Anxiolytic effects of N-(4,5-dihydro-5-oxo-1,2-dithiolo-[4,3,b]-pyrrole-6-yl)-N-methylformamide, a pyrroloformamide isolated from a marine Streptomyces sp., in adult zebrafish by the 5-HT system.

General anxiety disorders are among the most prevalent mental health problems worldwide. The emergence and development of anxiety disorders can be due to genetic (30-50%) or non-genetic (50-70%) factors. Despite medical progress, available pharmacotherapies are sometimes ineffective or can cause undesirable side effects. Thus, it becomes necessary to discover new safe and effective drugs against anxiety. This study evaluated the anxiolytic effect in adult zebrafish (Danio rerio) of a natural pyrroloformamide (PFD), N-(4,5-dihydro-5-oxo-1,2-dithiolo-[4,3,b]-pyrrole-6-yl)-N-methylformamide, isolated from a Streptomyces sp. bacterium strain recovered from the ascidian Eudistoma vannamei. The complete structure of PFD was determined by a detailed NMR analysis, including 1H-13C and 1H-15N-HBMC data. In addition, conformational and DFT computational studies also were performed. A group of fishes (n = 6) was treated orally with PFD (0.1, 0.5 and 1.0 mg/mL; 20 µL) and subjected to locomotor activity and light/dark tests, as well as, acute toxicity 96 h. The involvement of the GABAergic and serotonergic (5-HT) systems was investigated using flumazenil (a silent modulator of GABA receptor) and 5-HT1, 5-HT2A/2C and 5-HTR3A/3B receptors antagonists, known as pizotifen, granisetron and cyproheptadine, respectively. PFD was nontoxic, reduced locomotor activity and promoted the anxiolytic effect in zebrafish. Flumazenil did not inhibit the anxiolytic effect of the PFD via the GABAergic system. This effect was reduced by a pretreatment with pizotifen and granisetron, and was not reversed after treatment with cyproheptadine. Molecular docking and dynamics studies confirmed the interaction of PFD with the 5-HT receptor.Communicated by Ramaswamy H. Sarma.

Pyrroloformamide (PFD), isolated from the marine Streptomyces sp. associated ascidian Eudistoma vannamei, showed no toxicity in adult zebrafish but reduced its locomotor activity.The structural elucidation of PFD was determined by the analysis of 1D and 2D NMR and HRESIMS data.The density functional theory (DFT) study confirmed the existence of two conformers as determined by NMR spectra.The serotonergic system modulated the anxiolytic effect of PFD via the 5-HT receptor in adult zebrafish.Molecular docking and dynamics studies confirmed the interaction of PFD with the 5-HT receptor.

Effect of transcutaneous electrical stimulation on nociception and edema induced by peripheral serotonin.

Transcutaneous electrical nerve stimulation (TENS) is defined as the application of an electrical current to the skin through surface electrodes for pain relief. Various theories have been proposed in order to explain the analgesic mechanism of TENS. Recent studies have demonstrated that part of this analgesia is mediated through neurotransmitters acting at peripheral sites. The aim of this study was to investigate the effects of low frequency (LF: 10 HZ) TENS and high frequency (HF: 130 HZ) TENS on hyperalgesia and edema when applied before the serotonin (5-HT) administered into the rat paw. LF and HF TENS were applied to the right paw for 20 min, and 5-HT was administered immediately after TENS. The Hargreaves method was used to measure nociception, while the hydroplethysmometer (Ugo Basile®) was used to measure edema. Neither HF nor LF TENS inhibited 5-HT-induced edema. However, LF TENS, but not HF TENS, completely reduced 5-HT-induced hyperalgesia. Pre-treatment of the paw with naltrexone, prior to application of TENS, (Nx: 50 µg; I.pl.) showed a complete blockade of the analgesic effect induced by low frequency TENS. Thus, our results confirmed the lack of an anti-inflammatory effect through the use of TENS as well as the participation of peripheral endogenous opioid receptors in LF TENS analgesia in addition to its central action.

Enxaqueca: revisäo / Migraine: a review

A enxaqueca tem sido citada na literatura médica por mais de 2000 anos, desde antes do começo da era cristä. É a causa mais frequente de cefaléia em nosso meio. Neste sentido procuramos fazer uma revisäo da migrânea abordando desde o histórico, classificaçäo, fisiopatologia, até o tratamento

Enxaqueca: revisao

A enxaqueca tem sido citada na literatura medica por mais de 2.000 anos, desde antes do comeco da era crista. E a causa mais frequente de cefaleia em nosso meio. Neste sentido procuramos fazer uma revisao da migranea abordando desde o historico, classificacao, fisiopatogenia, ate o tratamento.

Estudo clínico com Pizotifeno na prevençäo da enxaqueca / Clinical trial with pizotifen in the prevention of migraine

Säo avaliadas a eficácia e a tolerabilidade do pizotifeno no trratamento profilático da enxaqueca. foi administrado, por via oral, 0,5 mg desta substância, duas vezes ao dia, durante três meses ininterruptos. Ao final da observaçäo, 80% dos pacientes tratados com pizotifeno riveram significativa melhora ou tornaram-se assintomáticos, 18% apresentaram crises ou convulsöes e 2% abandonaram o tratamento. Os efeitos colaterais advindos do uso desta droga foram leve sonolência e discreta sensaçäo de perda de equilíbrio. Nos casos sintomáticos a näo regressäo dos sintomas deveu-se a fotores diversos, como sejam síndrome de Horton e eclâmpsia. De modo geral, o pizotifeno mostrou-se eficaz e bem tolerado pela maioria dos pacientes analisados em tratamentos de curta e média duraçäo

[Headache in childhood: diagnosis and therapy. A prospective study of 77 cases]. / Cefaléia na infância: diagnóstico e terapêutica. Estudo prospectivo de 77 casos.

Seventy seven cases of migraine in children were studied. Age average was 9 years +/- 2; there were any sex differences. The frontal localization was found in roughly 49% of cases, whereas hemicrania was just found in 9% of cases. The most frequent factors associated were nausea, vomiting and dizziness. The most common triggering factor was the stress. Family history of migraine occurred in 76.5%. Out of 36 patients suffering migraine, 31 underwent a prophylactic treatment with pizotifen or propranolol. There was satisfactory clinical responses in roughly 90% of cases.

Cefaléia na infância: diagnóstico e terapêutica; estudo prospectivo de 77 casos / Headache in childhood: diagnosis and therapy; prospective study of 77 cases

Foram analisados 77 casos de cefaléia na infância. A faixa etária situou-se em 9 anos ñ 2 sem diferença entre os sexos. A localizaçäo frontal foi encontrada em aproximadamente 49% dos casos com relato de hemicrania em apenas 9%. Os fatores associados mais freqüentes foram náuseas, vômitos e tontura, sendo o fator desencadeante mais comum o stress emocional. Antecedente familiar de cefaléia ocorreu em 76,5%. Dos 36 pacientes considerados como tendo enxaqueca, 31 foram submetidos a tratamento profilático com pizotifeno ou propranolol. Houve resposta clínica satisfatória em aproximadamente 90% dos casos

Estudo clínico com pizotifeno na prevençäo da enxaqueca / Clinical trial with pizotifen in migraine prophylaxis

Os autores avaliaram a eficácia e a tolerabilidade do pizotifeno no tratamento profilático da enxaqueca. Foi administrado 0,5 mg desta substancia, duas vezes ao dia, durante três meses ininterruptos, por via oral. Ao final da observaçäo, 80% dos pacientes tratados com pizotifeno tiveram significativa melhora ou tornaram-se assintomáticos. 18% apresentaram crises ou convulsöes e 2% abandonaram o tratamento. Os efeitos colaterais advindos do uso da droga foram leve sonolência e discreta sensaçäo de perda de equilíbrio. Nos casos sintomáticos, a näo regressäo dos sintomas deveu-se a fatores diversos como sejam síndrome de Horton, eclâmpsia e antecedente familiar, sendo estes refratários ao uso do medicamento. De um modo geral, o pizotifeno mostrou-se eficaz e bem tolerado pela maioria dos pacientes analisados em tratamento de curta e media duraçäo