Electrophysiological, histopathological, and biochemical evaluation of the protective effect of probiotic supplementation against pentylenetetrazole-induced seizures in rats.

BACKGROUND AND PURPOSE: Research on the relationship between the gut microbiome and epilepsy is accumulating. The present study was conducted to evaluate the effect of probiotic supplementation on pentylenetetrazole (PTZ)-induced seizures in rats. METHODS: Twenty-one adult male Wistar albino rats were included. The animals were divided into three groups of seven rats. Group 1 was a control group, whereas Group 2 rats received PTZ treatment and Group 3 rats had PTZ+PB (probiotic) treatment. For 6 weeks, Groups 1 and 2 were given saline (1 ml), whereas Group 3 had probiotic supplement. In the 5th week, tripolar electrodes were attached to the rats. Electrophysiological, behavioral, biochemical, and immunohistochemical evaluations were performed in the 6 weeks after the treatment. RESULTS: PB treatment significantly reduced seizures. In the PTZ group, expression levels of brain-derived neurotrophic factor, nerve growth factor (NGF), and Sox2 (SRY sex-determining region Y-box 2) in rat brains decreased significantly compared to the control group, whereas the expression levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), total oxidant status (TOS), and nitric oxide (NO) levels increased. In the PTZ+PB group, NGF expression increased significantly compared to the PTZ group, whereas TNF-α, IL-6, TOS, and NO levels decreased. In histopathological examination, an abundance of necrotic neurons was notable in the PTZ group, which was less in the PTZ+PB group. In addition, body weight of the group supplemented with probiotics decreased after the treatment. CONCLUSIONS: Our results suggest that probiotic supplementation may alleviate seizure severity and exert neuroprotective effects by reducing neuroinflammation and oxidative stress and altering the expression of neurotrophins in epileptogenic brains.

Modulation of PTZ-induced convulsions in rats using topiramate alone or combined with low dose gamma irradiation: involving AKT/m-TOR pathway.

The current study evaluates the anticonvulsant effect low dose whole body gamma irradiation (LDR) alone or combined with topiramate against pentylenetetrazole (PTZ)-induced convulsions. Male Wister rats received either saline or PTZ (75 mg/kg i.p.). The other three groups were pretreated with single low dose radiation (0.5 Gy), topiramate (50 mg/kg, p.o., seven days) and TPM with LDR respectively before PTZ injection. Racine' score, latency, and duration of the convulsions were assessed. Glutamate and GABA were measured. AKT/m-TOR signaling pathway including AKT (protein kinase B), mammalian target of rapamycin (m-TOR), protein S6, and caspase 3 were also assessed. Measurements of markers of oxidative stress including malondialdehyde (MDA), glutathione (GSH), and nitric oxide (NO) were carried out. Histological examinations of hippocampi were done. PTZ produced behavioral changes (high Racine score, short latency, and long duration). It elevated MDA and NO contents, while reduced GSH content. TPM treatment alone or combined with LDR ameliorated the PTZ-induced convulsions and caused significant improvement in behavioral changes, brain mediators, m-TOR pathway, oxidative stress, and histological pictures in hippocampal regions. Histopathological examinations of the normal group showed normal structure with intact cells, while PTZ-treated rats exhibited necrosis, pyknosis, and atrophy of pyramidal cells. The histological findings corroborated with the amendment of biochemical parameters. The positive effects of LDR could offer a possible contributor in management of convulsions due to modulation of AkT/m-TOR signaling pathway, reduction of oxidative stress and modulation of brain amino acids. LDR improved the oxidative stress side effects of topiramate.

Chemical composition of Zhumeria majdae essential oil and its effects on the expression of morphine withdrawal syndrome and tolerance to the anticonvulsant effect of morphine on pentylenetetrazole-induced seizures in mice / Composição química do óleo essencial de Zhumeria majdae e seus efeitos na expressão da síndrome de abstinência de morfina e tolerância ao efeito anticonvulsivante da morfina em crises induzidas por pentilenotetrazol em camundongos

Abstract Regarding the proven anticonvulsant effect of Zhumeria majdae essential oil (ZMEO) in previous studies we were prompted to investigate the ZMEO effects on the tolerance to the anticonvulsant effects of morphine and the morphine withdrawal syndrome. Tolerance to the morphine anticonvulsant effect was induced in mice by subcutaneous injection of 2.5 mg/kg of morphine for 4 days. Subsequent doses of ZMEO (20 mg/kg) were used to study the expression and development of morphine tolerance. Clonidine was used as the standard drug to inhibit the morphine withdrawal syndrome symptoms. To study the ZMEO effect on withdrawal syndrome, mice received appropriate morphine values for 4 days and on the fifth day, 60 min before administration of naloxone. The effective dose of ZMEO was determined and the number of jumps, stands and changes in the dry stool weight, as symptoms of withdrawal syndrome were evaluated. The dose of 20 mg/kg of ZMEO decreased the tolerance in development and expression groups significantly. Counting the number of jumping, standing and defecation were assessed 30 min after morphine and 1 h after the vehicle and clonidine. The dose of 40 mg/kg ZMEO decreased all the signs of withdrawal syndrome significantly. ZMEO was analyzed by GC/MS and linalool (53.1%) and camphor (23.8%) were characterized as the main components. The results suggest that ZMEO possesses constituent(s) that have activity against tolerance to the anticonvulsant effects of morphine and the morphine withdrawal symptoms.

Resumo Em relação ao efeito anticonvulsivante comprovado do óleo essencial de Zhumeria majdae (ZMEO) em estudos anteriores, fomos instigados a investigar os efeitos do ZMEO em relação à tolerância aos efeitos anticonvulsivantes da morfina e da síndrome de abstinência de morfina. A tolerância ao efeito anticonvulsivante da morfina foi induzida em camundongos por injeção subcutânea de 2,5 mg/kg de morfina por 4 dias. Doses subsequentes de ZMEO (20 mg/kg) foram utilizadas para estudar a expressão e o desenvolvimento da tolerância à morfina. A clonidina foi usada como droga padrão para inibir os sintomas da síndrome de abstinência da morfina. Para estudar o efeito do ZMEO na síndrome de abstinência, os camundongos receberam valores apropriados de morfina por 4 dias e, no 5º dia, 60 minutos antes da administração de naloxona. A dose efetiva de ZMEO foi determinada, e o número de saltos e de permanência e as alterações no peso das fezes secas, conforme os sintomas da síndrome de abstinência, foram avaliados. A dose de 20 mg/kg de ZMEO diminuiu significativamente a tolerância nos grupos de desenvolvimento e expressão. A contagem do número de saltos, permanência e defecação foi avaliada 30 minutos após a morfina e 60 minutos após o veículo e a clonidina. A dose de 40 mg/kg de ZMEO diminuiu significativamente todos os sinais da síndrome de abstinência. O ZMEO foi analisado por GC/MS, e linalol (53,1%) e cânfora (23,8%) foram caracterizados como os principais componentes. Os resultados sugerem que o ZMEO apresenta constituintes que possuem atividade contra a tolerância aos efeitos anticonvulsivantes da morfina e aos sintomas de abstinência da morfina.

Antiseizure potential of peptides from the venom of social wasp Chartergellus communis against chemically-induced seizures.

Epilepsy is one of the most common neurological diseases in the world. The objective of this research was to investigate a new peptide from the venom of the social wasp Chartergellus communis useful to the study or pharmacotherapy of epilepsy. The wasps were collected, and their venom was extracted. Afterward, the steps of fractionation, sequencing, and identification were carried out to obtain four peptides. These molecules were synthesized for behavioral evaluation tests and electroencephalographic assays to determine their antiseizure potential (induction of acute seizures using the chemical compounds, pentylenetetrazole - PTZ, and pilocarpine - PILO) and analysis of neuropharmacological profile (general spontaneous activity and alteration in motor coordination). Chartergellus-CP1 (i.c.v. - 3.0 µg/animal) caused beneficial alterations in some of the parameters evaluated in both models: PTZ (latency and duration of maximum seizures) and PILO (latency and duration of, and protection against, maximum seizures, and reduction of the median of the seizure scores. When evaluated in 3 doses in the seizure model induced by PILO, the dose of 3.0 µg/animal protected the animals against seizures, with an estimated ED50 of 1.49 µg/animal. Electroencephalographic evaluation of Chartergellus-CP1 showed an improvement in latency, quantity, and percentage of protection against generalized electroencephalographic seizures in the PILO model. Further, Chartergellus-CP1 did not cause adverse effects on general spontaneous activity and motor coordination of animals. This study demonstrated how compounds isolated from wasps' venom may be important resources in the search for new drugs. Such compounds can be considered valuable therapeutic and biotechnological tools for the study and future treatment of epileptic disorders. In this context, a peptide that is potentially useful for epilepsy pharmacotherapy was identified in the venom of C. communis.

The role of nitric oxide in anticonvulsant effects of lycopene supplementation on pentylenetetrazole-induced epileptic seizures in rats.

Recent studies have shown that natural antioxidant compounds have positive effects on the nervous system. Lycopene, the red pigment in tomatoes, is one of the potent natural antioxidants, and is used as supplementation because of its well-known health benefits. However, its effect on epileptic seizures and underlying mechanisms are still unclear. In this study, it was aimed to investigate the effect of lycopene on pentylenetetrazole-induced epileptic seizures in rats and to elucidate the nitric oxide pathway in this effect. In this study, thirty male Wistar albino rats were used. Animals were divided into five groups (n = 6 for each group) as control, saline (1 mL/kg/day serum physiologic), positive control (2 mg/kg/day diazepam), and lycopene (5 and 10 mg/kg/day) for ten days. Pentylenetetrazole (45 mg/kg) was given to induce a seizure in the tenth day except for the control. Passive avoidance test was carried out to evaluate memory function. Inducible nitric oxide synthase (iNOS), neuronal nitric oxide synthase (nNOS), and nitric oxide (NO) levels were measured in the cortex and hippocampal brain regions using the ELISA kits. Lycopene supplementation prolonged epileptic seizure onset times and reduced seizure stages. Besides, lycopene supplementation improved memory impairment after seizures. Moreover, lycopene significantly reduced the level of iNOS, nNOS, and NO in the brain. Lycopene supplementation significantly alleviated seizures and memory impairment. Its anticonvulsive effect could be associated with the nitric oxide pathway. Lycopene supplementation could be useful as a supportive therapeutic agent in epileptic patients.

Chemical composition of Zhumeria majdae essential oil and its effects on the expression of morphine withdrawal syndrome and tolerance to the anticonvulsant effect of morphine on pentylenetetrazole-induced seizures in mice.

Regarding the proven anticonvulsant effect of Zhumeria majdae essential oil (ZMEO) in previous studies we were prompted to investigate the ZMEO effects on the tolerance to the anticonvulsant effects of morphine and the morphine withdrawal syndrome. Tolerance to the morphine anticonvulsant effect was induced in mice by subcutaneous injection of 2.5 mg/kg of morphine for 4 days. Subsequent doses of ZMEO (20 mg/kg) were used to study the expression and development of morphine tolerance. Clonidine was used as the standard drug to inhibit the morphine withdrawal syndrome symptoms. To study the ZMEO effect on withdrawal syndrome, mice received appropriate morphine values for 4 days and on the fifth day, 60 min before administration of naloxone. The effective dose of ZMEO was determined and the number of jumps, stands and changes in the dry stool weight, as symptoms of withdrawal syndrome were evaluated. The dose of 20 mg/kg of ZMEO decreased the tolerance in development and expression groups significantly. Counting the number of jumping, standing and defecation were assessed 30 min after morphine and 1 h after the vehicle and clonidine. The dose of 40 mg/kg ZMEO decreased all the signs of withdrawal syndrome significantly. ZMEO was analyzed by GC/MS and linalool (53.1%) and camphor (23.8%) were characterized as the main components. The results suggest that ZMEO possesses constituent(s) that have activity against tolerance to the anticonvulsant effects of morphine and the morphine withdrawal symptoms.

The Influence of Palmatine Isolated from Berberis sibiricaRadix on Pentylenetetrazole-Induced Seizures in Zebrafish.

Palmatine (PALM) and berberine (BERB) are widely identified isoquinoline alkaloids among the representatives of the Berberidaceae botanical family. The antiseizure activity of BERB was shown previously in experimental epilepsy models. We assessed the effect of PALM in a pentylenetetrazole (PTZ)-induced seizure assay in zebrafish, with BERB as an active reference compound. Both alkaloids were isolated from the methanolic root extract of Berberis sibirica by counter-current chromatography, and their ability to cross the blood-brain barrier was determined via quantitative structure-activity relationship assay. PALM exerted antiseizure activity, as confirmed by electroencephalographic analysis, and decreased c-fos and bdnf levels in PTZ-treated larvae. In a behavioral assay, PALM dose-dependently decreased PTZ-induced hyperlocomotion. The combination of PALM and BERB in ED16 doses revealed hyperadditive activity towards PTZ-induced hyperlocomotion. Notably, we have indicated that both alkaloids may exert their anticonvulsant activity through different mechanisms of action. Additionally, the combination of both alkaloids in a 1:2.17 ratio (PALM: BERB) mimicked the activity of the pure extract, which indicates that these two active compounds are responsible for its anticonvulsive activity. In conclusion, our study reveals for the first time the anticonvulsant activity of PALM and suggests the combination of PALM and BERB may have higher therapeutic value than separate usage of these compounds.

Anxiety-related behavioral responses of pentylenetetrazole-treated zebrafish larvae to light-dark transitions.

Pentylenetetrazole (PTZ), γ-aminobutyrate (GABA) antagonist, is a convulsant drug, known to induce anxiety and seizures in zebrafish. Changes in the mobility of zebrafish under light-dark transitions reflect anxiety level, serving as a useful behavioral readout. The effects of PTZ treatment have yet to be assayed in this manner. Zebrafish larvae (AB strain) at both 5dpf (days post-fertilization) and 7dpf were treated with different concentrations of PTZ. General locomotor activity and thigmotaxis were analyzed under continuous illumination (normal conditions) or alternating light-dark cycles (stressful conditions). Zebrafish larvae of 5dpf and 7dpf exhibited different sensitivities to PTZ. Anxiety level, measured in terms of response to illumination transitions under the influence of PTZ, demonstrated contrasting tendencies. Dark-light transitions dramatically increased the locomotor activity of zebrafish larvae receiving 8mM PTZ which was indicative of anxiety. This study suggests that PTZ increases the susceptibility by activating the neuron, which perhaps makes light change easier to influence the anxiety level of larvae. We provide useful evidence for putative anti-anxiety drug screening.

Anticonvulsant activity of Citrus aurantium blossom essential oil (neroli): involvment of the GABAergic system.

Citrus aurantium L. blossoms are an important medicinal plant part in Iran and some other countries. It is used in traditional medicine as an antiseizure and anticonvulsant natural agent. Early in vitro research of the anticonvulsant activity of the blossom extracts were done but there has been no investigation focused on the blossom essential oil and its anticonvulsant activity. The anticonvulsant activity of the essential oil of C. aurantium blossoms (neroli) was investigated. The anticonvulsant activity of neroli was assessed in pentylenetetrazole (PTZ)-induced convulsion by i.v. and i.p. methods and maximal electroshock (MES) in mice, with diazepam as the standard drug. While mechanistic studies were conducted using flumazenil, a GABA A-benzodiazepine receptor complex site antagonist. Neroli produced protection against clonic by i.v adminiatration of PTZ at 20 and 40 mg/kg, compared with protection with benzodiazepine. The mean onset and percentage protection against convulsion in neroli-treated mice were reduced by flumazenil. Intraperitonaeal PTZ also decreased the latency of clonic seizure in the neroli (40 mg/kg) treated group. We also showed that neroli (20 and 40 mg/kg), exhibited inhibition of the tonic convulsion induced by MES and decreased the mortality rate. Neroli was analyzed by GC and GC-MS and twenty three constituents, representing 91.0 % of the chromatographical oil were identified. The major components of neroli were characterized as linalool (28.5%), linalyl acetate (19.6%), nerolidol (9.1%) E,E-farnesol (9.1%), α-terpineol (4.9%) and limonene (4.6%) which might be responsible for the anticonvulsant activity. The results suggest that neroli possesses biologically active constituent(s) that have anticonvulsant activity which supports the ethnomedicinal claims of the use of the plant in the management of seizure.

Valproate-induced liver injury: modulation by the omega-3 fatty acid DHA proposes a novel anticonvulsant regimen.

BACKGROUND: The polyunsaturated, ω-3 fatty acid, docosahexaenoic acid (DHA), claims diverse cytoprotective potentials, although via largely undefined triggers. Thus, we currently first tested the ability of DHA to ameliorate valproate (VPA)-evoked hepatotoxicity, to modulate its anticonvulsant effects, then sought the cellular and molecular basis of such actions. Lastly, we also verified whether DHA may kinetically alter plasma levels/clearance rate of VPA. METHODS AND RESULTS: VPA (500 mg/kg orally for 14 days in rats) evoked prominent hepatotoxicity that appeared as a marked rise (2- to 4-fold) in serum hepatic enzymes (γ-glutamyl transferase [γ-GT], alanine aminotransferase [ALT], and alkaline phosphatase [ALP]), increased hepatic lipid peroxide (LPO) and tumor necrosis factor-alpha (TNFα) levels, as well as myeloperoxidase (MPO) activity (3- to 5-fold), lowering of serum albumin (40 %), and depletion of liver reduced-glutathione (GSH, 35 %). Likewise, histopathologic examination revealed hepatocellular degeneration, replacement by inflammatory cells, focal pericentral necrosis, and micro/macrovesicular steatosis. Concurrent treatment with DHA (250 mg/kg) markedly blunted the elevated levels of liver enzymes, lipid peroxides, TNFα, and MPO activity, while raising serum albumin and hepatic GSH levels. DHA also alleviated most of the cytologic insults linked to VPA. Besides, in a pentylenetetrazole (PTZ) mouse convulsion model, DHA (250 mg/kg) markedly increased the latency in convulsion evoked by VPA, beyond their individual responses. Lastly, pharmacokinetic studies revealed that joint DHA administration did not alter serum VPA concentrations. CONCLUSIONS: DHA substantially ameliorated liver injury induced by VPA, while also markedly boosted its pharmacologic effects. DHA manipulated definite cellular machinery to curb liver oxidative stress and inflammation, without affecting VPA plasma levels. Collectively, these protective and synergy profiles for DHA propose a superior VPA-drug combination regimen.

Anticonvulsant activity of DNS II fraction in the acute seizure models.

AIM OF THE STUDY: Delphinium nordhagenii belongs to family Ranunculaceae, it is widely found in tropical areas of Pakistan. Other species of Delphinium are reported as anticonvulsant and are traditionally used in the treatment of epilepsy. Delphinium nordhagenii is used by local healer in Pakistan but never used for scientific investigation as anticonvulsant. Thus, Delphinium nordhagenii was subjected to bioassay-guided fractionation and the most active fraction, i.e. DNS II acetone was chosen for further testing in the acute seizure models of epilepsy to study the antiepileptic potential in male mice. MATERIALS AND METHODS: Different doses (60, 65 and 70mg/kg, i.p.) of DNS II acetone fraction of Delphinium nordhagenii was administered 30min prior the chemoconvulsant's injection in the male mice. Convulsive doses of chemoconvulsants (pentylenetetrazole 90mg/kg, s.c. and picrotoxin 3.15mg/kg, s.c.) were used. The mice were observed 45-90min for the presence of seizures. Moreover, four different doses of DNS II (60, 65, 70 and 100mg/kg, i.p.) were tested in the MES test. RESULTS: The DNS II acetone fraction of Delphinium nordhagenii has exhibited the anticonvulsant actions by preventing the seizures against PTZ- and picrotoxin-induced seizure as well as 100% seizure protection in MES test. The results are comparable with standard AEDs (diazepam 7.5mg/kg, i.p. and phenytoin 20mg/kg, i.p.). CONCLUSIONS: These findings suggest that the Delphinium nordhagenii possesses the anticonvulsant activity. Further analysis is needed to confirm the structure and target the extended activity profile.

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.

História dos tratamentos biológicos / Biologicals treatments's history

Contexto: Trata-se de uma discussão de como surgiram os tratamentos biológicos no decorrer da história da psiquiatria.

Pharmacology of dementia.

The authors discuss cerebral vasodilators, cerebral metabolic enhancers, nootropics, opioid antagonists, psychostimulants, cholinergic agents, and neuropeptides. Their efficacy in the treatment of dementing illnesses is evaluated.

[Effect of various analeptics on the outcome of acute microwave lesion in mice]. / Vliianie nekotorykh analeptikov na iskhod ostrogo mikrovolnovogo porazheniia myshei.

The survival of albino mice irradiated by microwaves till the terminal state (wave length of 12.5 cm, intensity-62 +/- 5 microvat, for 14-16 minutes), given directly after irradiation diethylamide of nicotinic acid (cordiamine) in a dose of 50 mg/kg intraperitoneally and strychnine nitrate in a dose of 1 mg/kg, subcutaneously, i. e. nearly 1.5 times as much as received by controls, was studied. The application of caffeine sodium benzoate, camphor, metrasol, lobeline hydrochloride and cytisine, employed in different doses, proved to be little effective.