Pharmacological effects and behavioral interventions on memory consolidation and reconsolidation

In this article, we will review some behavioral, pharmacological and neurochemical studies from our laboratory on mice, which might contribute to our understanding of the complex processes of memory consolidation and reconsolidation. We discuss the post-training (memory consolidation) and post-reactivation (memory reconsolidation) effects of icv infusions of hemicholinium, a central inhibitor of acetylcholine synthesis, of intraperitoneal administration of L-NAME, a non-specific inhibitor of nitric oxide synthase, of intrahippocampal injections of an inhibitor of the transcription factor NF-κB, and the exposure of mice to a new learning situation on retention performance of an inhibitory avoidance response. All treatments impair long-term memory consolidation and retrieval-induced memory processes different from extinction, probably in accordance with the "reconsolidation hypothesis".

Miastenia gravis desencadenada por el uso de estatinas: presentación de once casos / Myasthenia gravis precipitated by statin use: presentation of eleven cases

Los inhibidores de 3-hidroxi-3 metil glutaril coenzima A reductasa (estatinas) son eficaces para el descenso de los nivelesde colesterol sérico y, consecuentemente, la prevención de la enfermedad isquémica cardíaca, cerebrovascular y vascularperiférica. Una de las principales limitaciones del uso de estas drogas es la aparición de sintomatología muscular como la elevación de la CK, mialgias, miositis o rabdomiolisis. La miastenia gravis (MG) es una enfermedad autoinmune caracterizada por la presencia de debilidad fluctuante de los músculos voluntarios. La enfermedad se desencadena por el ataque de anticuerpos dirigidos contra los receptores nicotínicosde acetilcolina (ACRA) localizados en la membrana del músculo a nivel de la unión neuromuscular. Existe un número interesante de fármacos que empeoran el curso de la enfermedad o que en algunos casos la "desenmascaran". Recientemente se publicaron casos de pacientes con MG que presentaron exacerbación de su enfermedad con laingesta de estatinas. Presentamos 11 pacientes que comenzaron con síntomas de MG luego de la toma de estas drogas. Seis recibieron atorvastatina (54.5%), tres simvastatina (27.3%) y dos rosuvastatina (18.2%).

3-hydroxi-3 metyl glutaryl coenzyme A reductase inhibitors, also known as statins, are effective in reducing plasmaticcholesterol and thus preventing cardiac, cerebral, and peripheral vascular ischemia. One of the main reasons that limit their use is the potential for muscular disorders, such as the increase of plasmatic CK, myalgia, myositis, and rhabdomyolysis. Myasthenia gravis (MG) is an autoimmune disease characterized by the presence of fluctuating voluntary muscle weakness. It is triggered by antibodies directed against nicotinic acetylcholine receptors (AChR) located at the neuromuscular junction, within the muscle membrane. A number of drugs may either unmask the disease or worsen it when installed. Recent publications have reported on cases of MG who aggravated their condition with the intake of statins. Here, we report on eleven patients who presented symptoms of MG after medication with statins. Six patients received atorvastatin (54.5%), three simvastatin (27.3%), and two rosuvastatin (18.2%).

O íon magnésio no tratamento de acidentes causados pelos escorpiöes Tityus serrulatus, T. bahiensis e Centruroides sculpturatus: estudo experimental / Magnesium in the treatment of accidents caused by the scorpions Tityus serrulatus, T. bahiensis and Centruroides sculpturatus: an experimental study

Os efeitos produzidos pelas peçonhas escorpiônicas säo consequentes, em sua maioria, à liberaçäo de acetilcolina (ACh) e catecolaminas. A verificaçäo de que o magnésio (Mg2+) inibe a liberaçäo de ACh em razäo de bloquear o influxo de cálcio nas terminaçöes nervosas, levou-nos a investigar a açäo deste cátion sobre os distúrbios produzidos pelas peçonhas escorpiônicas. Relatamos na presente comunicaçäo a açäo do Mg2+ sobre os efeitos induzidos pelas peçonhas dos escorpiöes Tityus serrulatus, T. bahiensis e Centruroides sculpturatus nas preparaçöes isoladas nervo frênico-diafragma, íleo, canal deferente e átrios de rato e in vivo, em ratos anestesiados com registro da pressäo arterial e do eletrocardiograma. Os efeitos da peçonha dos escorpiöes nas preparaçöes isoladas foram abolidos ou muito atenuados pelo Mg2+. O Mg2+, no entanto, somente antagonizou os efeitos da peçonha de C. sculpturatus no íleo de rato. Em ratos anestesiados, a hipertensäo e arritmias provocadas pela peçonha de T. serrulatus foram revertidas com exclusäo de bradicardia pela injeçäo do Mg2+. A peçonha de C. sculpturatus na maioria das experiências causou hipotensäo e arritmias de pequena gravidade. O Mg2+ reverteu as arritmias, mas causou quedas acentuadas da pressäo arterial. Os resultados da pesquisa sugerem o emprego do Mg2+ em acidentes graves na ausência de hipotensäo e bradicardia, produzidos por T. serrulatus e T. bahiensis. Parece contra-indicado nos acidentes causados por C. sculpturatus em vista de seu efeito acima referido na pressäo arterial.

Effects of diltiazem on calcium ion translocation: a study on isolated frog rectus abdominis muscle.

Diltiazem, a calcium channel blocker was studied to observe its effects on the acetylcholine contractile responses of isolated frog rectus abdominis muscle. This response was modified in a dual manner i.e., initial potentiation, followed by inhibition. Diltiazem may not have anticholinesterase like mechanism, as it potentiated the responses to both acetylcholine and succinylcholine. Rectus muscle preparation, incubated in calcium free frog Ringer, showed dose dependent inhibition of acetylcholine contractile responses by diltiazem. The study suggests that diltiazem inhibits calcium ion influx across receptor operated calcium channels and may also inhibit calcium ion release from intracellular structures.

Antinociceptive property of new 4-acyl-arylhydrazone pyrazole compounds

A series of new 4-acyl-arylhydrazone pyrazole compunds were tested for antinociceptive activity using the inhibition of abdominal contortions induced by acetylcholine (4 mg/Kg, ip) in the mouse. Dipyrone was used for comparison of the antinociceptive potency of the compounds being tested. All drugs wee administered po in saline (dipyrone) or in propylene flycol 94-acyl-arylhydrazones). The maximum response induced by dipyrone (86% inhibition) was assigned an efficacy index of 1.0. Although none of the compounds had an efficacy index greater than 1.0, all three reached 1.0. The two most potent compounds, Wd1 and W1g, which also had an efficacy similar to that of dipyrone, contain a p-N(CH3)2 and m-OH,p-OCH3 group in the aromatic ring of the acyl-hydrazone, respectively. W1d presented the lowest antinociceptive ED50 in the series (1.41 mg/Kg) and was eleven times more potent than dypyrone (ED50 = 15.80 mg/Kg). Other substitutions at the para position had lower potency than W1d. The present results indicate that the introduction of a group at the para postion of the acyl-arylhydrazone ring increases the antinociceptive activity of these compounds to provide compounds of the same efficacy but greater potency than dipyrone to which these new compounds ara structurally related. Other assays of nociceptive activity are veing used to characterize the mechanism of action of the potential new drugs

Açäo da amiodarona sobre as contraçöes induzidas por acetilcolina em duodeno isolado de rato / Effect of amiodarone on contractions induced by acetylcholine in isolated rat duodenum

O estudo dos efeitos da amiodarona sobre as respostas contráteis de duodeno isolado de rato induzidas por acetilcolina (5x10 -8M a 5x10 4-M), mostram que as contraçöes foram antagonizadas da maneira dose-dependente por amiodarona em concentraçöes de 2,5x10 -5M. A inibiçäo foi caracterizada como antagonismo näo-competitivo, pois houve reduçäo progressiva da resposta máxima. O valor médio de pD'2 com seu erro padräo foi calculado em 3,92 + ou - 0,31

Anti-spasmogenic effect of cyproheptadine on guinea-pig ileum.

Antagonistic activity of cyproheptadine against common spasmogens, like acetylcholine, histamine, serotonin, bradykinin and angiotensin, was studied on isolated guinea-pig ileum. Cyproheptadine produced a reversible antagonism of non-competitive type and was most effective against serotonin. It was less potent against histamine, bradykinin and angiotensin and least potent against acetylcholine.

Modification of the toxicity of acetylcholine by prior atropinization in mice.

The potentiation of acetylcholine (Ach) toxicity in mice with prior atropinization was tested. The experiments were carried out with three doses of 200 mg, 300 mg, and 400 mg/kg of Ach administered ip. Prior atropinization was observed to potentiate the Ach toxicity at all dose levels of atropine except the highest in the group that received Ach 200 mg/kg and the results were variable in the other two groups.

The effect of imipramine on isolated skeletal muscle preparations.

Imipramine (2-10 microng/ml) noncompetitively inhibited acetylcholine responses of the frog rectus abdominis muscle, and markedly inhibited the contracture produced by carbachol and succinylcholine without affecting the contracture produced by KCl, caffeine, and chlorpromazine. The twitch responses to indirect and direct stimulation of the rat phrenic nerve-diaphragm and the frog sciatic nerve-gastrocnemius were first augmented and then depressed markedly and irreversibly by imipramine (5-20 microng/ml). The indirect stimulation was inhibited earlier and to a greater degree than the direct stimulation. The blockade in the nerve-sartorius developed and progressed quickly without prior augmented responses, and with a parallel time course for indirect and direct stimulation. On the frog rectus, physostigmine antagonised whereas d-tubocurarine and CaCl2 increased the imipramine-induced inhibition. In the nerve muscle preparations, physostigmine, CaCl2 and KCl did not affect the neuromuscular blockade produced by imipramine; tubocurarine (0.05 microng/ml) markedly increased the blocking effect of imipramine (20 microng/ml) on the rat phrenic nerve-diaphragm. The results have been discussed in relation to the memberane stabilizing and the calcium releasing actions of imipramine.

Action of acetylcholine on the atropinised frog heart during the winter months.

During the winter months, high doses of acetylcholine produced positive inotropic action without any chronotropic action on the perfused atropinised frog heart, in 5 out of 24 preparations. In the remaining preparations acetylcholine failed to produce any action and positive inotropic effect of acetylcholine on these preparations was noticed if they were perfused with the medium containing excess of calcium. However, the rate remained unchanged. The positive inotropic action was blocked by the local anaesthetic amethocaine and thus may be due to increased penetration of calcium into the cardiac cell.

Spasmolytic activity of two synthetic anilide local anaesthetics.

Two basic anilides EA-7 and EA-8 were investigated for their antispasmodic activity against a variety of spasmogens on different tissues from different species of animals and comparison was made with lignocaine. EA-8 was found to be the most potent in this respect, followed by EA-7 and lignocaine. The antispasmodic potency does not correspond to their local anaesthetic potency. This suggests a direct depressant effect on tissues.