Phytohormone abscisic acid boosts pentobarbital-induced sleep through activation of GABA-A, PPARß and PPARγ receptor signaling / O fito-hormônio ácido abscísico estimula o sono induzido por fenobarbital por meio de ativação da sinalização de receptores GABA-A, PPARß e PPARγ

ABSTRACT Background: Sleep disorders induce anxiety and forgetfulness and change habits. The chemical hypnotic drugs currently used have serious side effects and, therefore, people are drawn towards using natural compounds such as plant-based healing agents. Abscisic acid (ABA) is produced in a variety of mammalian tissues and it is involved in many neurophysiological functions. Objective: To investigate the possible effect of ABA on pentobarbital-induced sleep and its possible signaling through GABA-A and PPAR (γ and β) receptors, in male Wistar rats. Methods: The possible effect of ABA (5 and 10 µg/rat, intracerebroventricularly) on sleep onset latency time and duration was evaluated in a V-maze model of sleep. Pentobarbital sodium (40 mg/kg, intraperitoneally) was injected to induce sleep 30 min after administration of ABA. PPARβ (GSK0660, 80 nM/rat), PPARγ (GW9662, 3 nM/rat) or GABA-A receptor (bicuculline, 6 µg/rat) antagonists were given 15 min before ABA injection. Diazepam (2 mg/kg, intraperitoneally) was used as a positive control group. Results: ABA at 5 µg significantly boosted the pentobarbital-induced subhypnotic effects and promoted induction of sleep onset in a manner comparable to diazepam treatment. Furthermore, pretreatment with bicuculline significantly abolished the ABA effects on sleep parameters, while the amplifying effects of ABA on the induction of sleep onset was not significantly affected by PPARβ or PPARγ antagonists. The sleep prolonging effect of ABA was significantly prevented by both PPAR antagonists. Conclusions: The data showed that ABA boosts pentobarbital-induced sleep and that GABA-A, PPARβ and PPARγ receptors are, at least in part, involved in ABA signaling.

RESUMO Introdução: Os distúrbios do sono induzem a ansiedade e esquecimento e mudam hábitos. Os medicamentos hipnóticos químicos utilizados atualmente têm efeitos colaterais graves e, portanto, as pessoas são atraídas para o uso de compostos naturais, como agentes de cura à base de plantas. O ácido abscísico (ABA) é produzido em uma variedade de tecidos de mamíferos e está envolvido em muitas funções neurofisiológicas. Objetivo: Investigar o possível efeito do ABA no sono induzido por pentobarbital e sua possível sinalização por meio dos receptores GABA-A e PPAR (γ e β), em ratos Wistar machos. Métodos: O possível efeito do ABA (5 e 10 µg/rato, intracerebroventricularmente) no tempo de latência e duração do início do sono foi avaliado em um modelo de labirinto em V de sono. Pentobarbital sódico (40 mg/kg, intraperitonealmente) foi injetado para induzir o sono 30 minutos após a administração de ABA. PPARβ (GSK0660, 80 nM/rato), PPARγ (GW9662, 3 nM/rato) ou antagonistas do receptor GABA-A (bicuculina, 6 µg/rato) foram administrados 15 minutos antes da injeção de ABA. Diazepam (2 mg/kg, intraperitonealmente) foi utilizado como grupo de controle positivo. Resultados: ABA a 5 µg aumentou significativamente os efeitos sub-hipnóticos induzidos por pentobarbital e promoveu a indução do início do sono de forma comparável ao tratamento com diazepam. Além disso, o pré-tratamento com bicuculina aboliu significativamente os efeitos do ABA nos parâmetros do sono, ao passo que os efeitos amplificadores do ABA na indução do início do sono não foram significativamente afetados pelos antagonistas do PPARβ ou PPARγ. O efeito de prolongamento do sono do ABA foi significativamente prevenido por ambos os antagonistas do PPAR. Conclusões: Os dados mostraram que o ABA estimula o sono induzido por pentobarbital e que os receptores GABA-A, PPARβ e PPARγ estão, pelo menos em parte, envolvidos na sinalização ABA.

Muscular performance characterization in athletes: a new perspective on isokinetic variables

Background: Isokinetic dynamometry allows the measurement of several variables related to muscular performance, many of which are seldom used, while others are redundantly applied to the characterization of muscle function. Objectives: The present study aimed to establish the particular features of muscle function that are captured by the variables currently included in isokinetic assessment and to determine which variables best represent these features in order to achieve a more objective interpretation of muscular performance. Method: This study included 235 male athletes. They performed isokinetic tests of concentric knee flexion and extension of the dominant leg at a velocity of 60º/s. An exploratory factor analysis was performed. Results: The findings demonstrated that isokinetic variables can characterize more than muscle torque production and pointed to the presence of 5 factors that enabled the characterization of muscular performance according to 5 different domains or constructs. Conclusions: The constructs can be described by torque generation capacity; variation of the torque generation capacity along repetitions; movement deceleration capacity; mechanical/physiological factors of torque generation; and acceleration capacity (torque development). Fewer than eight out of sixteen variables are enough to characterize these five constructs. Our results suggest that these variables and these 5 domains may lead to a more systematic and optimized interpretation of isokinetic assessments. .

Potentiating effects of Lactuca sativa on pentobarbital-induced sleep

Traditionally, Lactuca sativa [lettuce] has been recommended for its hypnotic property. The present study was planned to investigate sleep-prolonging effect of this plant. The hydro-alcoholic extract [HAE] of lettuce and its water fraction [WF], ethyl acetate fraction [EAF], and n-butanol fraction [NBF] were administrated [IP] to mice 30 min before the pentobarbital injection. Moreover, both in-vivo and in-vitro toxicity of the extracts were determined. The quality of HAE and NBF was also evaluated using HPLC fingerprint. The HAE prolonged the pentobarbital-induced sleep duration at dose of 400 mg/Kg. The NBF was the only fraction which could increase the sleep duration and decrease sleep latency. The effects of NBF were comparable to those of induced by diazepam. The LD[50]-value for HAE was found to be 4.8 g/Kg. No neurotoxic effect was observed either by HAE or by its fractions in cultured PC12 neuron-like cells. The results suggest that lettuce potentiates pentobarbital hypnosis without major toxic effect. The main component[s] responsible for this effect is most likely to be non-polar agent[s] which found in NBF of this plant

Potentiation of pentobarbital hypnosis by Rosa damascena in mice.

Rosa damascena has been found to act on central nervous system including brain. It inhibits the reactivity of the hypothalamous and pituitary systems in rat. In traditional medicine hypnotic effect of Rose is also suggested. In the present study hypnotic effect of ethanolic, aqueous and chloroformic extracts of R. damascena was investigated in mice. Hypnotic method was based on potentiation of pentobarbital induced sleeping time by extracts. Three doses of extracts (100, 500 and 1000 mg/kg) were injected i.p. in comparison with diazepam (3mg/kg) as positive control and saline as negative control. After 30 min of injection of extracts, pentobarbital (30mg/kg) was injected and increase in sleeping time by extracts was recorded. The results showed that the ethanolic and aqueous extracts in 500 and 1000 mg/kg doses significantly increased pentobarbital induced sleeping time which was comparable to diazepam. The chloroformic extract had no hypnotic effect.

Influence of S(+)-ketamine analgesia in renal intraoperative ischemia: histological study in rats

OBJETIVO: Investigar, em ratos, o efeito da S(+)cetamina na histologia renal após hemorragia intra-operatória.MÉTODOS: Vinte ratos Wistar machos, anestesiados com pentobarbital sódico, foram divididos, aleatoriamente, em 2 grupos: G1 – controle (n=10) e G2 - S(+)cetamina (n=10), submetidos a hemorragia de 30% da volemia em 3 momentos (10% a cada 10 min) 60 min após anestesia. G2 recebeu S(+)cetamina, 15 mg. kg-1, i.m., 5 min após anestesia e 55 min antes do 1.º momento de hemorragia (M1). Foram monitorizadas a pressão arterial média (PAM), temperatura retal (T) e freqüência cardíaca. Os animais foram sacrificados (M4) 30 min após o 3.º momento de hemorragia (M3). Os rins e o sangue das hemorragias foram utilizados para estudo histológico e do hematócrito (Ht). RESULTADOS: Houve redução significativa da PAM, T e Ht. Na histologia, G1=G2 na dilatação tubular, congestão e necrose. A soma total dos escores foi significativamente diferente e G2>G1. CONCLUSÃO: Hemorragia e hipotensão determinaram alterações na histologia renal. O aumento da concentração sangüínea de catecolaminas provavelmente determinou escores mais altos de alterações histológicas com o uso de S(+)cetamina.

Psychopharmacological profile of hydro-alcoholic extract of Euphorbia neriifolia leaves in mice and rats.

The leaf extract of E. neriifolia significantly reduced apomorphine-induced stereotypy in mice at all doses (100, 200, 400 mg/kg body weight) in mice and rats and was devoid of catalepsic effect thereby, suggesting specific dopaminergic receptor modulating activity. The extract (400 mg/kg) potentiated pentobarbitone-induced hypnosis. It showed protection against maximal electro-shock-induced convulsion at 400 mg/kg. E. neriifolia leaf extract had anxiolytic action at 400 mg/kg by increasing the percentage of time spent in open arm in elevated plus-maze. The extract did not reverse scopolamine-induced amnesia on elevated plus-maze. It increased transfer latency at 200 and 400 mg/kg and also in combination with scopolamine. These results indicated anti-anxiety, anti-psychotic and anti-convulsant activity of E. neriifolia leaf extract in mice and rats. Phytochemical study showed the presence of steroidal saponin, reducing sugar, tannins, flavonoids in the crude leaf extract

Atividade depressora do extrato de Anacardium giganteum sobre o sistema nervoso central em modelos experimentais / Depressive activity of the extract of Anacardium giganteum in the central nervous system in experimental models

Objetivo:Identificar atividade depressora do Anacardium giganteum sobre o sistema nervosos central (SNC) utilizando modelos experimentais. Método: Utilizaram-se 70 camundongos Swiss e 20 ratos Wistar. após a preparação do extrato bruto aquos, o (EBA) da planta, observou-se a potencialização do tempo de sono induzido por pentobarbital sódico (PBS). Acessaram-se, também, efeitos sobre a coordenação motora por meio do "Rota-rod", exploração pelo teste do "Holeboard" e locomoção pelo método do "Open field". Agrupados os animais em grupos controle (GC), que recebeu água destilada, e experimental (GE) tratado com EBA na dose de 500mg/kg, com exceção do "Rota-rod" onde se adcionou o grupo padrão tratado com diazepan na dose de 2,5mg/kg. Na análise estatística foram utilizados os tetes T de Student ou ANOVA seguida pelo teste posthoc de Newman-Keuls, dependendo do modelo experimental, considerando significância estatística quando p<0,05. Resultados: O EBA de Anacardium giganteum diminuiu o tempo de latência e aumentou o tempo de sono induzido por PBS, diminuiu o tempo de permanência no "Rota-rod" 30 minutos após a gavagem, diminuiu o número e tempo de "head-dips", mas não interferiu na atividade locomotora. Conclusão: Os efeitos do extrato de Anacardium giganteum são sugestivos de ação depressora sobre o SNC

Evidence for a role of nitric oxide in hindlimb vasodilation induced by hypothalamic stimulation in anesthetized rats

Em animais anestesiados a EE do hipotálamo produz um padrão de ajustes cardiovasculares caracterizado por hipertensão arterial, taquicardia, vasodilatação muscular e vasoconstrição mesentérica, entretanto, os mecanismos periféricos envolvidos nestes ajustes cardiovasculares ainda não foram completamente esclarecidos. O presente estudo teve como objetivo caracterizar os mecanismos periféricos responsáveis pela redistribuição de fluxo sanguíneo produzidas pela EE do hipotálamo. Os resultados obtidos demonstraram que 1) em ratos anestesiados a EE do hipotálamo produziu hipertensão arterial, taquicardia, vasoconstrição no leito mesentérico e acentuada vasodilatação dos membros posteriores; 2) a combinação do bloqueio farmacológico de receptores a1 e a2 adrenérgicos com fentolamina mais adrenalectomia bilateral reduziu a vasoconstrição mesentérica e a vasodilatação dos membros posteriores. Nestes animais o bloqueio da síntese de NO com L-NAME provocou nova redução significante da vasodilatação dos membros posteriores; 3) a administração de L-NAME, previamente o bloqueio farmacológico com fentolamina mais adrenalectomia bilateral, reduziu as respostas de vasoconstrição mesentérica e de vasodilatação dos membros posteriores. Estes resultados sugerem a existência de pelo menos três possíveis mecanismos responsáveis pela vasodilatação dos membros posteriores induzida pela EE do hipotálamo: 1) ativação de receptores b-adrenérgicos por catecolaminas liberadas pela medula adrenal; 2) redução do tono vasoconstritor simpático e 3) um terceiro mecanismo que utiliza NO como mediador.

Role of 5-hydroxytryptamine in Moringa oleifera induced potentiation of pentobarbitone hypnosis in albino rats.

The role of 5-hydroxytryptamine (5-HT) in pentobarbitone (PB) sleeping time, gross behaviour, electrical activity of the brain and serum 5-HT level was studied in Holtzman strain adult albino rats following treatment with M. oleifera (MO). MO (350mg/kg) caused inhibition of awareness, touch response, motor activity, righting reflex, and grip strength. It significantly increased the PB sleeping time, serum 5-HT level (P<0.001) and alpha-wave activity. These observations indicate that the aqueous extract of MO potentiated PB induced sleeping time and increased the alpha-wave activity through 5-HT.

Neuropharmacological actions of panchagavya formulation containing Emblica officinalis Gaerth and Glycyrrhiza glabra Linn in mice.

A panchagavya Ayurvedic formulation containing E. officinalis, G. glabra, and cow's ghee was evaluated for its effect on pentobarbital-induced sleeping time, pentylenetetrazol-induced seizures, maximal electroshock-induced seizures, spontaneous motor activity, rota-rod performance (motor coordination) and antagonism to amphetamine in mice. The formulation (300, 500 mg/kg, po) produced a significant prolongation of pentobarbital-induced sleeping time and reduced spontaneous locomotor activity. The formulation also significantly antagonised the amphetamine induced hyper-locomotor activity (500, 750 mg/kg, po) and protected mice against tonic convulsions induced by maximal electroshock (500, 750 mg/kg, po). The formulation slightly prolonged the phases of seizure activity but did not protect mice against lethality induced by pentylenetetrazole. The formulation did not show neurotoxicity. The results suggest that the panchagavya formulation is sedative in nature.

Pharmacological studies on the venomous spotted butterfish (Scatophagus argus Linn) sting extract on experimental animals.

A sting of the fish S. argus, a venomous edible spotted butterfish, produces tremendous local pain, severe swelling, rise of body temperature, throbbing sensation etc. To establish the pharmacological activities of S. argus sting extract, the present investigation, was carried out on experimental animals. The LD50 of extract was found to be 9.3 mg/kg (iv) in male albino mice. The extract showed loss of sensation, urination and salivation in mice. It potentiated pentobarbitone induced sleeping time in male albino mice and produced hypothermia. Extract produced a fall of cat and guinea pig blood pressure, which was completely abolished by mepyramine. It produced a transient reduction of respiratory rate in rat, but decreased respiratory amplitude in cat, which was abolished after vagotomy. On isolated toad heart, the extract increased both the amplitude and rate of contraction. On isolated guinea pig heart, the sting extract decreased both the rate and amplitude of contraction leading to cardiac arrest, but it had no effect on isolated guinea pig auricle. The extract produced a reversible blockade of electrically induced twitch response of isolated chick biventer cervices preparation, but it had no effect on the isolated rat phrenic nerve diaphragm preparation. It produced a slow contractile response on isolated guinea pig ileum, rat uterus and rat fundal strip preparations but produced slow relaxation on isolated rat duodenum preparation. The contractile response on isolated guinea pig ileum and rat fundal strip was antagonised by SC19220. It did not produce any significant cutaneous haemorrhage in mice and did not produce any haemolysis on saline washed erythrocytes. The sting extract significantly increased capillary permeability of guinea pig dorsal flank and produced oedema in mice hind paw.

Effect of leaf essential oil from Piper solmsianum C.DC. in mice behaviour

The essential oil from Piper solmsianum leaves and its major compound (sarisan) were tested to verify their influences upon mice behaviour. The essential oil was obtained by hydrodistillation in a modified Clevenger extractor and analysed by GC/ MS. This analysis revealed in the oil the presence of monoterpenes, sesquiterpenes and of arylpropanoids. The compound sarisan, a myristicin analogue, was isolated from the oil to perform the pharmacological tests. Emulsions of the oil and of sarisan (5.0 and 10.0 percent v/v) were used in the tests. Pentobarbital (30 mg/ kg s.c.) or diazepam (2.5 mg/ kg s.c.) were tested as standard drugs to verify depressant or anxiolytic effects, respectively. Both essential oil and sarisan showed to have exciting and depressant effects in the tested animals

Increased sleeping time after pentobarbital anesthesia in rats treated with intravenous injection of BCG

Intravenous injection of BCG in rats induces protection against liver cell necrosis produced by CCl4. Impairment of hepatic mixed function oxidases by cytokines produced by activated Kupffer cells is the mechanism proposed to explain that protection. To verify the function of hepatic mixed function oxidases after Kupffer activation, the sleeping time after sodium pentobarbital anesthesia was evaluated in rats after intravenous injection of BCG. Male adult albino rats received BCG (50 mug, intravenous) and 48 h or 6 days after were anestethized with sodium pentobarbital (33 or 66 mg/g i.p.). The sleeping time was measured from the beginning of sleep until animal started having spontaneous movement and stand up on the forepaws. The results showed that the animals treated with BCG presented a significative increase in the sleeping time, indicating reduced inactivation of the pentobarbital, an indirect evidence of inhibittion of mixed function oxidase system. BCG treated rats showed hepatic and splenomegaly, both 48 and 6 days after treatment. Histology showed increase in number of mononuclear cells in the sinusoids in the liver and in the red pulp of the spleen 48 h after injection. Small epitheliod granulomas scattered in the hepatic lobules and in the red pulp were observed in rats killed six days after the BCG injection. Hepatocyte injury, induced by activated macrophages, would be not responsible for the reduced pentobarbital inactivation, because at six days there were several granulomas scattered in lobules, but the increase of sleep time in this group was similar to that observed in rats 48 h after injection of BCG. These results demonstrate that activation of Kupffer cells with BCG induces impairment of mixed function oxidase system soon as 48 h after injection of activator, probably due to production of IL-1, IL-6 and TNF alpha by activated Kupffer cells and other mononuclear cells migrated to the liver.

Antipsychotic profile of alstonine: ethnopharmacology of a traditional Nigerian botanical remedy

Although recently developed drugs have brought significant improvement, the treatment of psychotic disorders still presents serious drawbacks. Since inherent complexity and lack of satisfactory understanding of the underlying pathophysiology impose limits for rational drug design, resourceful approaches in the search for antipsychotics are pertinent. This paper reports pharmacological properties of alstonine, a heteroyohimbine type alkaloid, Which exbitited an antipsychotic-like profile, inhibiting amphetamine-induced lethaly, apomorphine-induced steotypy and potentiating barbiturate-induced slleping time. Atypical features of alstonine were the prevention of haloperidol-induced catalepsy and lack of direct interaction with D1, D2 and 5-HT2A receptors, classically linked to antipsychotic mechanism of action.

Trypanocidal effect of SKF525A, proadifen, on different developmental forms of Trypanosoma cruzi

SKF525A, an inhibitor and inducer of cytochrome P450, was tested on different developmental stages of Trypanosoma cruzi. Growth, motility and structure of epimastigotes, motility and infectivity of trypomastigotes, and infectivity of trypomastigotes to Vero cells in culture were abolished by the drug at 10-100 muM concentration. When blood from infected mice was treated with the drug, and used to infect 8 day-old-mice, no parasites were observed at 0.6-1 mM, and all animals survived. Blood cell morphology was well preserved, and the sleeping time of pentobarbital-treated mice inoculated with the same amount of drug was not increased. The present results suggest that SKF525A or other related inhibitors of cytochrome P450 coned be tested as an additive for blood sterilization in blood banks.

Effect of high-dose fentanyl on renal function in dogs

Our objective was to determine the effects of high-dose fentanyl on canine renal function (RF). We anesthetized with sodium pentobarbital (SP) 16 dogs, randomly divided into 2 groups:in G1, SP was given alone, and in G2, combined with 0.05 mg.kg(-1) fentanyl. All animals were ventilated artificially and had catheterized left and righ femoral veins and left femoral artery for fluid infusion, drug administration, blood collection, and hemodynamic measurement. Urine was collected throughout the experiment. Attributes of RF were studied. SP did not alter RF, which was significantly altered by fentanyl. In G2, slower heart rates, mean arterial pressure, creatinine clearance, urinary output, osmolar clearance and fractional excretion of sodium and potassium were observed. G1 had a behavior attributed to extracellular volume expansion and no RF alterations. In G2, we observed significant decreases in RF due to opioid-induced hemodynamic changes, not discarding the possible action of aldosterone.

Mecánica respiratoria del conejo bajo la acción del uretano, el pentobarbital o la mezcla cloralosa-uretano / Respiratory mechanics of the rabbit under the action of urethane, pentobarbital or chloralose-urethane mixture

Se caracterizó el patrón respiratorio dle conejo bajo la acción de 3 anestésicos. Se registraron el flujo y el volumen respiratorios mediante un neumotacógrafo, la presión intraesofágica y el electrocardiograma, en animales que respiraban espontáneamente en condiciones basales, agrupados y anestesiados como sigue: grupo 1: pentobarbital EV, 30 mg/kg; grupo 2: mezcla de uretano EV, 400 mg/kg y cloralosa EV, 60-80 mg/kg y grupo 3: uretano IP, 1,5 g/kg. Se analizaron las variables frecuencia respiratoria, volumen corriente, volumen minuto, flujo inspiratorio medio, relación entre tiempo de inspiración y tiempo total de la respiración (tiempo útil), resistencia pulmonar, complianza dinámica y frecuencia cardíaca. En el grupo 3 las variables indicadoras de la ventilación difirieron significativamente respecto a los grupos 1 y 2, que no mostraron diferencias entre sí. El tiempo útil fue diferente en los 3 grupos. En las demás variables no hubo diferencias significativas. Se valora que el uretano pueda ejercer una acción estimulante sobre la respiración

Hyperalgesic effect induced by barbiturates, midazolam and ethanol: pharmacological evidence for GABA-A receptor involvement

The involvement of GABA-A receptors in the control of nociception was studied using the tail-flick test in rats. Non-hypnotic doses of the barbiturates phenobarbital (5-50 mg/kg), pentobarbital (17-33 mg/kg), and thiopental (7.5-30 mg/kg), of the benzodiazepine midazolam (10 mg/kg) or of ethanol (0.4-1.6 g/kg) administered by the systemic route reduced the latency for the tail-flick response, thus inducing a 'hyperalgesic' state in the animals. In contrast, non-convulsant doses of the GABA-A antagonist picrotoxin (0.12- 1.0 mg/kg) administered systemically induced an increase in the latency for the tail-flick response, therefore characterizing an 'antinociceptive' state. Previous picrotoxin (0.12 mg/kg) treatment abolished the hyperalgesic state induced by effective doses of the barbiturates, midazolam or ethanol. Since phenobarbital, midazolam and ethanol reproduced the described hyperalgesic effect of GABA-A-specific agonists (muscimol, THIP), which is specifically antagonized by the GABA-A antagonist picrotoxin, our results suggest that GABA-A receptors are tonically involved in the modulation of nociception in the rat central nervous system.

Cyclodiene insecticides-induced changes in the central depressive effect of chlorpromazine in rats.

Spontaneous motor activity (SMA), conditioned avoidance response (CAR), muscle coordination (MC) and pentobarbital sleep were tested in rats treated orally for 90 days with tolerated doses of the cyclodiene insecticides, aldrin (1 mg/kg) and endosulfan (2 mg/kg). The same tests were repeated in similarly treated animals after injecting chlorpromazine (4 mg/kg, i.p.). Both the insecticides shortened pentobarbital sleeping time indicating their microsomal enzyme inducing property. Aldrin suppressed SMA, CAR and MC, whereas endosulfan stimulated SMA, inhibited CAR and unaltered MC. However, their concurrent action with CPZ did not result in change in the central depressive effects of the latter, but its potency during the course of its action was altered. Its potency 15 min after injection was greater and 60-180 min later was lesser in these animals than that observed in control animals. This finding was interpreted to suggest that aldrin and endosulfan has quickened the biotransformation of CPZ and thereby shortened its duration of action. A temporary promotion of its potency was accounted to its active metabolites, since prior to inactivation, CPZ is known to be metabolized by the microsomal enzymes to active compounds.