Citrus limon (L.) Burm f. Essential Oil Has Anxiolytic and Sedative Properties by Modulating GABAA-Receptors

Abstract The high prevalence of anxiety disorders associated with pharmacotherapy side effects have motivated the search for new pharmacological agents. Species from Citrus genus, such as Citrus limon (sicilian lemon), have been used in folk medicine as a potential therapy to minimize emotional disorders. In order to searching for new effective treatments with fewer side effects, the present study evaluated the anxiolytic mechanism of action and the hypnotic-sedative activity from the Citrus limon fruit's peels essential oil (CLEO). Adults male Swiss mice were submitted to barbiturate-induced sleep test; elevated plus-maze (EPM) and light-dark box (LDB) (evaluation of the mechanism of action); rotarod; and catalepsy tests. CLEO oral treatment decreased latency and increased the sleep total time; moreover it induced in animals an increased the number of entries and percentage of time spent into open arms of the EPM; an increased the number of transitions and the percentage of time into light compartment in the LDB; which were only antagonized by flumazenil pretreatment, with no injury at motor function. Thus, results suggest that CLEO treatment induced an anxiolytic behavior suggestively modulated by the benzodiazepine binding site of the GABAA receptor or by an increase of GABAergic neurotransmission, without cause impairment in the motor coordination.

Efecto antagonista del flumazenil sobre el isoflurano en la emersión de la anestesia general / Antagonist effect of flumazenil on isofluran in reversion of general anesthesia

INTRODUCTION AND OBJECTIVES: Isoflurane, an inhalational general anesthetic widely used in medical practice, belonging to the group of volatile liquids together with desflurane and sevoflurane, with various properties including sedation, hypnosis and anesthesia of patients undergoing treatment. surgical acts. Volatile inhalational anesthetics (halogenated) as mechanism of action, has the property of increasing inhibitory synaptic transmission at postsynaptic level by potentiating ion channels regulated by ligand activated by alpha-aminobutyric acid (GABA). Flumazenil is a benzodiazepine antagonist belonging to the group of imidazobenzodiazepine. It is currently known that there is no specific drug capable of antagonizing the effects of halogenates that allow the rapid and complete recovery of general anesthesia, for this reason this work focuses its efforts on demonstrating whether flumazenil has the ability to reverse the actions of the patient. isoflurane and allow an early restoration of the level of consciousness. MATERIAL AND METHODS: The study to be performed is a clinical type of longitudinal, prospective, unicentric and double blind. The sample will be formed by patients who are going to be subjected to a balanced general anesthesia. The sample will be divided into 2 large groups: group C (control) and group F (Flumazenil). At the end of the surgery, the mixture will be administered according to the selected group in a random manner (Flumazenil 0.25 mg or 0.9% solution in a 20 cc syringe) and the time of extubation, recovery time of the level of consciousness, time of discharge UCPA and hemodynamic state (FC, TAM and SO2). RESULTS: The flumazenil group showed a significantly shorter time from injection to extubation than the placebo group (p = 0.007). Differences in terms of shorter times needed to achieve Aldrete of 9 points in the flumazenil group (P = 0.04) were observed as were shorter anesthetic arousal times represented by a Ramsey 2. Heart rate, mean arterial pressure and saturation they had similar values between the 2 groups. CONCLUSION: The study showed that a single dose of 0.25 mg of flumazenil administered at the end of the surgical act, just after completing all surgical stimulation was beneficial (P = 0.007) in the context of extubation times and shorter anesthetic arousal times.

INTRODUCCIÓN Y OBJETIVOS: El isoflurano un anestésico general inhalatorio usado ampliamente en la práctica médica, perteneciente al grupo de los líquidos volátiles junto con el desflurano y sevoflurano, con variadas propiedades entre las que se encuentran la sedación, hipnosis y anestesia de los pacientes sometidos a actos quirúrgicos. Los anestésicos inhalatorios volátiles (halogenados) como mecanismo de acción, tiene la propiedad de aumentar la transmisión sináptica inhibidora a nivel postsináptico potenciando los canales iónicos regulados por ligando activados por ácido alfa-aminobutírico (GABA). El flumazenil es un antagonista benzodiazepínico perteneciente al grupo de los imidazobenzodiazepina. Se conoce actualmente que no existe un fármaco específico capaz de antagonizar los efectos de los halogenados que permitan la recuperación rápida y completa de la anestesia general, por tal motivo este trabajo centra sus esfuerzos en demostrar si el flumazenil tiene la capacidad para revertir las acciones del isoflurane y permitir un restablecimiento temprano del nivel de conciencia. MATERIALES Y MÉTODOS: El estudio a realizar es de tipo clínico de corte longitudinal, prospectivo, unicéntrico y doble ciego. La muestra se conformará por pacientes que vayan a ser sometidos a anestesia general balanceada. Se procederá a dividir la muestra en 2 grandes grupos: grupo C (control) y grupo F (flumazenil). Al final de la cirugía se administrará la mezcla según grupo seleccionado de manera al azar (flumazenil 0,25 mg o solución 0,9% en una jeringa de 20 cc) y se valorará el tiempo de extubación, tiempo de recuperación del nivel de conciencia, tiempo de alta de la UCPA y estado hemodinámico (FC, TAM y SO2). RESULTADOS: El grupo de flumazenil presentó un tiempo desde la inyección hasta la extubación significativamente más bajo que el grupo placebo (p = 0,007). Se observaron diferencias en términos de tiempos más bajos necesario para alcanzar Aldrete de 9 puntos en el grupo flumazenil (P = 0,04) al igual que tiempos de despertar anestésico más cortos representados por un Ramsey 2. La frecuencia cardíaca, presión arterial media y la saturación tuvieron valores similares entre los 2 grupos. CONCLUSIÓN: El estudio demostró que una única dosis de 0,25 mg de flumazenil administrado al final del acto quirúrgico, justo después de culminar toda estimulación quirúrgica fue beneficiosa (P = 0,007) en el contexto de tiempos de extubación y tiempos de despertar anestésico más cortos.

Effect of (+)-dehydrofukinone on GABAA receptors and stress response in fish model

(+)-Dehydrofukinone (DHF) is a major component of the essential oil of Nectandra grandiflora (Lauraceae), and exerts a depressant effect on the central nervous system of fish. However, the neuronal mechanism underlying DHF action remains unknown. This study aimed to investigate the action of DHF on GABAA receptors using a silver catfish (Rhamdia quelen) model. Additionally, we investigated the effect of DHF exposure on stress-induced cortisol modulation. Chemical identification was performed using gas chromatography-mass spectrometry and purity was evaluated using gas chromatography with a flame ionization detector. To an aquarium, we applied between 2.5 and 50 mg/L DHF diluted in ethanol, in combination with 42.7 mg/L diazepam. DHF within the range of 10-20 mg/L acted collaboratively in combination with diazepam, but the sedative action of DHF was reversed by 3 mg/L flumazenil. Additionally, fish exposed for 24 h to 2.5-20 mg/L DHF showed no side effects and there was sustained sedation during the first 12 h of drug exposure with 10-20 mg/L DHF. DHF pretreatment did not increase plasma cortisol levels in fish subjected to a stress protocol. Moreover, the stress-induced cortisol peak was absent following pretreatment with 20 mg/L DHF. DHF proved to be a relatively safe sedative or anesthetic, which interacts with GABAergic and cortisol pathways in fish.

Alpha power oscillation in the frontal cortex under Bromazepam and Modafinil effects / Oscilações da potência alfa no córtex frontal sob influência do Bromazepam e Modafinil

ABSTRACTObjective Our aim was to investigate and compare the neuromodulatory effects of bromazepam (6 mg) and modafinil (200 mg) during a sensorimotor task analyzing the changes produced in the absolute alpha power.Method The sample was composed of 15 healthy individuals exposed to three experimental conditions: placebo, modafinil and bromazepam. EEG data were recorded before, during and after the execution of the task. A three-way ANOVA was applied, in order to compare the absolute alpha power among the factors: Group (control, bromazepam and modafinil) Condition (Pre and Post-drug ingestion) and Moment (pre and post-stimulus).Results Interaction was found between the group and condition factors for Fp1, F4 and F3. We observed a main effect of moment and condition for the Fp2, F8 and Fz electrodes.Conclusion We concluded that drugs may interfere in sensorimotor processes, such as in the performance of tasks carried out in an unpredictable scenario.

RESUMOObjetivo Investigar e comparar os efeitos neuromoduladores do bromazepam (6mg) e modafinil (200mg), durante a prática de uma tarefa sensoriomotora, analisando as modificações produzidas na potência absoluta de alfa.Método A amostra foi composta por 15 indivíduos saudáveis, expostos a três condições experimentais: Placebo, modafinil e bromazepam. Dados eletroencefalográficos foram registrados antes, durante e após a execução da tarefa motora. Um ANOVA three-way foi aplicado para comparar a potência absoluta de alfa nos fatores Grupo (controle, bromazepam e modafinil), Condição (Pré e Pós ingestão da droga) e Momento (Pré e Pós estimulo).Resultados Verificou-se interação entre os fatores grupo e condição para os eletrodos Fp1, F4 e F3. Observamos um efeito principal para momento e condição nos eletrodos Fp2, F8 e Fz.Conclusão Concluímos que as drogas, podem interferir em processos sensoriomotores, como no desempenho de tarefas executadas em um cenário imprevisível.

Delayed Flumazenil Injection after Endoscopic Sedation Increases Patient Satisfaction Compared with Immediate Flumazenil Injection

BACKGROUND/AIMS: Flumazenil was administered after the completion of endoscopy under sedation to reduce recovery time and increase patient safety. We evaluated patient satisfaction after endoscopy under sedation according to the timing of a postprocedural flumazenil injection. METHODS: In total, 200 subjects undergoing concurrent colonoscopy and upper endoscopy while sedated with midazolam and meperidine were enrolled in our investigation. We randomly administered 0.3 mg of flumazenil either immediately or 15 minutes after the endoscopic procedure. A postprocedural questionnaire and next day telephone interview were conducted to assess patient satisfaction. RESULTS: Flumazenil injection timing did not affect the time spent in the recovery room when comparing the two groups of patients. However, the subjects in the 15 minutes injection group were more satisfied with undergoing endoscopy under sedation than the patients in the immediate injection group according to the postprocedural survey (p=0.019). However, no difference in overall satisfaction, memory, or willingness to undergo a future endoscopy was observed between the two groups when the telephone survey was conducted on the following day. CONCLUSIONS: This study demonstrated that a delayed flumazenil injection after endoscopic sedation increased patient satisfaction without prolonging recovery time, even though the benefit of the delayed flumazenil injection did not persist into the following day.

Effect of non-steroidal anti-inflammatory drugs on behavioral actions of diazepam in mice

To investigate the behavioral pharmacological interactions of diazepam with non steroidal anti-inflammatory drugs. Non selective cyclooxygenase enzyme inhibitors [100 mg/kg acetylsalicylic acid, 10 mg/kg indomethacin, and 10 mg/kg diclofenac], a selective cyclooxygnase-1 inhibitor [10mg/kg acetylsalicylic acid], and a selective cyclooxygnase-2 inhibitor [10 mg/km celecoxib] of non steroidal anti-inflammatory drugs were individually pretreated to 15 and 24 groups of Albino mice for dose and time dependent models [n=8, each treatment] before sleeping induced by diazepam [20 mg/kg, intraperitoneally]. In 6 groups using an open field and 4 groups using traction test models [n=10], 5 and 10 mg/kg of diazepam, intraperitoneally were given to induce sedation and muscle relaxation, and 2mg / kg, to induce anxiolytic action after treatment with acetylsalicylic acid [10 mg/kg] to 4 groups [n=6]. This study was carried out at the Al-Fateh Medical Science University, Tripoli, Libya between February and May 2009. In dose and time dependent models non selective cyclooxygenase and selective cyclo-oxygnase-1 inhibitors significantly reduced the duration of sleep induced by diazepam in mice by 60-75%, while the selective cyclooxygnase-2 inhibitor did not [p>0.05]. However, anxiolytic, muscle relaxant, and sedative effects of diazepam were unchanged by acetylsalicylic acid. Non-steroidal anti-inflammatory drugs, most likely cyclooxygenase selective-1 inhibitors reduced the duration of sleep induced by diazepam, and this interaction could be of a pharmacodynamic type

Cardioprotection Via Modulation of Calcium Homeostasis by Thiopental in Hypoxia-Reoxygenated Neonatal Rat Cardiomyocytes

PURPOSE: Ca2+ homeostasis plays an important role in myocardial cell injury induced by hypoxia-reoxygenation, and prevention of intracellular Ca2+ overload is key to cardioprotection. Even though thiopental is a frequently used anesthetic agent, little is known about its cardioprotective effects, particulary in association with Ca2+ homeostasis. We investigated whether thiopental protects cardiomyocytes against hypoxia-reoxygenation injury by regulating Ca2+ homeostasis. MATERIALS AND METHODS: Neonatal rat cardiomyocytes were isolated. Cardiomyocytes were exposed to different concentrations of thiopental and immediately replaced in the hypoxic chamber to maintain hypoxia. After 1 hour of exposure, a culture dish was transferred to the CO2 incubator and cells were incubated at 37degrees C for 5 hours. At the end of the experiments, the authors assessed cell protection using immunoblot analysis and caspase activity. The mRNA of genes involved in Ca2+ homeostasis, mitochondrial membrane potential, and cellular Ca2+ levels were examined. RESULTS: In thiopental-treated cardiomyocytes, there was a decrease in expression of the proapoptotic protein Bax, caspase-3 activation, and intracellular Ca2+ content. In addition, both enhancement of anti-apoptotic protein Bcl-2 and activation of Erk concerned with survival were shown. Furthermore, thiopental attenuated alterations of genes involving Ca2+ regulation and significantly modulated abnormal changes of NCX and SERCA2a genes in hypoxia-reoxygenated neonatal cardiomyocytes. Thiopental suppressed disruption of mitochondrial membrane potential (Delta Psi m) induced by hypoxia-reoxygenation. CONCLUSION: Thiopental is likely to modulate expression of genes that regulate Ca2+ homeostasis, which reduces apoptotic cell death and results in cardioprotection.

Recurrent opisthotonus in catatonia: An atypical presentation.

Opisthotonus is known to occur in tetanus, rabies, cerebral malaria, neurosyphilis, acute cerebral injury and other medical conditions. Opisthotonus, so far, has not been reported in any major psychiatric disorder. Authors report a case of recurrent opisthotonus presenting concurrently with other catatonic signs which showed dramatic response to combination of lorazepam and electroconvulsive therapy (ECT). Clinicians should consider the possibility of catatonia in the differential diagnosis of opisthotonus since catatonia can be treated easily with benzodiazepines and ECT.

Effects of a cognitive modulator in the theta and alpha asymmetry during a typewriting task: a sensorimotor integration perspective / Efeitos de um modulador cognitivo na assimetria de teta e alfa durante uma tarefa de datilografia: uma perspectiva da integração sensório-motora

This study aimed to elucidate cortical mechanisms and to identify the areas where occur such mechanisms due to interaction between bromazepam and motor learning. The sample was composed of 45 healthy subjects randomly distributed in 3 groups: placebo (n=15), bromazepam 3 mg (n=15) or bromazepam 6 mg (n=15). To perform the experimental task, subjects sat comfortably at a distance of approximately 20 cm from the typewriter. The typewriter keyboard was covered with a wooden box to avoid visual information about the hands' position. The typewriting task was performed concomitantly with EEG recording. ANOVA two-way results indicated a decreased asymmetry in sensorimotor areas in the experimental groups. Our interpretation is that moderate doses of bromazepam may improve performance on tasks with predictable elements to promote stability of psychomotor functions, but may also impair performance on tasks executed in unpredictable environments.

O objetivo do estudo foi elucidar mecanismos corticais e identificar as áreas onde estas ocorrem tais mecanismos devido à interação entre bromazepam e aprendizagem motora. A amostra compreendeu 45 sujeitos hígidos distribuídos randomicamente em 3 grupos: placebo (n=15), bromazepam 3 mg (n=15) ou bromazepam 6 mg (n=15). Para a realização da tarefa experimental, sujeitos sentaram-se confortavelmente a uma distância de aproximadamente 20 cm da máquina de escrever. O teclado da máquina foi coberto com uma caixa de madeira para evitar informações visuais sobre a posição das mãos. O registro do EEGq ocorreu simultaneamente à tarefa de datilografia. Os resultados da ANOVA two-way indicaram menor assimetria em áreas sensório-motoras nos grupos experimentais. Nossa interpretação é que doses moderadas de bromazepam podem melhorar o desempenho em tarefas previsíveis por promover estabilidade das funções psicomotoras, mas pode prejudicar o desempenho em tarefas realizadas em ambientes imprevisíveis.

Differential response to gepirone but not to chlordiazepoxide in malnourished rats subjected to learned helplessness

The learned helplessness (LH) paradigm is characterized by learning deficits resulting from inescapable events. The aims of the present study were to determine if protein-calorie malnutrition (PCM) alters learning deficits induced by LH and if the neurochemical changes induced by malnutrition alter the reactivity to treatment with GABA-ergic and serotonergic drugs during LH. Well-nourished (W) and PCM Wistar rats (61 days old) were exposed or not to inescapable shocks (IS) and treated with gepirone (GEP, 0.0-7.5 mg/kg, intraperitoneally, N = 128) or chlordiazepoxide (0.0-7.5 mg/kg, intraperitoneally, N = 128) 72 h later, 30 min before the test session (30 trials of escape learning). The results showed that rats exposed to IS had higher escape latency than non-exposed rats (12.6 ± 2.2 vs 4.4 ± 0.8 s) and that malnutrition increased learning impairment produced by LH. GEP increased the escape latency of W animals exposed or non-exposed to IS, but did not affect the response of PCM animals, while chlordiazepoxide reduced the escape deficit of both W and PCM rats. The data suggest that PCM animals were more sensitive to the impairment produced by LH and that PCM led to neurochemical changes in the serotonergic system, resulting in hyporeactivity to the anxiogenic effects of GEP in the LH paradigm.

Effects of acupuncture in Siguan points on man-machine counteraction in respiratory failure patients during mechanical ventilation / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To investigate the value of applying acupuncture in patients with respiratory failure Sixty (RF) during mechanical ventilation (MV) when there happened man-machine counteraction.</p><p><b>METHODS</b>RF patients with nonsynchronous spontaneous breath (SB) during mechanical ventilation were divided into two groups randomly, 30 in each group. The control group treated with intravenous midazolam injection, and the treated group with acupuncture in Siguan points combined intravenous midazolam injection to maintain synchronized SB and MV, and to calm patients. The dose of midazolam used, the sedative effect as well as the complications occurred at different time points in the two groups were observed and compared.</p><p><b>RESULTS</b>Compared with the control group, advantages such as smaller dose of midazolam used, lighter in deepness of sedation, and less complications were observed in the treated group (all P < 0.05).</p><p><b>CONCLUSION</b>Acupuncture auxiliary Western medicine treatment has better effects than that of Western treatment alone in treating RF patients with man-machine counteraction during mechanical ventilation.</p>

Zumbido pulsátil: tratamento com clonazepan e propranolol / Pulsatile tinnitus: treatment with clonazepam and propranolol

O zumbido pulsátil sincrônico com os batimentos cardíacos é pouco freqüente, sendo de etiologia tanto vascular arterial (malformacões, fístulas artério-venosas) ou venosa (anormalidades do bulbo jugular, tumor glômico jugular ou timpânico). A identificacão precoce da etiologia é essencial para que a terapêutica adequada possa ser instituída. A angioressonância possibilita a identificacão de alteracões vasculares com maior precisão. Relatamos um caso onde, após o diagnóstico de uma alteracão vascular arterial, foi instituído o tratamento com propranolol e clonazepam, com melhora da sintomatologia.

On the sleep promoting effects of BR-16A: interaction with GABAergic modulators.

Pentobarbitone-induced hypnosis test was used as an animal model to explore the role of BR-16A, a polyherbal formulation in sleep. Pentobarbitone produces quick sleep latency (onset) and prolongation of total sleep time (duration). Sleep latency and total sleep time were used as a parameters for the evaluation. BR-16A potentiated the effect of triazolam (0.1 mg/kg, ip) and alprazolam (0.25 mg/kg, ip). Melatonin (5.0 mg/kg, ip) and zolpidem (0.5 mg/kg, ip) did not produce any significant effect on sleep parameters. However, alprazolam (0.25mg/kg, ip) potentiated the effect of BR-16A (100 mg/ kg, po) in higher dose only. Sleep promoting effect of BR-16A in combination with GABAergic drugs (triazolam and alprazolam,) suggested that these drugs have common mechanism in sleep promoting effect of pentobarbitone and could be used along with other GABAergic hypnotics for the treatment of insomnia. This may reduce the dose of the latter drug(s). BR-16A can be used for the treatment of sleep and sleep-related disorders.

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.

Protective action of an anti-oxidant (L-Ascorbic acid) against genotoxicity and cytotoxicity in mice during p-DAB-induced hepatocarcinogenesis.

BACKGROUND: DNA damage from micronutrient deficiencies has been suggested as one major cause of cancer. Therefore studies involving vitamin supplementation, particularly with those with anti-oxidant activity, in combating cancer have routinely been carried out in both in vivo and in vitro systems, but relatively much less in mice. AIMS: The present study examines if L-Ascorbic acid (AA; vitamin C) administration has any protective abilities in combating p-DAB induced hepatocarcinogenesis in mice at cytogenetical, biochemical, histological and ultra-structural levels. SETTINGS AND DESIGN: To test if AA had a protective action against genotoxicity, cytotoxicity and tissue damage in liver during p-dimethylaminoazobenezene (p-DAB) induced hepatocarcinogenesis in mice, a group of mice were chronically fed 0.06% p-DAB and 0.05% phenobarbital (PB) for a varying period of time (7, 15, 30, 60, 90 and 120 days). A sub-group of the p-DAB plus PB fed mice were also fed 1% L-ascorbic acid. Several assays were periodically conducted (at the six intervals of fixation) for determination of genotoxic (based on chromosomal, nuclear and sperm head anomalies), cytotoxic (based on the marker enzymes aspartate transaminase; AST, alanine aminotransferase; ALT; acid phosphatase; ACP; alkaline phosphatase; ALKP; lipid peroxidation; LPO); and tissue damaging (based on optical and electron microscopic studies of liver at day 60 only) effects in these different groups of mice as compared to normal healthy control. METHODS AND MATERIAL: Adult healthy mice of Swiss Albino strain, reared and maintained in the animal house of the Department of Zoology, Kalyani University, under supervision of Animal Welfare Committee (which oversees ethical issues), served as materials for the present study. Widely practiced standard technique has been followed for each protocol. STATISTICAL ANALYSIS USED: The significance test between different series of data was conducted by student's t-test. RESULTS AND CONCLUSIONS: The results of all these studies indicated that AA had protective action against p-DAB induced hepatocarcinogenesis in mice.

Newer aspects of hepatic encephalopathy.

Recently attempts have been made to standardize terminology in the field of hepatic encephalopathy. We are now facing a new problem. Chronic hepatitis C-induced cirrhosis occurs in an older population; this may change the presentation pattern of hepatic encephalopathy in future. Ammonia has once again become prominent as the leading toxin likely to play a role in the pathogenesis of this syndrome. How ammonia interacts with other proposed mechanisms should be an area of active research. The treatment arena has seen some advances. Unfortunately, the economics of having newer treatments approved in the USA is formidable. Rifaximine, L-ornithine-L-aspartate, sodium benzoate and possibly flumazenil appear to be significant advances. More elective shunt suppression for selected patients will be seen. Liver transplantation remains the only option for truly intractable hepatic encephalopathy.

Cardiovascular responses to microinjections of GABA or anesthetics into the rostral ventrolateral medulla of conscious and anesthetized rats

The rostral ventrolateral medulla (RVLM) contains neurons involved in tonic and reflex control of arterial pressure. We describe the effects of gamma-aminobutyric acid (GABA) and anesthetics injected into the RVLM of conscious and urethane (1.2 g/kg, iv) anesthetized Wistar rats (300-350 g). In conscious rats, bilateral microinjection of GABA (50 nmol/200 nl) induced a small but significant decrease in blood pressure (from 130 ± 3.6 to 110 ± 5.6 mmHg, N = 7). A similar response was observed with sodium pentobarbital microinjection (24 nmol/200 nl). However, in the same animals, the fall in blood pressure induced by GABA (from 121 ± 8.9 to 76 ± 8.8 mmHg, N = 7) or pentobarbital (from 118 ± 4.5 to 57 ± 11.3 mmHg, N = 6) was significantly increased after urethane anesthesia. In contrast, there was no difference between conscious (from 117 ± 4.1 to 92 ± 5.9 mmHg, N = 7) and anesthetized rats (from 123 ± 6.9 to 87 ± 8.7 mmHg, N = 7) when lidocaine (34 nmol/200 nl) was microinjected into the RVLM. The heart rate variations were not consistent and only eventually reached significance in conscious or anesthetized rats. The right position of pipettes was confirmed by histology and glutamate microinjection into the RVLM. These findings suggest that in conscious animals the RVLM, in association with the other sympathetic premotor neurons, is responsible for the maintenance of sympathetic vasomotor tone during bilateral RVLM inhibition. Activity of one or more of these premotor neurons outside the RVLM can compensate for the effects of RVLM inhibition. In addition, the effects of lidocaine suggest that fibers passing through the RVLM are involved in the maintenance of blood pressure in conscious animals during RVLM inhibition

Sildenafil improves acquisition and retention of memory in mice.

Sildenafil (Viagra) has been introduced recently in market to correct male impotency and has gained immense popularity for its dramatic effects all over the world. The present study was designed to investigate the effect of sildenafil on learning and memory in mice using elevated plus maze. A total of XV groups of animals were employed in the present study. Central cholinergic pathways play a crucial role in learning and memory processes. Physostigmine, an anticholinesterase agent (0.5 mg, 1.0 mg kg(-1), i.p) was employed for its memory enhancing property and alprazolam a benzodiazepine receptor agonist served as a memory-impairing agent. In the present study, alprazolam produced anterograde amnesia (at 0.5 mg kg(-1), i.p) and retrograde amnesia (at 0.25 mg, 0.5 mg, 0.75 mg kg(-1), i.p.) in separate groups of animals. Caffeine at 5 mg, 10 mg and 20 mg kg(-1), i.p. (an established psychostimulant) did not show any significant change in learning and memory of mice. Sildenafil (at 8 mg kg(-1), i.p.) administered 30 minutes prior to training on first day produced a marginal decrease in transfer latency time on first day; whereas, sildenafil (at 2 mg, 4 mg, 8 mg kg(-1), i.p.) administered immediately after training on first day produced a dose-dependent improvement of memory in mice. However, further studies need to be carried out to elucidate the underlying mechanism of sildenafil as a memory enhancer.