Simvastatin treatment reduces the cholesterol content of membrane/lipid rafts, implicating the N -methyl-D-aspartate receptor in anxiety: a literature review

ABSTRACT Membrane/lipid rafts (MLRs) are plasmalemmal microdomains that are essential for neuronal signaling and synaptic development/stabilization. Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (statins) can disable the N-methyl-D-aspartate (NMDA) receptor through disruption of MLRs and, in turn, decrease NMDA-mediated anxiety. This hypothesis will contribute to understanding the critical roles of simvastatin in treating anxiety via the NMDA receptor.

Guanidinoacetate alters antioxidant defenses and butyrylcholinesterase activity in the blood of rats

Deficiency of guanidinoacetate methyltransferase, the first described creatine biosynthesis defect, leads to depletion of creatine and phosphocreatine, and accumulation of guanidinoacetate (GAA) in brain and body fluids. The present study aimed to investigate the influence of GAA on the activities of antioxidant enzymes, as well as on thiobarbituric acid-reactive substances (TBARS) and butyrylcholinesterase (BuChE) activity in the blood of rats. We also evaluated the effect of trolox (6-hydr oxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), GSH (glutathione) and L-NAME (NG-nitro-L-arginine methyl ester) on the alterations elicited by GAA. Methods: The rats were randomly divided into 8 groups: (1) control; (2) GAA (10, 30, 50, 100 mM/kg); (3) trolox (1 mM/kg) + control; (4) trolox (1 mM/kg) + GAA (100 mM/kg); (5) GSH (1 mM/kg) + control; (6) GSH (1 mM/kg) + GAA (100 mM/kg); (7) L-NAME (1 mM/kg) + control; (8) L-NAME + GAA (100 mM/kg). After the addition of compounds, erythrocytes and plasma were pre-incubated at 37°C for 1h and tested immediately. Results: GAA enhanced the activities of catalase (CAT) and glutathione peroxidase (GSH-Px) in the erythrocytes and BuChE activity. In addition, GAA enhanced TBARS levels in the plasma. Trolox, GSH and L-NAME addition prevented the majority of alterations in oxidative stress parameters and the increase of BuChE activity that were caused by GAA. Data suggest that GAA alters antioxidant defenses and induces lipid peroxidation in the blood, as well altering BuChE activity. However, in the presence of trolox, GSH and L-NAME some of these alterations in oxidative stress and BuChE activity were prevented. Conclusions: Our findings lend support to a potential therapeutic strategy for this condition, which may include the use of appropriate antioxidants for ameliorating the damage caused by GAA...

Adjuvant effects of classical music on simvastatin induced reduction of anxiety but not object recognition memory in rats

Simvastatin is one of many hydroxymethylglutaryl-coenzyme-A reductase inhibitors that are prescribed to lower cholesterol. Some emerging evidence indicates that classical music can serve as an effective adjuvant in rats treated with simvastatin. Moreover, simvastatin and classical music have been shown to influence some cognitive functions. To further understand the mechanisms of action, we exposed rats to classical music for 1 month, and then treated them orally with simvastatin. The behavioral experiments suggested that exposure to subchronic simvastatin (1 or 10 mg/kg/day) reduced anxiety levels in the elevated plus-maze and open-field test in rats exposed to Mozart music. The recognition object test results indicated that simvastatin altered non-spatial working memory only at the 1 mg/kg/day dose and improved both short- and long-term object recognition. No significant differences were found between Mozart music and silence in the object recognition test, suggesting that music did not significant affect learning and memory in adult rats. We hypothesize that the anxiolytic, but not object-recognition memory, effects of simvastatin and classical music occur through similar mechanisms, providing an important foundation for future preclinical and clinical research...

The effects of swimming exercise on recognition memory for objects and conditioned fear in rats / Os efeitos do exercício de natação sobre a memória para reconhecimento de objetos e de medo condicionados em ratos

Experiments conducted in animals have repeatedly demonstrated the ability of exercise to enhance cognitive function. This study examines the effects of chronic swimming exercise on non-spatial memory in adult rats after 12 weeks of swimming exercise in object recognition and elevated T-maze tests. In the object recognition test, repeated measures analysis of variance revealed a group effect (F1,42 = 26,093; p < 0.001), control rats had lower discrimination ratios than the exercise group. However, the swimming exercise did not affect the performance of inhibitory avoidance and escapes, when memory was tested in elevated T-maze. Analysis of variance showed a significant reduction in inhibitory avoidance 24h after the first training (F1,42 = 14,552; p < 0.001). Results indicated that regular swimming exercise significantly increased non-spatial memory in object recognition behavior, but did not affect the performance of inhibitory avoidance and escape on elevated T-maze test in adult rats. These findings suggest that the perirhinal cortex plays a role in memory consolidation and storage in addition to that of the amygdala, which could be regarded as the center of a second memory system, separate from those governed by the perirhinal cortex.

As experiências realizadas em animais mostram a capacidade do exercício em melhorar as funções cognitivas. Este estudo analisa os efeitos do exercício crônico de natação sobre a memória não-espacial em ratos adultos após 12 semanas de exercício de natação nos testes de reconhecimento de objetos e labirinto em T elevado. O teste de reconhecimento de objetos, pelas repetidas análises de variância revelaram um efeito de grupo (F1,42 = 26.093; p < 0,001), os ratos controles discriminaram uma razão inferior ao do grupo de exercício. Entretanto, o exercício de natação não afetou o desempenho de esquiva inibitória e escape, quando a memória foi testada no labirinto em T elevado. Análise de variância mostrou redução significativa na esquiva inibitória 24h após o primeiro treino (F1,42 = 14.552; p < 0,001). Os resultados indicam que o exercício regular de natação aumenta significativamente a memória não-espacial no comportamento de reconhecimento de objetos, mas não afeta o medo condicionado no teste do labirinto em T elevado em ratos adultos. Estes resultados sugerem que o córtex peririnal desempenha papel nos processos de consolidação e armazenamento de memória além da amígdala, podendo esta ser encarada como um segundo centro de sistema de memória, separada dos regidos pelo córtex peririnal.

Anxiolytic effects of swimming exercise and ethanol in two behavioral models: beneficial effects and increased sensitivity in mice

Several behavioral mechanisms have been suggested to explain the effects of ethanol or physical exercise on anxiety. The purpose of the current study was to assess the effects of chronic and acute administration of ethanol on swimming exercise in mice, sequentially submitted to the elevated plus-maze and open- tests. In the first experiment, sedentary or physical exercise groups received chronic treatment with ethanol (0.1, 0.2, 0.4, 2 or 4 g ethanol/kg/day by oral gavage) for 14 days before the tests. In the second experiment, groups received a single dose of ethanol (ip: 0.6, 0.8, 1.0 or 1.2 g/kg), ten minutes before the start of behavioral tests. The present study found an anxiolytic-like effect after chronic ethanol treatment or swimming exercise, evidence of beneficial effects. Moreover, we conclude that exercise can increase behavioral sensitivity to ethanol in acute treatment. The experiments described here show that the effects of ethanol on the behavior displayed in the elevated plus-maze and open- are not only dose-dependent but also modified by swimming exercise. These results may provide valuable insights into possible molecular mechanisms governing these adaptations.

Vários mecanismos comportamentais foram propostos para explicar os efeitos do etanol ou do exercício sobre a ansiedade. O objetivo do presente estudo foi avaliar os efeitos da administração crônica e aguda de etanol sobre o exercício de natação em camundongos, seqüencialmente submetidos aos testes do labirinto em cruz elevado e campo aberto. No primeiro experimento, os grupos de sedentários e exercício físico receberam tratamento crônico com etanol (0,1; 0,2; 0,4; 2 e 4 g de etanol/kg/dia através de gavagem oral) durante 14 dias antes dos testes. No segundo experimento, os grupos receberam uma única dose de etanol, i.p. (0,6; 0,8; 1,0 ou 1,2 g de etanol/kg), dez minutos antes do início dos testes comportamentais. O presente estudo encontrou efeitos ansiolíticos após tratamento crônico com etanol ou exercício de natação, provas dos efeitos benéficos. Além disto, concluímos que o exercício pode aumentar a sensibilidade comportamental ao etanol no tratamento agudo. Os experimentos aqui descritos mostram que os efeitos do etanol sobre o comportamento exibido no labirinto em cruz elevado ou campo aberto não são apenas dose-dependente, mas também depende do exercício de natação. Este trabalho pode fornecer ?insights? valiosos sobre os possíveis mecanismos moleculares que regem essas adaptações.

Incidência de delirium durante a internação em unidade de terapia intensiva em pacientes pré-tratados com estatinas no pós-operatório de cirurgia cardíaca / The incidence of delirium in patients pretreated with statins who remain in an intensive care unit after cardiac surgery

OBJETIVO: Determinar a associação entre a administração pré-operatória de estatina e o delírium pós-operatório em uma corte prospectiva de pacientes submetidos à cirurgia cardíaca. MÉTODOS: Foram analisados pacientes adultos internados na unidade de terapia intensiva após cirurgia cardíaca entre janeiro e junho de 2011. A triagem para delirium foi realizada utilizando o Confusion Assessment Method para analisar delirium em uma unidade de terapia intensiva (CAM-ICU) e Delirium Screening Checklist para terapia intensiva (ICDSC) durante a internação na terapia intensiva RESULTADOS: Cento e sessenta e nove pacientes foram submetidos à cirurgia cardíaca eletiva, dos quais 40,2% estavam utilizando estatina no pré-operatório. Delirium foi identificado em 14,9% dos pacientes que não utilizavam estatina comparado com 11,8% dos que utilizavam (p=0,817) quando avaliados pelo CAM-ICU. Utilizando o ICDSC 18,8% dos pacientes que não usam estatina comparado com 10.3% dos que usam (p=0,191). CONCLUSÃO: Não há relação entre uso de estatinas com a ocorrência de delirium em pacientes submetidos a cirurgia cardíaca.

OBJECTIVE: To determine the association between the preoperative administration of statins and postoperative delirium in a prospective cohort of patients undergoing cardiac surgery. METHODS: All adult patients who were admitted to the intensive care unit following cardiac surgery between January and June 2011 were included. Delirium was screened during the postoperative period using the Confusion Assessment Method for Intensive Care Unit (CAM-ICU) and Intensive Care Delirium Screening Checklist (ICDSC). RESULTS: A total of 169 patients underwent elective cardiac surgery, and 40.2% of the patients were treated preoperatively with statins. Delirium was identified using the CAM-ICU in 14.9% of patients not taking preoperative statins in comparison with 11.8% of the patients taking statins (p = 0.817). Using the ICDSC, delirium was identified in 18.8% of patients not taking statins in comparison with 10.3% of the patients taking statins (p = 0.191). CONCLUSION: The use of preoperative statins is not correlated with postoperative delirium in patients undergoing cardiac surgery.

O efeito da morfina na inibição vagal do coração: demonstração da dupla via do nodo atrioventricular / The effect of morphine on vagal inhibition of the heart: demonstration of dual atrioventricular nodal pathways

A estimulação elétrica do nervo vago diminui a freqüência cardíaca e aumenta o intervalo PQ no eletrocardiograma, podendo ativar a via anterógrada do nodo atrioventricular. Neste experimento é investigada a interação da morfina sobre o controle nervoso parassimpático cardíaco em relação à dupla condução do nodo atrioventricular. A estimulação do nervo vago induz uma significativa bradicardia e um bloqueio atrioventricular de terceiro grau, com a onda P aparecendo negativa na derivação II. Devido aos efeitos moduladores da anestesia sobre o coração, administração de injeções de morfina induz o aparecimento de onda P positiva através de uma ação inibitória sobre a reentrância do nodo atrioventricular. Tudo sugere a presença de duas vias atrioventriculares, anatômica e funcionalmente distintas.

That electrical stimulation of the vagus decreased heart rate and increased the PQ interval in electrocardiogram, consistent with anterograde dual atriventricular conduction. The present experiments were investigating the interaction of the morphine with cardiac parasympathetic nervous control in dual atrioventricular node. Electrical stimulation of the vagus nerve induced significant bradycardia and of third degree atrioventricular block and the P wave appearance was negative in leads II. Because background anesthesia modulates the heart, administered morphine injection the P waves appearance was positive through one inhibitory action on atrioventricular nodal reentry. All suggest the presence of two functionally and anatomically distinct atrioventricular pathways.

Anxiolytic effect of spermine microinjected into the dorsal periaqueductal grey in rats / Efeito ansiolítico da espermina microinjetada na substância cinzenta periaquedutal dorsal de ratos

Investigamos o possível efeito das espermina e receptores das poliaminas na substância cinzenta periaquedutal dorsal, sobre a ansiedade. Grupos de ratos receberam microinjeções de espermina (2,5 nmol) no interior da matéria cinzenta periaquedutal dorsal e foram testados no labirinto em cruz elevado. Os resultados indicam um aumento significativo na porcentagem de entradas e no tempo de permanência nos braços abertos. Outro experimento mostra que o efeito ansiolítico obtido após microinjeção de espermina (2,5 nmol) no interior da matéria cinzenta periaquedutal dorsal, foi bloqueado pela microinjeção prévia dos antagonistas das poliaminas, arcaina (4 nmol) ou ifenprodil (5 nmol), neste sítio. Estes resultados indicam que o receptor da espermina interage na modulação da ansiedade em ratos expostos ao labirinto em cruz elevado. Considerando que as poliaminas são encontradas normalmente no cérebro, estes resultados sugerem que o sistema de poliaminas na matéria cinzenta periaquedutal dorsal possuem um importante papel na ansiedade

To investigate a possible effect of the spermine and its polyamins receptors in the dorsal periaqueductal grey (DPAG) in anxiety. Groups of rats received microinjections of spermine (2.5 nmol) into DPAG and were tested in the elevated plus-maze apparatus. Results indicated an overall significant increase in the percentage of entries and in the time spent in open arms. In another experiment the anxiolytic effect obtained after the microinjection of spermine (2.5 nmol) into DPAG was block by previous microinjection of polyamines antagonists, arcaine (4 nmol) or ifenprodil (5 nmol) into the same site. These results indicate that the spermine receptor interaction in the modulation of anxiety in rats exposed to the elevated plus-maze. Considering that polyamines are natural component of the brain, these results suggest that polyamine system within DPAG may play a role in aversion and anxiety