Modulatory effects of neuropeptides on pentylenetetrazol-induced epileptic seizures and neuroinflammation in rats

SUMMARY OBJECTIVE We aimed to explore the effects of neuropeptides ghrelin, obestatin, and vasoactive intestinal peptide (VIP) on seizures and plasma concentrations of neuroinflammation biomarkers including calcitonin gene-related peptide (CGRP), substance-P (SP), and interleukin-1 beta (IL-1β) in pentylenetetrazol-induced seizures in rats. METHODS Ghrelin (80 µg/kg), obestatin (1 µg/kg), VIP (25 ng/kg) or saline were administered to rats intraperitoneally 30 min before pentylenetetrazole (PTZ, 50 mg/kg) injections. Stages of epileptic seizures were evaluated by Racine's scale, and plasma CGRP, SP, and IL-1β concentrations were measured using ELISA. RESULTS Both obestatin and VIP shortened onset-time of generalized tonic-clonic seizure, respectively, moreover VIP also shortened the onset-time of first myoclonic-jerk induced by PTZ. While PTZ increased plasma CGRP, SP and IL-1β concentrations, ghrelin reduced the increases evoked by PTZ. While VIP further increased PTZ-evoked CGRP levels, it diminished IL-1β concentrations. However, obestatin did not change CGRP, SP, and IL-1β concentrations. CONCLUSION Our results suggest that ghrelin acts as an anticonvulsant, obestatin acts as a proconvulsant, and VIP has dual action on epilepsy. Receptors of those neuropeptides may be promising targets for epilepsy treatment.

RESUMO OBJETIVO Nosso objetivo foi explorar os efeitos dos neuropeptídeos grelina, obestatina e peptídeo intestinal vasoativo (VIP) nas convulsões e concentrações plasmáticas de biomarcadores neuroinflamatórios, incluindo peptídeo relacionado ao gene da calcitonina (CGRP), substância-P (SP) e interleucina-1 beta (IL-1β) em convulsões induzidas por pentilenotetrazol em ratos. MÉTODOS Grelina (80 µg/kg), obestatina (1 µg/kg), VIP (25 ng/kg) ou solução salina foram administrados a ratos intraperitonealmente 30 minutos antes de injeções de pentilenotetrazol (PTZ, 50 mg/kg). Os estágios das crises epilépticas foram avaliados pela escala de Racine e as concentrações plasmáticas de CGRP, SP e IL-1β foram medidas usando Elisa. RESULTADOS Tanto a obestatina quanto o VIP encurtaram o tempo de início da crise tônico-clônica generalizada, respectivamente. Além disso, o VIP também encurtou o tempo de início do primeiro impulso mioclônico induzido por PTZ. Enquanto o PTZ aumentou as concentrações plasmáticas de CGRP, SP e IL-1β, a grelina reduziu os aumentos evocados por PTZ. Enquanto o VIP aumenta ainda mais os níveis de CGRP evocados por PTZ, diminui as concentrações de IL-1β. No entanto, a obestatina não alterou as concentrações de CGRP, SP e IL-1β. CONCLUSÃO Nossos resultados sugerem que a grelina tem anticonvulsivante, a obestatina tem proconvulsivante e o VIP tem ação dupla na epilepsia. Receptores desses neuropeptídeos podem ser alvos promissores para o tratamento da epilepsia.

Akt Inhibitor Perifosine Prevents Epileptogenesis in a Rat Model of Temporal Lobe Epilepsy / 神经科学通报·英文版

Accumulating data have revealed that abnormal activity of the mTOR (mammalian target of rapamycin) pathway plays an important role in epileptogenesis triggered by various factors. We previously reported that pretreatment with perifosine, an inhibitor of Akt (also called protein kinase B), abolishes the rapamycin-induced paradoxical increase of S6 phosphorylation in a rat model induced by kainic acid (KA). Since Akt is an upstream target in the mTOR signaling pathway, we set out to determine whether perifosine has a preventive effect on epileptogenesis. Here, we explored the effect of perifosine on the model of temporal epilepsy induced by KA in rats and found that pretreatment with perifosine had no effect on the severity or duration of the KA-induced status epilepticus. However, perifosine almost completely inhibited the activation of p-Akt and p-S6 both acutely and chronically following the KA-induced status epilepticus. Perifosine pretreatment suppressed the KA-induced neuronal death and mossy fiber sprouting. The frequency of spontaneous seizures was markedly decreased in rats pretreated with perifosine. Accordingly, rats pretreated with perifosine showed mild impairment in cognitive functions. Collectively, this study provides novel evidence in a KA seizure model that perifosine may be a potential drug for use in anti-epileptogenic therapy.

Montelukast reduces seizures in pentylenetetrazol-kindled mice

Cysteinyl leukotrienes (CysLTs) have been implicated in seizures and kindling; however, the effect of CysLT receptor antagonists on seizure frequency in kindled animals and changes in CysLT receptor expression after pentylenetetrazol (PTZ)-induced kindling have not been investigated. In this study, we evaluated whether the CysLT1 inverse agonist montelukast, and a classical anticonvulsant, phenobarbital, were able to reduce seizures in PTZ-kindled mice and alter CysLT receptor expression. Montelukast (10 mg/kg, sc) and phenobarbital (20 mg/kg, sc) increased the latency to generalized seizures in kindled mice. Montelukast increased CysLT1 immunoreactivity only in non-kindled, PTZ-challenged mice. Interestingly, PTZ challenge decreased CysLT2 immunoreactivity only in kindled mice. CysLT1 antagonists appear to emerge as a promising adjunctive treatment for refractory seizures. Nevertheless, additional studies are necessary to evaluate the clinical implications of this research.

Evaluation of prenatal care in unit with family health strategy / Evaluación del cuidado prenatal en unidad con estrategia salud de la familia / Avaliação da assistência pré-natal em unidade com estratégia saúde da família

We analyzed prenatal care (PN) provided at a unit of the Family Health Strategy Service in São Paulo, according to the indicators of the Program for the Humanization of Prenatal and Birth (PHPB). We compared adequacy of PN in terms of sociodemographic variables, procedures, examinations and maternal and perinatal outcomes. Cross-sectional study with data from records of 308 pregnant women enrolled in 2011. We observed early initiation of PN (82.1%), conducting of a minimum of six consultations (84.1%), puerperal consultation (89.0%); to the extent that there is a sum of the actions, there is a significant drop in the proportion of adequacy. Prenatal care was adequate for 67.9%, with a significant difference between adequacy groups in relation to gestational age and birth weight. Prenatal care deficiencies exist, especially in regards to registration of procedures, exams and immunization. The difference between adequacy groups with respect to perinatal outcomes reinforces the importance of prenatal care that adheres to the parameters of the PHPB.
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Se evaluó el prenatal (PN) de un servicio de salud que cuenta con Estratégia Salud de la Familia, de la ciudad de São Paulo, conforme indicadores del Programa de Humanización del Prenatal y Nacimiento (PHPN) y se comparó la adecuación del PN con variables sociodemográficas, procedimientos, exámenes y los resultados maternos y perinatales. Estudio transversal con datos de los registros de 308 embarazadas inscritas en 2011. Se observó el inicio precoz de PN (82,1%), realización del mínimo de seis consultas (84,1%) y la consulta puerperal (89%) y, en la medida en que hay una suma de las acciones, hay una caída significativa en coeficiente de adecuación. El PN fue adecuado para el 67,9%, con una diferencia significativa entre los grupos de adecuación en relación a la edad gestacional y el peso al nacer. Hay deficiencias en el PN, especialmente en los registro de procedimientos, exámenes y vacunas. La diferencia entre los grupos en adecuación con respecto a los resultados perinatales refuerza la importancia de un PN conforme parámetros del PHPN.
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Analisou-se a assistência pré-natal (PN) de uma unidade com Estratégia Saúde da Família do Município de São Paulo, conforme os indicadores do Programa de Humanização do Pré-Natal e Nascimento (PHPN), e comparou-se adequação do PN com variáveis sociodemográficas, procedimentos, exames e desfechos maternos e perinatais. Estudo transversal com dados de registros de 308 gestantes inscritas em 2011. Observou-se início precoce do PN (82,1%), realização do mínimo de seis consultas (84,1%), consulta puerperal (89,0%) e, à medida que há um somatório das ações, há uma queda importante na proporção de adequação. O PN foi adequado para 67,9%, com diferença significante entre os grupos de adequação em relação à idade gestacional e peso ao nascer. No PN existem deficiências, especialmente no registro de procedimentos, exames e imunização. A diferença nos grupos de adequação com relação aos desfechos perinatais reforça a importância de um PN, conforme os parâmetros do PHPN.

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Anticonvulsant profile of 2-ethylthio-7-methyl-4-(4-methylphenyl)pyrazolo[1, 5-a][1, 3, 5]triazine

This work evaluates the central nervous effects in ICR strain mice of 2-ethylthio-7-methyl-4-(4-methylphenyl)pyrazolo[1,5-a][1,3,5]triazine (MH4b1), a compound obtained by an efficient one-step reaction of S,S-diethyl 4-methylbenzoylimidodithiocarbonate with 5-amino-3-methyl-1H-pyrazole, in order to assess its neuro-pharmacological profile. The tests applied were: maximal electroshock seizure (MES), pentylenetetrazole (PTZ) seizures, forced swimming, plus maze, marble burying, sleeping time, rota-rod and catalepsy. In addition, MH4b1 binding to the benzodiazepine site of the GABA-A receptor and MH4b1 inhibition of monoamine oxidase (MAO) subtypes A and B were evaluated. MH4b1 showed anticonvulsant effects in a dose dependent manner (30-300 mg/kg, p.o.) against MES and inhibition of MAO-B (IC50: 24.5 µM) without activity at the benzodiazepine site. These data suggest that MH4b1 has anticonvulsant properties related to MAO-B inhibition.

Este trabalho avalia o efeito do 2-etiltio-7-metil-4-(4-metilfenil)pirazol[1,5-a][1,3,5]triazina (MH4b1) no sistema nervoso central de camundongos ICR. O MH4b1 foi obtido por a reação de 4-metilbenzoilimidoditiocarbonato de S,S-dietil e 5-amino-3-metil-1H-pirazol em uma única etapa. O perfil neurofarmacológico foi realizado por testes de convulsão induzida por eletrochoque (MES) e pentilenotetrazol (PTZ) e por testes de nado forçado, labirinto em cruz, esconder as esferas, sono barbitúrico, rota-rod e catalepsia. Também foi avaliada a união do MH4b1 ao o local de ligação de benzodiazepínicos do receptor GABA-A e a capacidade inibitória do MH4b1 sobre a monoaminoxidase (MAO) A e B. O MH4b1 mostrou efeito anticonvulsivante dependente da dose (30-300 mg) no teste do MES e apresentou atividade inibitória da MAO-B (CI50: 24.5 µM) sem interagir com o local de ligação de benzodiazepínicos do receptor. Os resultados sugerem que o MH4b1 tem atividade anticonvulsivante relacionada com a inibição da MAO-B.

Antiepileptic potential of Anisomeles indica (Linn.) Kuntze aerial parts in pentylenetetrazole-induced experimental convulsions in Wistar rats.

The chloroform (4.20% w/w), ethyl acetate (4.23% w/w) and aqueous decoction (12.11% w/w) extracts of the aerial parts of A. indica were screened for the antiepileptic activity against maximal electroshock (MES) model and pentylenetetrazole (PTZ) models at  doses of 200, 400 mg/kg, po once. Phenytoin and diazepam (25 and 2 mg/kg, ip) were used as standard drugs in MES and PTZ model, respectively. Further, ethyl acetate extract (active extract) was fractionated into flavonoid and tannin fraction, which were subsequently evaluated for the antiepileptic potential against both MES and PTZ models at a dose of 50 mg/kg, po. Pretreatment with ethyl acetate extract 200, 400 mg/kg, po, for 1 week showed significant antiepileptic activity against PTZ induced convulsions only. Isolated flavonoid fraction showed more potent antiepileptic activity as compared to ethyl acetate extract, without any neurotoxic effect. However, tannin fraction did not produce antiepileptic activity against PTZ induced convulsions. It may be concluded that the flavonoids fraction of ethyl acetate extract of aerial parts of A. indica, but not the aqueous decoction has antiepileptic potential, without producing neurotoxic effects.

involvement of GABA-ergic transmission in the anticonvulsant effect of ginkgo biloba against kainic acid-induced seizures in mice

Ginkgo biloba[GbE] is an herbal product that has been proven to be effective in many neurological disorders. However, its anticonvulsant activity is not sufficiently studied. The aim of this work is to study the anticonvulsant activity of GbE and the role of GABA-ergic transmission in this effect.[1] Studying the anticonvulsant activity of GbE in different dose levels [20, 30 and 50 mg/kg/d, orally] for 15 days against kainic acid [KA]-induced seizures in mice. [2] Measurement of the brain giutamate and GAB A levels and glutamate decarboxylase [GAD] activity. GbE showed a protective effect for animals against KA-induced seizures in a dose-related manner. This appeared in form of a significant increase in time of seizure onset and decrease in percent of seizures and mortality in animals treated with GbE. Furthermore, there was a significant decrease in brain glutamate level and increase in GABA level and GAD activity in GbE-treated groups relative to KA-treated group. From the obtained results, we can conclude that GbE has effective anticonvulsant activity against KA-induced seizures. This effect may be mediated via various mechanisms but GABA-ergic transmission plays a vital role in this effect. Future research directions include further studies of the other possible mechanisms of GbE involved in its anticonvulsant and neuropotective activity

Determination of brucine and strychnine in rat after cutaneous administration of semen strychni niosome gel by LC-MS/MS / 中国中药杂志

<p><b>OBJECTIVE</b>A sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method has been developed and validated for the determination of brucine and strychnine in rat plasma.</p><p><b>METHOD</b>Samples were extracted by ethyl acetate-n-butanol (7: 3). Chromatographic separation was operated on ZORBAX XDB-C18 column with gradient elution of acetonitrile-methanol-water (0.05% acetic acid and 10 nmol x L(-1) ammonium formate contained), followed by LC-MS/MS in positive electrospray ionization. Quantification was carried out on multiple reaction monitoring (MRM) of the transition m/z 395.2/324.2, m/z 335.2/184.2 and m/z 199.1/171.1 for brucine, strychnine and tacrine (internal standard), respectively.</p><p><b>RESULT</b>The method was linear in the range of 0.195-100 and 0.07840 microg x L(-1) for brucine and strychnine, with coefficient correlation 0.994 and 0.996 respectively. The recoveries of extraction were 78.9% - 102.4% for brucine and 95.2% - 106.1% for strychnine. Precision, accuracy, stability and matrix effect of the analytes met the requirement. The method was applied to a pharmacokinetic study of brucine and strychnine after cutaneous administration of Semen Strychni niosome gel. The C(max) were (26.20 +/- 5.81) and (12.50 +/- 3.00) microg x L(-1) while the AUC(0-infinity), were (193.75 +/- 39.43) and (98.25 +/- 28.54) microg x h x L(-1) of the two components.</p><p><b>CONCLUSION</b>We conclude that the niosomes may reduce the systemic exposures and prolong the local release of brucine and strychnine.</p>

Sedative, hypnotic and anticonvulsive effects of an adenosine analogue WS090501 / 药学学报

This study is to examine the sedative, hypnotic and anticonvulsive effects of an adenosine analogue, WS090501. The spontaneous locomotor activity was recorded by open field equipment, and the EEG of rats was recorded by polyphysiograph. Pentylenetetrazol (PTZ)-induced seizure model was used. The spontaneous locomotor activity was decreased by WS090501 at various doses (0.06, 0.13, and 0.25 mg x kg(-1)), and the decreasing rate was 28.4%, 47.1% and 61.2% respectively. Furthermore, the effect of WS090501 on spontaneous locomotor activity of mice can be antagonized by DPCPX, a selective adenosine A1R antagonist, but cannot be antagonized by SCH58261, a selective adenosine A2AR antagonist. The NREM sleep was significantly increased by WS090501 (0.05 and 0.2 mg x kg(-1)), and the increasing rate was 27.6% and 102.8%, respectively, at 6th hour after administration. The REM sleep decreased significantly at the higher dose. PTZ induced serious convulsion in mice. The latency of convulsion was prolonged, and the number of seizure and mortality decreased after administration of WS090501. These results show that WS090501 has potent sedative, hypnotic and anticonvulsive effects, which may be mediated through adenosine A1R.

The role of magnesium sulfate in prevention of seizures induced by pentylenetetrazole in rats / O papel do sulfato de magnésio na prevenção de crises induzidas por pentilenotetrazol em ratos

Magnesium sulfate (MgSO4) has been used to prevent seizures in eclampsia. This study examined the central effects of MgSO4 on different types of pentylenetetrazole (PTZ)-induced seizures. Male Wistar rats were submitted to intracerebroventricular (ICV) administration of MgSO4 at different doses followed by intraperitoneal administration of PTZ. The latency to the onset of the first seizure induced by PTZ was significantly increased by ICV administration of MgSO4 at a dose of 100 µg compared to the control treatment. In addition, the total period during which animals presented with seizures was significantly reduced at this dose of MgSO4. Furthermore, the latency to the onset of the first partial complex seizure was significantly increased by the lowest dose of MgSO4. However, a high dose of MgSO4 had no effect or even potentiated the effect of PTZ. These results suggest that, depending on the dose, MgSO4 may be important in prevention of epileptic seizures.

Sulfato de magnésio (MgSO4) é utilizado para prevenir crises epilépticas na eclampsia. Este estudo examina os efeitos do MgSO4 em diferentes tipos de crise induzidas por pentilenotetrazol (PTZ). Ratos Wistar foram submetidos à administração intracerebroventricular (ICV) de diferentes doses de MgSO4 seguida de administração intraperitoneal de PTZ. A latência para o início da primeira crise induzida por PTZ foi aumentada pela administração ICV de MgSO4 na dose de 100 µg quando comparada ao tratamento controle. Além disso, o período durante o qual os animais apresentaram crises foi reduzido com a mesma dose de MgSO4. A latência para o início da primeira crise parcial complexa também foi aumentada com a dose menor de MgSO4 (32 µg). No entanto, a maior dose (320 µg) de MgSO4 não foi efetiva ou até potencializou os efeitos do PTZ. Esses resultados sugerem que, dependendo da dose, o MgSO4 pode ser útil na prevenção de crises epilépticas.

An experimental study of the anticonvulsant effect of amlodipine in mice

<p><b>INTRODUCTION</b>The need for the rational development of newer and adjuvant drugs to treat epilepsy has prompted this study of the potential anticonvulsant effect of amlodipine.</p><p><b>METHODS</b>The acute effect was studied in mice in single doses of 1 mg/kg, 2 mg/kg and 4 mg/kg of amlodipine and the chronic effect was studied in doses of 1 mg/kg and 4 mg/kg (administered daily for 21 days) using the maximal electroshock seizure and pentylenetetrazole-induced seizure models of epilepsy. Sodium valproate and normal saline were used as the standard and control, respectively.</p><p><b>RESULTS</b>For the acute study, in the maximal electroshock seizure model, the administration of 1 mg/kg of amlodipine resulted in the complete abolition of seizures in 33 percent of the mice, and this was increased to 67 percent with the administration of 4 mg/kg. In the pentylenetetrazole-induced seizure model, the administration of 1 mg/kg and 2 mg/kg amlodipine protected 33 percent of the animals from mortality, and 67 percent were protected with the administration of 4 mg/kg. For the chronic study, in the maximal electroshock seizure model, the administration of 1 mg/kg amlodipine resulted in the complete abolition of seizures in 40 percent of the mice and in 60 percent, with the administration of 4 mg/kg. In the pentylenetetrazole-induced seizure model, 50 percent of the mice were protected from mortality with 1 mg/kg amlodipine and 60 percent, with 4 mg/kg amlodipine.</p><p><b>CONCLUSION</b>These findings indicate that amlodipine may be a good candidate as an add-on therapy for epilepsy.</p>

No spatial memory deficit exists in Kunming mice that recently recovered from motor defects following 3-nitropropionic acid intoxication / 神经科学通报·英文版

<p><b>OBJECTIVE</b>Numerous studies have described both motor defects and cognitive impairments in several strains of rodents following 3-nitropropionic acid (3-NP) intoxication. In the present study, we investigated spatial recognition memory in Kunming mice that just recovered from motor defects induced by 3-NP.</p><p><b>METHODS</b>Mouse model was made by systemic subacute 3-NP treatment, and spatial recognition memory was measured through the Y-maze Test, a simple two-trial recognition test.</p><p><b>RESULTS</b>(1) On day 15 following 3-NP treatment, affected Kunming mice did not show motor defects in the Rotarod test and presented normal gait again. (2) In the following Y-maze test after 1h interval, the percentage (90.0%) of mice showing novel arm preference in 3-NP treatment group was significantly higher than the random chance level (50%), although it was only slightly higher than that (83.3%) in control group. On day 45 after 3-NP treatment, mice failed to choose unfamiliar novel arm as first choice, and the same occured in the control group. (3) For both post-intoxicated (on day 15 and day 45 following 3-NP treatment) and control groups, the duration in the novel arm and the frequency of entering it, were longer and higher compared with familiar start and other arms. For these mice that recently recovered from motor defects following 3-NP intoxication, no spatial memory deficits were observed through Y-maze Test.</p><p><b>CONCLUSION</b>Kunming mice used in our assays might possess resistance to cognitive impairment induced by 3-NP, which is consistent with previous findings in Swiss EPM-M1 mice.</p>

Changes of serum adrenocorticotropic hormone and cortisol levels during sleep seizures / 神经科学通报·英文版

<p><b>OBJECTIVE</b>Measuring the serum concentrations of adrenocorticotropic hormone (ACTH) and cortisol in epileptic seizures during sleep to investigate their link to the EEG changes.</p><p><b>METHODS</b>Pre-surgical evaluation was performed by video-EEG monitoring using 24 channel recording. Thirty six epilepsy patients could be attributed to two groups: 28 patients had spontaneous seizures, and the other 8 patients whose seizures were induced by bemegride. Another 11 persons with confirmed psychogenic non-epileptic seizures (PNES) served as control group. Blood samples were obtained at five points: wake (08:00 a.m.), sleep (00:00 a.m.), and shortly before, during and after an epileptic seizure. The serum ACTH and cortisol were measured and analyzed by chemiluminescent immunoassay.</p><p><b>RESULTS</b>The levels of ACTH and cortisol in serum underwent significant changes: declining below the average sleep-level shortly before seizures, increasing during seizures, and far above the average wake-level after seizures (P < 0.001). Such changes did not occur in the control group (P > 0.05). The ACTH and cortisol levels had no significant difference between spontaneous group and bemegride-induced group (P > 0.05).</p><p><b>CONCLUSION</b>The serum concentrations of ACTH and cortisol during sleep seizures are linked with pre-ictal and ictal EEG changes in epilepsy patients.</p>

Depressive-like behavior in mice recently recovered from motor disorders after 3-nitropropionic acid intoxication / 神经科学通报·英文版

<p><b>OBJECTIVE</b>Striatum may be involved in depressive disorders according to the neuroimaging analysis and clinical data. However, no animal model at present supported the possible role of striatum in the pathogenesis of depression. In the present study, we have investigated the depressive-like behavior in mice recently intoxicated with 3-nitropropionic acid (3-NP), a widely known toxin that selectively damages the striatum in the brain.</p><p><b>METHODS</b>Mouse model was made with subacute systemic 3-NP treatment, and the depressive-like behavior was measured using the duration of immobility during forced swimming test (FST).</p><p><b>RESULTS</b>When the mice at day 15 post-intoxication just totally recovered from motor deficits, the duration of immobility in FST was significantly longer than that in controls. The depressive-like behavior was not due to the fatigue or general sickness following 3-NP intoxication and could be reversed by the antidepressant, desipramine hydrochloride. In two successive FST in 24 h interval, the depressive-like behavior could be observed again in subsequent FST (at day 16 post-intoxication), and the mice presented a normal "learned helplessness".</p><p><b>CONCLUSION</b>A novel depression animal model could be established in mice during the initial period of recovery from 3-NP intoxication. The depression-like behavior might occur independently without involvement of cognitive defects, and the striatal lesions may underlie the depression-like behavior attributable to 3-NP intoxication.</p>

O advento do tratamento psiquiátrico moderno: a terapia convulsiva de László Meduna / Lessons from an early account of convulsive therapy

A terapia convulsiva (TC) constitui uma das principais contribuições européias ao tratamento psiquiátrico moderno e à psiquiatria biológica. A TC foi introduzida na psiquiatria em 1934 por László Meduna, neuropsiquiatra húngaro. As publicações subseqüentes sobre o primeiro paciente tratado com TC, Zoltán L (ZL), baseiam-se nos artigos e na autobiografia de Meduna. De acordo com essas referências, após quatro anos de estupor catatônico, ZL recebeu TC induzida por cânfora que resultou em plena remissão dos sintomas esquizofrênicos, culminando com alta da instituição. Este artigo reconstrói a história do caso de ZL a partir da recente recuperação de anotações - algumas escritas pelo próprio Meduna - dos Arquivos do Instituto Nacional de Psiquiatria e Neurologia (Hungria). Essas anotações mostram que ZL recebeu repetidas sessões de TC entre 1934 e 1937, primeiramente induzidas por cânfora e depois por cardiazol. A primeira série de TC resultou na suspensão do estupor catatônico e na remissão parcial da psicose. Entretanto, a remissão foi breve e, a despeito de repetidas sessões de TC, ZL nunca esteve inteiramente livre de sintomas, nunca teve alta hospitalar e veio a falecer no Instituto em 1945. Na discussão do caso de ZL, tentamos explicar as possíveis razões das discrepâncias entre o relato de Meduna e as notas originais do prontuário médico.

Convulsive therapy (COT) is a major European contribution to the psychiatric armamentarium and biological psychiatry. COT was introduced in psychiatry by László Meduna, a Hungarian neuropsychiatrist. All subsequent publications about the first patient treated with COT, Zoltán L (ZL), were based on Meduna's papers and autobiography. After 4 years of catatonic stupor, ZL received camphor-induced COT which resulted in full remission and discharge from the institution. The aim of this paper is to reconstruct ZL's case history from the original case notes-partly written by Meduna himself-which were recovered from the archives of the National Institute of Psychiatry and Neurology. The case notes show that ZL repeatedly received COT between 1934 and 1937, first with camphor and then with cardiazol induction. After the first course of COT the catatonic stupor was resolved and the psychotic symptoms subsided. However, the remission lasted for only a few months and was followed by a relapse. Despite repeated courses of COT, ZL never became symptom free again, was never discharged and died in the Institute in 1945. This historical case is discussed from both the diagnostic and therapeutic points of view, and an attempt is made to explain the possible reasons for the discrepancies found between Meduna's account and ZL's case notes.

Pro-convulsant effect of cefazolin sodium against pentylenetetrazol- or picrotoxin-induced convulsions in mice.

Cefazolin injection (3000 mg/kg, i.v.) in mice showed several behavioral excitations such as wild running, jumping, rolling, and finally undergoing severe convulsions followed by death. It's lower doses (500-2000 mg/kg, i.v.) were unable to produce any convulsions or behavioral excitations in mice. However, cefazolin (500 or 1000 mg/kg, i.v.) when administered before different doses of pentylenetetrazol (PTZ; 40 or 60 mg/kg, i.p.) or picrotoxin (PTX; 4 or 8 mg/kg, i.p.), it produced severe tonic-clonic convulsions in mice. The convulsions or behavioral excitations produced by 3000 mg/kg, i.v. cefazolin was also reversed by different doses of diazepam (0.5-2 mg/kg, i.p.) further proving the GABAergic modulatory effect of cefazolin. The results conclude the pro-convulsant action of cefazolin on PTZ- or PTX-induced convulsions, and further confirm the clinical reports.

Estado epiléptico: dos episodios en un embarazo: reporte de un caso / Epileptic status: two episodes in one pregnancy: case report

Paciente epiléptica, de 22 años de edad, con crisis convulsivas generalizadas desde los 12 años, que ingresó a la Maternidad "Concepción Palacios" en dos oportunidades durante su quinto embarazo por sendos episodios de estado epiléptico. El primero ocurrió en la semana 14 y el segundo en la 20 de gestación. En la semana 36 se práctico cesárea por desprendimiento prematuro de placenta y se extrajo recién nacido vivo, de 2700 g de peso y 44 cm de talla. Requirió atención en la Unidad de Cuidados Intensivos Neonatales por asfixia severa, con evolución satisfactoria. No se detectaron malformaciones al nacer

Anti-seizure efficacy of nimodipine in pentylenetetrazole and kainic acid combined seizure models in mice.

The present study aimed at establishing two models of experimental seizures by combination treatment with subconvulsive doses of PTZ and kainic acid in adult male mice and evaluating the modulatory role of cerebroselective dihydropyridine calcium channel blocker, nimodipine. The CD50 +/- SEM value for PTZ was found to be 20.00 +/- 0.92 mg/kg, ip in kainic acid (administered at per se subconvulsive dose of 1.00 mg/kg, ip) pretreated mice while CD50 +/- SEM value for kainic acid was found to be 0.30 +/- 0.08 mg/kg, ip in PTZ (administered at per se subconvulsive dose of 30.00 mg/kg, ip) pretreated mice. Nimodipine (5.00 mg/kg, ip) significantly protected the mice from seizure in both of the combination in vivo seizure models. The results suggested synergistic interaction between PTZ and kainic acid at subconvulsive dose combination while the protective efficacy of nimodipine suggested the role of calcium ion as an important mediator for the genesis of seizures.

Effect of repeated intraperitoneal exposure to picrotoxin on rat liver lysosomal function.

Effect of repeated (20 days) exposure to picrotoxin (PTX) on rat liver lysosomal function was evaluated by measuring the free and total activities of acid phosphatase, cathepsin D, ribonuclease II (RNAse II) and deoxyribonuclease II (DNAse II). The free activities of the nucleases (both RNAse II and DNAse II) were increased following PTX exposure. The total DNAse II activity was increased by 2.2-fold whereas the total acid phosphatase activity was decreased by 28%. Consequently, the ratios of total activity / free activity were low in the PTX exposed groups, implying loss of membrane integrity. Cathepsin D activity was completely abolished. The results show that repeated exposure to PTX can lead to lysosomal dysfunction in liver.

Neurobehavioural study of subchronic administration of oxydemeton-methyl (insecticide and acaricide) in rats.

Oxydemeton-methyl, an organophosphate insecticide and acaricide produced decrease in the exploratory behaviour and prolongation of barbitone sodium induced hypnosis in rats after intermittent aerosol spray inhalational exposure, for 1/2 hour daily for 7 consecutive days, compared to the saline control group. Further, ED50 +/- SEM value for haloperidol induced catalepsy, CD50 +/- SEM value for pentylenetetrazole induced seizure and CI50 +/- SEM value for electroshock (i.e. the dose of haloperidol, PTZ and intensity of electroshock producing catalepsy or positive seizure response in 50% of rats) were significantly decreased after 7 days exposure to oxydemeton-methyl compared to that of saline control group. The study has established the central nervous system depressant effect, extrapyramidal effect and proconvulsant potential of oxydemeton-methyl which is widely used by the agricultural workers in the form of field spray.