RESUMEN
CONTEXT: Curcumin has been reported to have anti-inflammatory, antioxidant and hypoglycaemic properties, besides reducing mortality in sepsis. OBJECTIVE: This study evaluates the biological activities of a curcumin dispersion formulated by spray-drying in experimental sepsis. MATERIALS AND METHODS: Male Wistar rats were subjected to sepsis by caecal ligation and puncture (CLP), controls were sham operated. The animals were treated with curcumin dispersion (100 mg/kg, p.o.) or water for 7 days prior to CLP and at 2 h after surgery. One group was used to analyze curcumin absorption through HPLC; another had the survival rate assessed during 48 h; and from a third group, blood was collected by decapitation to analyze metabolic and inflammatory parameters. RESULTS: The plasma curcumin levels reached 2.5 ng/mL at 4 h, dropped significantly (p < 0.001) at 6 h (1.2 ng/mL), and were undetectable at 24 h in both groups. Curcumin temporarily increased the survival rate of the septic rats by 20%. Moreover, it attenuated glycaemia (p < 0.05) and volemia (p < 0.05) alterations typically observed during sepsis, and decreased the levels of the proinflammatory cytokines IL-1ß and IL-6 in plasma (p < 0.001) and peritoneal lavage fluid (p < 0.05) of septic rats. Serum HSP70 levels were decreased (p < 0.01) at 24 h after CLP. DISCUSSION AND CONCLUSION: Our results show that the curcumin dispersion dose employed was not detrimental to the septic rats. In fact, it temporarily increased their survival rate, improved important metabolic parameters, reduced proinflammatory cytokines and HSP70 production.
Asunto(s)
Antiinflamatorios/farmacología , Curcumina/farmacología , Citocinas/sangre , Proteínas HSP70 de Choque Térmico/sangre , Mediadores de Inflamación/sangre , Sepsis/tratamiento farmacológico , Animales , Antiinflamatorios/sangre , Antiinflamatorios/química , Antiinflamatorios/farmacocinética , Biomarcadores/sangre , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Volumen Sanguíneo/efectos de los fármacos , Ciego/microbiología , Ciego/cirugía , Curcumina/química , Curcumina/farmacocinética , Modelos Animales de Enfermedad , Formas de Dosificación , Regulación hacia Abajo , Composición de Medicamentos , Hipoglucemiantes/farmacología , Ligadura , Masculino , Nitratos/sangre , Punciones , Ratas Wistar , Sepsis/sangre , Sepsis/microbiología , Factores de TiempoRESUMEN
Inhibition of GABAergic neural inputs to dorsal columns of the periaqueductal grey matter (dPAG), posterior (PH) and dorsomedial (DMH) hypothalamic nuclei elicits distinct types of escape behavioural reactions. To differentiate between the variety and intensity of panic-related behaviours, the pattern of defensive behaviours evoked by blockade of GABAA receptors in the DMH, PH and dPAG were compared in a circular open-field test and in a recently designed polygonal arena. In the circular open-field, the defensive behaviours induced by microinjection of bicuculline into DMH and PH were characterised by defensive alertness behaviour and vertical jumps preceded by rearing exploratory behaviour. On the other hand, explosive escape responses interspersed with horizontal jumps and freezing were observed after the blockade of GABAA receptors on dPAG neurons. In the polygonal arena apparatus, the escape response produced by GABAergic inhibition of DMH and PH neurons was directed towards the burrow. In contrast, the blockade of GABAA receptors in dPAG evoked non-oriented escape behaviour characterised by vigorous running and horizontal jumps in the arena. Our findings support the hypothesis that the hypothalamic nuclei organise oriented escape behavioural responses whereas non-oriented escape is elaborated by dPAG neurons. Additionally, the polygonal arena with a burrow made it easy to discriminate and characterise these two different patterns of escape behavioural responses. In this sense, the polygonal arena with a burrow can be considered a good methodological tool to discriminate between these two different patterns of escape behavioural responses and is very useful as a new experimental animal model of panic attacks.
Asunto(s)
Reacción de Fuga , Vivienda para Animales , Pruebas Psicológicas , Animales , Bicuculina/administración & dosificación , Diseño de Equipo , Reacción de Fuga/efectos de los fármacos , Reacción de Fuga/fisiología , Antagonistas de Receptores de GABA-A/administración & dosificación , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Microinyecciones , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Sustancia Gris Periacueductal/efectos de los fármacos , Sustancia Gris Periacueductal/metabolismo , Ratas Wistar , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/metabolismoRESUMEN
BACKGROUND: The aim of the present work was to investigate the involvement of the µ1-endogenous opioid peptide receptor-mediated system in post-ictal antinociception. METHODS: Antinociceptive responses were determined by the tail-flick test after pre-treatment with the selective µ1-opioid receptor antagonist naloxonazine, peripherally or centrally administered at different doses. RESULTS: Peripheral subchronic (24 h) pre-treatment with naloxonazine antagonised the antinociception elicited by tonic-clonic seizures. Acute (10 min) pre-treatment, however, did not have the same effect. In addition, microinjections of naloxonazine into the central, dorsal cortical and external cortical nuclei of the inferior colliculus antagonised tonic-clonic seizure-induced antinociception. Neither acute (10-min) peripheral pre-treatment with naloxonazine nor subchronic intramesencephalic blockade of µ1-opioid receptors resulted in consistent statistically significant differences in the severity of tonic-clonic seizures shown by Racine's index (1972), although the intracollicular specific antagonism of µ1-opioid receptor decreased the duration of seizures. CONCLUSION: µ1-Opioid receptors and the inferior colliculus have been implicated in several endogenous opioid peptide-mediated responses such as antinociception and convulsion. The present findings suggest the involvement of µ1-opiate receptors of central and pericentral nuclei of the inferior colliculus in the modulation of tonic-clonic seizures and in the organisation of post-ictal antinociception.
Asunto(s)
Colículos Inferiores/efectos de los fármacos , Péptidos Opioides/metabolismo , Pentilenotetrazol/administración & dosificación , Receptores Opioides mu/metabolismo , Animales , Colículos Inferiores/metabolismo , Masculino , Naloxona/administración & dosificación , Naloxona/análogos & derivados , Naloxona/farmacología , Pentilenotetrazol/farmacología , Ratas , Ratas Wistar , Receptores Opioides mu/antagonistas & inhibidores , Convulsiones/inducido químicamente , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiologíaRESUMEN
The postictal state is generally followed by antinociception. It is known that connections between the dorsal raphe nucleus, the periaqueductal gray matter, and the locus coeruleus, an important noradrenergic brainstem nucleus, are involved in the descending control of ascending nociceptive pathways. The aim of the present study was to determine whether noradrenergic mechanisms in the locus coeruleus are involved in postictal antinociception. Yohimbine (an α(2)-receptor antagonist) or propranolol (a ß-receptor antagonist) was microinjected unilaterally into the locus coeruleus, followed by intraperitoneal administration of pentylenetetrazole (PTZ), a noncompetitive antagonist that blocks GABA-mediated Cl(-) influx. Although the administration of both yohimbine and propranolol to the locus coeruleus/subcoeruleus area resulted in a significant decrease in tonic or tonic-clonic seizure-induced antinociception, the effect of yohimbine restricted to the locus coeruleus was more distinct compared with that of propranolol, possibly because of the presynaptic localization of α(2)-noradrenergic receptors in locus coeruleus neurons. These effects were related to the modulation of noradrenergic activity in the locus coeruleus. Interestingly, microinjections of noradrenaline into the locus coeruleus also decrease the postictal antinociception. The present results suggest that the mechanism underlying postictal antinociception involves both α(2)- and ß-noradrenergic receptors in the locus coeruleus, although the action of noradrenaline on these receptors causes a paradoxical effect, depending on the nature of the local neurotransmission.
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Neuronas Adrenérgicas/efectos de los fármacos , Locus Coeruleus/citología , Norepinefrina/farmacología , Umbral del Dolor/efectos de los fármacos , Receptores Adrenérgicos alfa 2/metabolismo , Convulsiones/fisiopatología , Transmisión Sináptica/efectos de los fármacos , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Antagonistas de Receptores Adrenérgicos alfa 2/uso terapéutico , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Vías de Administración de Medicamentos , Esquema de Medicación , Interacciones Farmacológicas , Locus Coeruleus/efectos de los fármacos , Masculino , Microinyecciones , Dimensión del Dolor/efectos de los fármacos , Pentilenotetrazol/toxicidad , Propranolol/farmacología , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacos , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Yohimbina/farmacología , Yohimbina/uso terapéuticoRESUMEN
The aim of this study was to investigate the capacity of the host dendrimer DAB-Am-16 as a drug carrier to reduce the time required for the encapsulated naloxonaxine to establish an irreversible covalent bond with µ(1)-opioid receptor (resulting in a pharmacologically selective effect). The efficacy of dendrimer-naloxonazine nanocomplex (DNC) was studied in antinociception induced by convulsions elicited by intraperitoneal (IP) administration of pentylenetetrazole, and analgesia was measured by the tail-flick test. We found that animals showed increased tail-flick latencies following convulsions. Furthermore, acute pre-treatment (10 minutes) with DNC, but not with naloxonazine alone, antagonized post-ictal analgesia in comparison with control pre-treatment. However, naloxonazine treatment 24 hours before PTZ decreased post-ictal antinociception, but DNC failed to antagonize tonic-clonic seizure-induced analgesia. In addition, according to Racine's index of seizure severity, naloxonazine, DAB-Am-16 dendrimer or DNC did not influence seizure severity when administered either 10 minutes or 24 hours before PTZ. FROM THE CLINICAL EDITOR: This study characterizes the effect of a dendrimer-naloxonazine complex on µ1 receptor-mediated post-ictal antinociception in an animal model of seizure disorder.
Asunto(s)
Dendrímeros/química , Portadores de Fármacos/química , Naloxona/análogos & derivados , Antagonistas de Narcóticos/administración & dosificación , Polipropilenos/química , Receptores Opioides mu/metabolismo , Analgesia , Animales , Masculino , Naloxona/administración & dosificación , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Pentilenotetrazol , Ratas , Ratas Wistar , Convulsiones/inducido químicamenteRESUMEN
Defensive behaviour has been extensively studied, and non-invasive methodologies may be interesting approaches to analyzing the limbic system function as a whole. Using experimental models of animals in the state of anxiety has been fundamental in the search for new anxiolytic and antipanic compounds. The aim of this present work is to examine a new model for the study of affective behaviour, using a complex labyrinth consisting of an arena and galleries forming a maze. Furthermore, it aims to compare the defensive behaviour of Wistar rats, Mongolian gerbils and golden hamsters in a complex labyrinth, as well as the defensive behaviour of Meriones unguiculatus in aggressive encounters with either Epicrates cenchria assisi or Boa constrictor amarali in this same model. Among species presently studied, the Mongolian gerbils showed better performance in the exploration of both arena and galleries of the labyrinth, also demonstrating less latency in finding exits of the galleries. This increases the possibility of survival, as well as optimizes the events of encounter with the predator. The duration of alertness and freezing increased during confrontation with living Epicrates, as well as the duration of exploratory behaviour in the labyrinth. There was an increase in the number of freezing and alertness behaviours, as well as in duration of alertness during confrontations involving E.c. assisi, compared with behavioural reactions elicited by jirds in presence of B.c. amarali. Interestingly, the aggressive behaviour of Mongolian gerbils was more prominent against B.c. amarali compared with the other Boidae snake. E.c. assisi elicited more offensive attacks and exhibited a greater time period of body movement than B.c. amarali, which spent more time in the arena and in defensive immobility than the E.c. assisi. Considering that jirds evoked more fear-like reaction in contact with E.c. assisi, a fixed E.c. assisi kept in a hermetically closed acrylic box was used as control. In these prey/predator encounter-based experiments, there was an increase in the number of alertness and freezing behaviours exhibited by gerbils, and a decrease in the number of crossing elicited by them, when comparing confrontations between the living E.c. assisi and the control. The experiments were performed at 7.0 p.m. In the labyrinth, the snakes showed in confrontation similar performance to that observed in nature (organizing hunting behaviour, offensive/defensive attack, constriction, prey inspection and feeding behaviour), which were essential to the validity of the experiments and gave behavioural validation within the complex labyrinth.
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Modelos Biológicos , Conducta Predatoria/fisiología , Animales , Ansiedad/etiología , Conducta Animal/fisiología , Cricetinae , Gerbillinae , Pánico , Ratas , SerpientesRESUMEN
The blockade of GABA-mediated Cl(-) influx with pentylenetetrazol (PTZ) was used in the present work to induce seizures in animals. The neurotransmission in the postictal period has been the focus of many studies, and there is evidence suggesting antinociceptive mechanisms following tonic-clonic seizures in both animals and men. The aim of this work was to study the involvement of acetylcholine in the antinociception induced by convulsions elicited by peripheral administration of PTZ (64 mg/kg). Analgesia was measured by the tail-flick test in eight albino Wistar rats per group. Convulsions were followed by significant increases in tail-flick latencies (TFLs) at least for 120 min of the postictal period. Peripheral administration of atropine (0.25, 1 and 4 mg/kg) caused a significant dose-dependent decrease in the TFL in seizing animals, as compared to controls. These data were corroborated by peripheral administration of mecamylamine, a nicotinic cholinergic receptor blocker, at the same doses (0.25, 1 and 4 mg/kg) used for the muscarinic cholinergic receptor antagonist. The recruitment of the muscarinic receptor was made 10 min postconvulsions and in subsequent periods of postictal analgesia, whereas the involvement of the nicotinic cholinergic receptor was implicated only after 30 min postseizures. The cholinergic antagonists caused a minimal reduction in body temperature, but did not impair baseline TFL, spontaneous exploration or motor coordination in the rotarod test at the maximal dose of 4 mg/kg. These results indicate that acetylcholine may be involved as a neurotransmitter in postictal analgesia.