expression levels in the hippocampus. Eight week-old Wistar rats (n = 20) were divided in: control diet (CD) group which received industrial food (n = 8) and hypercaloric diet (HD) group which received animal fat and soybean oil (n = 12). After 45 days on the diet, the animals were evaluated: body weight and blood biochemical analisys. Changes in mood disposition were evaluated using forced swim test and the elevated plus-maze, whereas hippocampal BDNF expression levels were quantified by ELISA. After 45 weeks, the CD group showed a significant increase in body weight relative to the HD group. However, the HD rats had a body fat percentage and exhibited increased level of the biochemical markers. Furthermore, the animals in the HD group presented increased immobility time in the forced swimming test, as well as reduced response to plus-maze test suggesting a depression- and anxiety-like emotional state. In addition, the HD group also showed lower BDNF expression levels in the hippocampus. This study demonstrates that a hypercaloric diet induced increase in adipose tissue concentration in young rats was associated with reduced hippocampal BDNF expression and resulted in an increase in depression- and anxiety-like behaviors. Graphical abstract.
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Afecto/fisiología , Ansiedad/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Depresión/metabolismo , Dieta Alta en Grasa , Hipocampo/metabolismo , Animales , Peso Corporal/fisiología , Masculino , Aprendizaje por Laberinto/fisiología , Ratas , Ratas Wistar , NataciónRESUMEN
AIM: To investigate the mechanism of action of sulfonyl(thio)urea derivative (SD) on glycemia and on insulin secretion in pancreatic islets. METHODS: Wistar rats were divided into hyperglycemic control group, rats received 4 g/kg body weight glucose plus sitagliptin 10 mg/kg (p.o.); hyperglycemic plus SD 10 mg/kg (p.o.); hyperglycemic plus SD plus sitagliptin. Blood was collected before glucose overloading (zero time), and at 15, 30, 60, and 180 min after glucose, from the afore mentioned groups for glycemia and glucagon-like peptide 1 (GLP-1) measurements and intestinal disaccharidases activity. Pancreatic islets were isolated for the calcium influx and insulin secretion in in vitro studies. RESULTS: SD reduced glycemia and increased GLP-1 secretion, while inhibited sucrase and lactase activity. This SD (1.0 and 10.0 µM) stimulated calcium influx in a similar percentile to that of glibenclamide, and in a nonsynergic manner. In addition, the trigger effect of SD on calcium influx was through the K+ -ATP-dependent channels, and partially by activating voltage-dependent K + channels and voltage-dependent calcium channels. Furthermore, SD-stimulated Na + and Ca 2+ entry, induced by the transient receptor potential ankyrin 1 and by modulation of Na + /Ca 2+ exchange. The activation of these pathways by SD culminated in in vitro insulin secretion, reinforcing the critical role of K + -ATP channels in the secretagogue effect of SD. CONCLUSIONS: SD diminish glycemia by inducing GLP-1 secretion and inhibiting disaccharidases. To our knowledge, this is the first report of an insulin secretagogue effect of SD that is mediated by potassium and calcium, as well as sodium, signal transduction.
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Hipoglucemiantes/farmacología , Secreción de Insulina/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Compuestos de Sulfonilurea/farmacología , Animales , Canales de Calcio/efectos de los fármacos , Canales de Calcio/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Hiperglucemia/metabolismo , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Masculino , Canales de Potasio con Entrada de Voltaje/efectos de los fármacos , Canales de Potasio con Entrada de Voltaje/metabolismo , Ratas , Ratas Wistar , Fosfato de Sitagliptina/farmacología , Canales de Sodio Activados por Voltaje/efectos de los fármacos , Canales de Sodio Activados por Voltaje/metabolismoRESUMEN
In sepsis, greater understanding of the inflammatory mechanism involved would provide insights into the condition and into its extension to the muscular apparatus in critically ill patients. Therefore, this study evaluates the inflammatory profile of pneumosepsis induced by Klebsiella pneumoniae (K.p.) in lungs and skeletal muscles during the first 72â¯h. Male BALB/c mice were divided into 4 groups, submitted to intratracheal inoculation of K.p. at a concentration of 2â¯×â¯108 (PS) or PBS, and assessed after 24 (PS24), 48 (PS48) and 72 (PS72) hours. The Maximum Physical Capacity Test (MPCT) was performed before and after induction. Pulmonary inflammation was assessed by total cell number, nitric oxide levels (NOx), IL-1ß and TNF-α levels in bronchoalveolar lavage fluid (BALF); inflammation and muscle trophism were evaluated by the levels of TNF-α, IL-6, TGF-ß and BDNF by ELISA and NF-κB by western blotting in muscle tissue. Cells and colony forming units (CFU) were also analyzed in blood samples. The PS groups showed an increase in total cells in the BALF (pâ¯<â¯0.05), as well in the number of granulocytes in the blood (pâ¯<â¯0.05) and a decrease in performance in the MPCT (pâ¯<â¯0.05). NOx levels showed significant increase in PS72, when compared to Control group (pâ¯=â¯0.03). The PS24 showed a significant increase lung in TNF-α levels (pâ¯<â¯0.001) and in CFU (pâ¯=â¯0.013). We observed an increase in muscular IL-6 and nuclear NF-κB levels in PS24 group, when compared to PS48 and Control groups (pâ¯<â¯0.05). Nevertheless, mild signs of injury in the skeletal muscle tissue does not support the idea of an early muscular injury in this experimental model, suggesting that the low performance of the animals during the MPCT may be related to lung inflammation.
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Biomarcadores/metabolismo , Inflamación/patología , Pulmón/patología , Músculos/patología , Sepsis/patología , Animales , Recuento de Células , Citocinas/metabolismo , Granulocitos/metabolismo , Klebsiella pneumoniae/fisiología , Pulmón/microbiología , Masculino , Ratones Endogámicos BALB C , Músculos/microbiología , Sepsis/microbiología , Análisis de Supervivencia , Factores de TiempoRESUMEN
Upper limb nerve injuries are common, and their treatment poses a challenge for physicians and surgeons. Experimental models help in minimum exploration of the functional characteristics of peripheral nerve injuries of forelimbs. This study was conducted to characterize the functional recovery (1, 3, 7, 10, 14, and 21 days) after median and ulnar nerve crush in mice and analyze the histological and biochemical markers of nerve regeneration (after 21 days). Sensory-functional impairments appeared after 1 day. The peripheral nerve morphology, the nerve structure, and the density of myelin proteins [myelin protein zero (P0) and peripheral myelin protein 22 (PMP22)] were analyzed after 21 days. Cold allodynia and fine motor coordination recovery occurred on the 10th day, and grip strength recovery was observed on the 14th day after injury. After 21 days, there was partial myelin sheath recovery. PMP22 recovery was complete, whereas P0 recovery was not. Results suggest that there is complete functional recovery even with partial remyelination of median and ulnar nerves in mice.
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Nervio Mediano/fisiopatología , Recuperación de la Función , Remielinización , Nervio Cubital/fisiopatología , Animales , Masculino , Nervio Mediano/lesiones , Nervio Mediano/metabolismo , Ratones , Proteína P0 de la Mielina/metabolismo , Proteínas de la Mielina/metabolismo , Compresión Nerviosa , Nervio Cubital/lesiones , Nervio Cubital/metabolismoRESUMEN
Species of the Byrsonima genus are widely used in Brazil, especially for the treatment of gastrointestinal disorders. However, species from the Amazonian region are still poorly studied. Thus, we studied the antioxidant, antinociceptive, and anti-inflammatory activities of for Amazonian species, Byrsonima crispa, Byrsonima duckeana, Byrsonima garcibarrigae, and Byrsonima incarnata. Phenolic composition was determined by chemical and chromatographic methods. The aqueous extracts were evaluated in DPPH⢠, ABTS+⢠, and superoxide (O2â¢- ) tests, LPS-activated macrophage assay, and formalin test. All species contained a high phenolic and flavonoid content. We identified 15 phenolic compounds, including phenolic acids, hydroxycinnamic acids, flavonoids, and catechins. The extracts showed high antioxidant activity and were more active than quercetin at inhibiting nitric oxide release in the LPS-activated macrophage assay. B. duckeana and B. garcibarrigae showed higher in vivo antinociceptive and anti-inflammatory activities. B. garcibarrigae presented significant effect on the early phase of the formalin test, pointing to an antinociceptive mechanism distinct from traditional anti-inflammatory medicines. In conclusion, the pharmacological potential of these species is closely related to their flavonoid-rich chemical composition, which seems to act through antioxidant mechanisms. Copyright © 2017 John Wiley & Sons, Ltd.
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Analgésicos/farmacología , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Malpighiaceae/química , Extractos Vegetales/farmacología , Células 3T3-L1 , Animales , Brasil , Femenino , Macrófagos/efectos de los fármacos , Malpighiaceae/clasificación , Ratones , Óxido Nítrico/análisis , Dimensión del Dolor , Fenoles/farmacologíaRESUMEN
PURPOSE: This study evaluated the tissue and inflammatory responses to the use of simvastatin and poly(lactic-co-glycolic acid) + hydroxyapatite + ß-tricalcium phosphate (PLGA+HA+ßTCP) scaffold for bone repair. MATERIALS AND METHODS: Two defects of 5 mm in diameter were made in the calvaria of rats, which were shared into the following 6 groups: naive, sham, vehicle, PLGA+HA+ßTCP scaffold, simvastatin (4 mg/mL), and simvastatin with the scaffold. Tissue samples were collected at 1, 7, 15, 30, and 60 days after surgery. Inflammation was evaluated by interleukin-1 beta and tumor necrosis factor alpha quantification and by a hemogram, whereas bone repair was evaluated using densitometry and scanning electron microscopy. Data were statistically analyzed using ANOVA followed by post hoc tests (P < 0.05). RESULTS: There was an increased cytokine expression in the scaffold and simvastatin groups (P < 0.001 and P < 0.05, respectively) 1 day after surgery but no alterations on the hemogram were observed. It was found on bone tissue samples that 60 days after surgery all groups presented similar densitometry values and morphology characteristics, despite the occurrence of bone formation delay in the simvastatin group (P < 0.01). CONCLUSION: The use of simvastatin and PLGA+HA+ßTCP scaffold, associated or not, did not lead to improvement in bone repair.
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Regeneración Ósea/efectos de los fármacos , Fosfatos de Calcio/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inflamación/prevención & control , Ácido Láctico/uso terapéutico , Ácido Poliglicólico/uso terapéutico , Simvastatina/uso terapéutico , Cráneo/efectos de los fármacos , Andamios del Tejido , Animales , Fosfatos de Calcio/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Ácido Láctico/administración & dosificación , Ácido Poliglicólico/administración & dosificación , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Ratas , Ratas Wistar , Simvastatina/administración & dosificación , Cráneo/crecimiento & desarrollo , Cráneo/cirugíaRESUMEN
The MnSOD Ala16Val single nucleotide polymorphism (SNP) has shown to be associated to risk factors of several metabolic and vascular diseases. However, little is known about interaction between MnSOD Ala16Val SNP in stroke, a frequent neurologic disease that involves clinic manifestations such as motor deficits and spasticity. In this sense, we decided to investigate the relationship between MnSOD Ala16Val SNP with spasticity in stroke and also its influence on interleukin levels, BDNF, and glycolipid parameters. Eighty post-stroke subjects and 80 healthy controls were investigated. We showed a higher spasticity, levels of total cholesterol, LDL, IL-1ß, IL-6, and INF-γ in VV post-stroke group. Interesting, we found a correlation between IL-1ß levels and spasticity in VV post-stroke. Triglycerides, glucose levels and caspases (1 and 3) activation were significantly higher, as well as BDNF levels were lower in VV and AV post-stroke. DNA damage was higher in post-stroke group. Thus, we can suggest that the V allele has a worse glycolipid profile, which would facilitate changes in neurovascular homeostasis. These events associated with an increase in inflammatory markers and a reduction in BDNF can contribute with the stroke and a worse clinical evolution in relation to spasticity in patients with VV genotype.
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Interleucina-6 , Accidente Cerebrovascular , Factor Neurotrófico Derivado del Encéfalo/genética , Caspasas/genética , LDL-Colesterol/genética , Genotipo , Glucosa , Glucolípidos , Humanos , Interleucina-1beta/genética , Interleucina-6/genética , Espasticidad Muscular/genética , Polimorfismo de Nucleótido Simple , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/genética , Superóxido Dismutasa/genética , TriglicéridosRESUMEN
The association between chronic kidney disease (CKD) and pulmonary pathophysiological changes is well stablished. Nevertheless, the effects of aerobic exercise (AE) on lungs of CKD need further clarification. Thus, Swiss mice were divided in control, AE, CKD, and CKD + AE groups. CKD was induced by 0.2% adenine intake during 8 weeks (4 weeks of CKD induction and 4 weeks of AE). AE consisted in running on treadmill, at moderate intensity, 30 min/day, 5 days/week, during 4 weeks. Twenty-four hours after the last training day, functional capacity test was performed, and 48 h after the test, mice were euthanized. CKD mice showed a significant increase in urine output, serum urea, and creatinine concentrations, and decreased body weight and urine density, besides oxidative damage (p = 0.044), edema area (p < 0.001), leukocyte infiltration (p = 0.040), and collagen area in lung tissue (p = 0.004). AE resulted in an increase of distance traveled (p = 0.049) and maximum speed (p = 0.046), increased activity of catalase (p = 0.031) and glutathione peroxidase (p = 0.048) in lungs, increased levels of nitric oxide (NOx) in serum (p = 0.001) and bronchoalveolar lavage fluid (p = 0.047), and decreased kidney histological injury (p = 0.018) of CKD mice. However, AE also increased oxidative damage (p = 0.003) and did not change collagen content or perivascular edema in lungs (p > 0.05) of CKD mice. Therefore, AE attenuated kidney injury and improved antioxidants defenses in lungs. Despite no significant changes in pulmonary damage, AE significantly improved physical performance in CKD mice.
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Antioxidantes , Insuficiencia Renal Crónica , Adenina/farmacología , Animales , Antioxidantes/farmacología , Catalasa/metabolismo , Creatinina , Glutatión Peroxidasa , Riñón/patología , Pulmón/metabolismo , Ratones , Óxido Nítrico , Estrés Oxidativo , Rendimiento Físico Funcional , Insuficiencia Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/patología , Urea/farmacologíaRESUMEN
This study presents the development and validation of a fast and simple bioanalytical ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) method intended for quantifying the anti-inflammatory candidate 5'-methoxynobiletin (5'-MeONB) in rat plasma. Standard of 5'-MeONB was purified from A. conyzoides extract by using preparative HPLC. After a pretreatment of plasma samples with acetonitrile, chromatographic separations were efficiently achieved with a C18 column using a 9 min gradient system of 0.1% aqueous formic acid and acetonitrile as eluent. Drug candidate 5'-MeONB and chrysin (internal standard, IS) detection were carried out using ESI+ through the extracted ion chromatograms approach, monitored at m/z 433.1494 (for 5'-MeONB, tR:1.78 min) and m/z 255.0657 (for IS, tR:1.57 min). Method was validated according to US FDA guidelines, presenting linearity (R2 > 0.999) over concentration range of 30-750 ng/mL. Relative standard deviation (RSD) of repeatability and intermediary precision respectively ranged between 1.93-3.65% and 2.16-7.54%, considering lower limit of quantitation (30 ng/mL) and quality control (90, 360 and 600 ng/mL) samples, while accuracy was between 82.51 and 109.44%. Moreover, no interference from plasma endogenous substances, no carryover effect, and no influence of extraction method even in hemolyzed blood samples were observed. Sample stability in auto-sampler and long-term -80 °C storage, as well as matrix effect were within acceptable limits. For the first time, using the validated UPLC-MS bioanalytical method, the plasma pharmacokinetics of 5'-MeONB following 2 mg/kg intravenous bolus dosing to Wistar rats was characterized allowing the determination of the parameters describing drug distribution and elimination.
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Antiinflamatorios/sangre , Cromatografía Líquida de Alta Presión/métodos , Flavonas/sangre , Espectrometría de Masas en Tándem/métodos , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacocinética , Flavonas/química , Flavonas/farmacocinética , Límite de Detección , Modelos Lineales , Masculino , Ratas , Ratas Wistar , Reproducibilidad de los ResultadosRESUMEN
While chronic high-fat feeding has long been associated with the rising incidence of obesity/type 2 diabetes, recent evidence has established that it is also associated with deficits in hippocampus-dependent memory. In this regard, environmental enrichment (EE) is an animal housing technique composed of increased space, physical activity, and social interactions, which in turn increases sensory, cognitive, motor, and social stimulation. EE leads to improved cerebral health as defined by increased neurogenesis, enhanced learning and memory and resistance to external cerebral insults. In the present study, the impacts of environmental enrichment (EE) on Swiss mice fed a high-fat, cholesterol-enriched diet (HFECD; 20% fat and 1.5% cholesterol) were investigated. Here, we demonstrated that EE, when initiated 4 weeks after the beginning of HFECD in mice, prevents HFECD-induced spatial memory and object recognition impairment, which were tested in T-maze and object recognition tests. Although EE did not affect HFECD-induced weight gain or hypercholesterolaemia, it improved glucose tolerance. On the other hand, EE was unable to mitigate a decrease in brain-derived neurotrophic factor (BDNF) and IL-6 hippocampal levels induced by the HFECD. Overall, while our results reinforce the positive and neuroprotective effects of EE on cognition they do not support a role for EE in preventing the neurochemical changes induced by the HFECD. Based on clinical observations that nondiabetic individuals with mild forms of impaired glucose tolerance have a higher risk of cognitive impairments, one can speculate about the connection between the effects of EE on glucose intolerance and its effects on cognition.
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Colesterol/efectos adversos , Disfunción Cognitiva/terapia , Dieta Alta en Grasa/efectos adversos , Ambiente , Vivienda para Animales , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/patología , Modelos Animales de Enfermedad , Intolerancia a la Glucosa/etiología , Intolerancia a la Glucosa/metabolismo , Intolerancia a la Glucosa/patología , Intolerancia a la Glucosa/terapia , Hipocampo/metabolismo , Hipocampo/patología , Hipercolesterolemia/etiología , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patología , Hipercolesterolemia/psicología , Interleucina-6/metabolismo , Masculino , Ratones , Obesidad/etiología , Obesidad/metabolismo , Obesidad/patología , Obesidad/psicología , Distribución Aleatoria , Reconocimiento en Psicología , Memoria EspacialRESUMEN
BACKGROUND: Neuropathic pain is relatively common and occurs in approximately 6-8% of the population. It is associated with allodynia and hyperalgesia. Thus, non-pharmacological treatments, such as transcranial direct current stimulation (tDCS) may be useful for relieving pain. OBJECTIVES: This study aimed to investigate the antiallodynic effect of tDCS in a mice model of neuropathic pain, and the underlying neurotransmission systems that could drive these effects. METHODS: Male, Swiss mice, weighing 25-35â¯g, were subjected to partial sciatic nerve ligation (PSNL). Allodynia was assessed using a Von Frey filament (0.6â¯g). First, the behavioral time-course of these mice was assessed after 5, 10, 15 and 20â¯min of tDCS (0.5â¯mA). Second, the mice that underwent PSNL were assigned to either the tDCS (0.5â¯mA, 15â¯min) or tDCS sham group, and further assigned to receive either saline or a drug (i.e., naloxone, yohimbine, a-methyl-p-tyrosine, q-chlorophenylalanine methyl ester, caffeine, 1,3-dipropyl-8-cyclopentylxanthine, AM281, AM630, flumazenil, MK-801, or lidocaine). RESULTS: The antiallodynic effect of tDCS lasted 2â¯h and 4â¯h, after 10â¯min and 15 or 20â¯min of treatment, respectively (Pâ¯<â¯.001, Pâ¯<â¯.01, and Pâ¯<â¯.05, respectively). The antiallodynic effect of tDCS was associated with all the systems that were analyzed, i.e., the opioidergic (Pâ¯<â¯.01), adenosinergic (Pâ¯<â¯.001), serotonergic (Pâ¯<â¯.01), noradrenergic (Pâ¯<â¯.001), cannabinoid (Pâ¯<â¯.001), GABAergic, and glutamatergic (Pâ¯<â¯.001) systems. Lidocaine did not reverse the antiallodynic effect of tDCS (Pâ¯>â¯.05). CONCLUSION: The antiallodynic effect of tDCS was associated with different neurotransmitters systems; the duration of these after-effects depended on the time exposure to tDCS.
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Hiperalgesia/etiología , Hiperalgesia/terapia , Neuralgia/complicaciones , Neuralgia/terapia , Umbral del Dolor/fisiología , Estimulación Transcraneal de Corriente Directa/métodos , Antagonistas del Receptor de Adenosina A1/uso terapéutico , Animales , Cafeína/uso terapéutico , Estimulantes del Sistema Nervioso Central/uso terapéutico , Modelos Animales de Enfermedad , Maleato de Dizocilpina/uso terapéutico , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Flumazenil/uso terapéutico , Moduladores del GABA/uso terapéutico , Masculino , Ratones , Morfolinas/uso terapéutico , Naloxona/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Estimulación Física/efectos adversos , Pirazoles/uso terapéutico , Xantinas/uso terapéuticoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Discaria americana (Rhamnaceae) root bark infusion have been used in traditional medicine as antipyretic, tonic, ameliorative of stomach and skin diseases and diabetes. This study was designed to investigate whether the methanolic extract of the root bark of Discaria americana (MEDa) exhibits antinociceptive effects in mice. Furthermore, it was investigated the involvement of the opioidergic system in MEDa mechanism of action as well the interactions with TRP/ASIC channels in its effect. MATERIALS AND METHODS: The antinociceptive effect of intra-gastric gavage (i.g.) of MEDa (0.3-300â¯mg/kg) was evaluated in mice subjected to acute chemical (acetic-acid, formalin, glutamate, capsaicin, cinnamaldehyde, and acidified saline) or thermal (hot plate) tests of pain. The involvement of opioid system was evaluated in the formalin test. A nonspecific effect of MEDa was observed by measuring locomotor activity and exploratory behavior in open field test. RESULTS: MEDa significantly reduced the number of writhing induced by acetic acid and inhibited the nociception in the two phases of formalin. These effects were inhibited by pretreatment with naloxone. The nociception induced by hot plate and intraplantar injection of glutamate, capsaicin, cinnamaldehyde and acidified saline were significantly inhibited by MEDa. Only the dose of 300â¯mg/kg altered the locomotor activity. CONCLUSIONS: Our results demonstrated, for the first time, that the methanolic extract of the root bark of Discaria americana presents antinociceptive effect in chemical and thermal stimuli and its analgesic properties can be due activation of the opioidergic system. These results support the use of Discaria americana in traditional medicine and demonstrate that this plant presents a therapeutic potential for the development of phytomedicines with antinociceptive profile.
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Analgésicos Opioides/uso terapéutico , Dolor/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Rhamnaceae , Bloqueadores del Canal Iónico Sensible al Ácido/farmacología , Analgésicos Opioides/farmacología , Animales , Conducta Animal/efectos de los fármacos , Masculino , Ratones , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Fitoterapia , Corteza de la Planta , Extractos Vegetales/farmacología , Raíces de Plantas , Canales de Potencial de Receptor Transitorio/antagonistas & inhibidoresRESUMEN
Hyperammonemia is a common finding in patients with methylmalonic acidemia. However, its contribution to methylmalonate (MMA)-induced neurotoxicity is poorly understood. The aim of this study was evaluate whether an acute metabolic damage to brain during the neonatal period may disrupt cerebral development, leading to neurodevelopmental disorders, as memory deficit. Mice received a single intracerebroventricular dose of MMA and/or NH4Cl, administered 12â¯hs after birth. The maze tests showed that MMA and NH4Cl injected animals (21 and 40 days old) exhibited deficit in the working memory test, but not in the reference memory test. Furthermore, MMA and NH4Cl increased the levels of 2',7'-dichlorofluorescein-diacetate (DCF), TNF-α, IL-1ß in the cortex, hippocampus and striatum of mice. MMA and NH4Cl also increased glial proliferation in all structures. Since the treatment of MMA and ammonia increased cytokines levels, we suggested that it might be a consequence of the glial activation induced by the acid and ammonia, leading to delay in the developing brain and contributing to behavioral alterations. However, this hypothesis is speculative in nature and more studies are needed to clarify this possibility.
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Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Amoníaco/metabolismo , Encéfalo/metabolismo , Hiperamonemia/metabolismo , Neuroglía/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/inducido químicamente , Errores Innatos del Metabolismo de los Aminoácidos/patología , Errores Innatos del Metabolismo de los Aminoácidos/psicología , Cloruro de Amonio , Animales , Conducta Animal , Encéfalo/patología , Encéfalo/fisiopatología , Proliferación Celular , Modelos Animales de Enfermedad , Fluoresceínas/metabolismo , Hiperamonemia/inducido químicamente , Hiperamonemia/patología , Hiperamonemia/psicología , Interleucina-1beta/metabolismo , Masculino , Malonatos , Aprendizaje por Laberinto , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/psicología , Memoria a Corto Plazo , Ratones , Neuroglía/patología , Compuestos de Amonio Cuaternario , Factores de Tiempo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Pramipexole (PPX), a dopamine D2/3 receptor preferring agonist, is currently in use for the treatment of Parkinson's disease symptoms and restless legs syndrome. Recently, anti-inflammatory properties of PPX have been shown in an autoimmune model of multiple sclerosis, and case reports indicate PPX ameliorates depressive symptoms. Since peripheral inflammation is known to induce depression-like behavior in rodents, we assessed the potential antidepressant effect of PPX in an inflammatory model of depression induced by LPS. Repeated (daily for 7days, 1mg/kg, i.p.), but not acute (1h before LPS) treatment with PPX abolished the depression-like behavior induced by LPS (0.1mg/kg, i.p.) in the forced swim test, and the anhedonic behavior in the splash test. Interestingly, PPX per se decreased interleukin 1ß levels and reversed LPS-induced increase in its content in mice hippocampusâ Repeated PPX treatment also prevented the increase in hippocampal levels of the 3-nitrotyrosine protein adducts induced by LPS. Haloperidol (0.2mg/kg, i.p.) and sulpiride (50mg/kg, i.p.) were unable to prevent the antidepressant-like effect of PPX in LPS-treated mice. Altogether, these results suggest that the observed antidepressant-like effect of PPX in LPS-treated mice may be dependent on its anti-inflammatory properties and may not be related to dopamine D2 receptor activation.
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Benzotiazoles/uso terapéutico , Depresión/tratamiento farmacológico , Depresión/etiología , Agonistas de Dopamina/uso terapéutico , Inflamación/complicaciones , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Conducta de Enfermedad/fisiología , Inflamación/inducido químicamente , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos/toxicidad , Locomoción/efectos de los fármacos , Malondialdehído/metabolismo , Ratones , Pramipexol , Natación/psicología , Factores de Tiempo , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMEN
Methylmalonic acid (MMA) accumulates in tissues in methylmalonic acidemia, a heterogeneous group of inherited childhood diseases characterized by neurological dysfunction, oxidative stress and neuroinflammation; it is associated with degeneration of striatal neurons and cerebral cortical atrophy. It is presently unknown, however, whether transient exposure to MMA in the neonatal period is sufficient to trigger inflammatory and apoptotic processes that lead to brain structural damage. Here, newborn mice were given a single intracerebroventricular dose of MMA at 12 hours after birth. Maze testing of 21- and 40-day-old mice showed that MMA-injected animals exhibited deficit in the working memory test but not in the reference test. MMA-injected mice showed increased levels of the reactive oxygen species marker 2',7'-dichlorofluorescein diacetate, tumor necrosis factor, interleukin-1ß, caspases 1, 3, and 8, and increased acetylcholinesterase activity in the cortex, hippocampus and striatum. This was associated with increased astrocyte and microglial immunoreactivity in all brain regions. These findings suggest that transient exposure to MMA may alter the redox state and cause neuroinflammatory/apoptotic processes and glial activation during critical periods of brain development. Similar processes may underlie brain dysfunction and cognitive impairment in patients with methylmalonic acidemia.
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Apoptosis/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Mediadores de Inflamación/metabolismo , Ácido Metilmalónico/toxicidad , Neuroglía/metabolismo , Animales , Apoptosis/fisiología , Encéfalo/patología , Células Cultivadas , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Neuroglía/patología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiologíaRESUMEN
The effect of 3ß-hidroxihop-22(29)ene (3-BHO) on insulin and glucagon-like peptide 1 (GLP-1) secretion as well as the mechanism of action of the compound in pancreatic islet on glucose homeostasis was investigated. The data from in vivo treatment show that 3-BHO significantly reduces the hyperglycemia by increasing the insulin and GLP-1 secretion, as well as by accumulating hepatic glycogen in hyperglycemic rats. In rat pancreatic ß-cell, 3-BHO stimulates the glucose uptake, insulin vesicles translocation to the plasma membrane and thus the insulin secretion through the involvement of potassium channels (ATP- and Ca(2+)-dependent K(+) channels) and calcium channels (L-type voltage-dependent calcium channels (L-VDCC)). Furthermore, this study also provides evidence for a crosstalk between intracellular high calcium concentration, PKA and PKC in the signal transduction of 3-BHO to stimulate insulin secretion. In conclusion, 3-BHO diminishes glycaemia, stimulates GLP-1 secretion and potentiates insulin secretion and increase hepatic glycogen content. Moreover, this triterpene modulates calcium influx characterizing ATP-K(+), Ca(2+)-K(+) and L-VDCC channels-dependent pathways as well as PKA and PKC activity in pancreatic islets underlying the signaling of 3-BHO for the secretory activity and contribution on glucose homeostasis.
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Canales de Calcio Tipo L/metabolismo , Péptido 1 Similar al Glucagón/sangre , Insulina/metabolismo , Islotes Pancreáticos/efectos de los fármacos , Canales KATP/metabolismo , Canales de Potasio Calcio-Activados/metabolismo , Triterpenos/farmacología , Animales , Transporte Biológico , Calcio/metabolismo , Canales de Calcio Tipo L/genética , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Regulación de la Expresión Génica , Péptido 1 Similar al Glucagón/genética , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Glucógeno/metabolismo , Homeostasis/genética , Humanos , Insulina/sangre , Secreción de Insulina , Islotes Pancreáticos/citología , Islotes Pancreáticos/metabolismo , Canales KATP/genética , Masculino , Canales de Potasio Calcio-Activados/genética , Proteína Quinasa C/genética , Proteína Quinasa C/metabolismo , Ratas , Ratas Wistar , Transducción de Señal , Técnicas de Cultivo de TejidosRESUMEN
Motor and sensory regeneration was studied in a 40 mm long graft interposed between the sectioned stumps of the rat median nerve. Animals were behaviorally assessed from 1 to 720 days after surgery by the grasping and modified Randall-Sellito tests. Rats recovered grasping function 43.7 (S.D. +/- 2.6) days after surgery. Grasping strength attained 50 and 65% of the normal control group, 280 and 360 days after surgery, respectively. From 90 to 360 days after surgery, sensory nociceptive recovery was only 30% of the normal control group. The results indicate that motor and sensory neurons were capable of regenerating additional axonal length, but functional return was clearly better in the motor system. This model of deficient reinnervation might prove to be of interest in testing of new strategies for the enhancement of nerve recovery.
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Nervio Mediano/trasplante , Destreza Motora/fisiología , Regeneración Nerviosa/fisiología , Umbral Sensorial/fisiología , Animales , Femenino , Fuerza de la Mano/fisiología , Nervio Mediano/lesiones , Ratas , Ratas Wistar , TrasplantesRESUMEN
BACKGROUND: This study was conducted to test whether the IBB Forelimb Scale (Irvine et al., 2010) which was originally developed for rats with spinal cord injury, is also capable of measuring the functional performance of Swiss mice with lesions of the median and ulnar nerves inflicted via crushing with standardized strength. NEW METHOD: This test was performed at days 1, 3, 7, 10, 14 and 21 after surgery and each animal gives a score of 9, where 0 represented the worst functionality and 9 represented the habitual behavior. RESULTS: The control animals usually exhibited movements in the task that were scored as 9 during the experimental period. The lesion group began with a score of 2 on the 1st and 3rd post-operative days. On the 7th and 10th postoperative days, respectively, they scored 7, and on the 14th post-operative day, they achieved a score of 8. Only on the 21st post-operative day, did they exhibit habitual skillful behaviors. COMPARISON WITH EXISTING METHOD(S): IBB Forelimb Scale is effective for determining how the animals perform the movements in detail, which is not readily revealed by other methods. Furthermore, this test show similar recovery periods with grasping test, staircase test and seems to be more sensitive than paw print analysis for this type of lesion. CONCLUSIONS: Our data demonstrate that IBB scale was capable of measuring gradual improvements in motor forelimb functions in this model and may be a new and effective assessment tool for peripheral nerve injury.
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Evaluación de la Discapacidad , Miembro Anterior , Nervio Mediano/lesiones , Traumatismos de los Nervios Periféricos/diagnóstico , Recuperación de la Función , Nervio Cubital/lesiones , Animales , Fenómenos Biomecánicos , Diagnóstico Diferencial , Modelos Animales de Enfermedad , Miembro Anterior/fisiopatología , Masculino , Ratones , Destreza Motora/fisiología , Traumatismos de los Nervios Periféricos/fisiopatología , Distribución Aleatoria , Índice de Severidad de la Enfermedad , Análisis y Desempeño de Tareas , Factores de TiempoRESUMEN
RATIONALE: There are evidences indicating the role of kinins in pathophysiology of traumatic brain injury, but little is known about their action on memory deficits. OBJECTIVES: Our aim was to establish the role of bradykinin receptors B1 (B1R) and B2 (B2R) on the behavioral, biochemical, and histologic features elicited by moderate lateral fluid percussion injury (mLFPI) in mice. METHODS: The role of kinin B1 and B2 receptors in brain damage, neuromotor, and cognitive deficits induced by mLFPI, was evaluated by means of subcutaneous injection of B2R antagonist (HOE-140; 1 or 10 nmol/kg) or B1R antagonist (des-Arg9-[Leu8]-bradykinin (DAL-Bk; 1 or 10 nmol/kg) 30 min and 24 h after brain injury. Brain damage was evaluated in the cortex, being considered as lesion volume, inflammatory, and oxidative damage. The open field and elevated plus maze tests were performed to exclude the nonspecific effects on object recognition memory test. RESULTS: Our data revealed that HOE-140 (10 nmol/kg) protected against memory impairment. This treatment attenuated the brain edema, interleukin-1ß, tumor necrosis factor-α, and nitric oxide metabolites content elicited by mLFPI. Accordingly, HOE-140 administration protected against the increase of nicotinamide adenine dinucleotide phosphate oxidase activity, thiobarbituric-acid-reactive species, protein carbonylation generation, and Na⺠K⺠ATPase inhibition induced by trauma. Histologic analysis showed that HOE-140 reduced lesion volume when analyzed 7 days after brain injury. CONCLUSIONS: This study suggests the involvement of the B2 receptor in memory deficits and brain damage caused by mLFPI in mice.