Anticonvulsant effects of desvenlafaxine on modulating brain monoamine and oxidative stress in mice / Efeitos anticonvulsivantes da desvenlafaxina na modulação da monoamina cerebral e do estresse oxidativo em camundongos

Desvenlafaxine succinate (DVS) inhibits serotonin reuptake selectively and is approved for major depressive disorders. This research investigated influence of DVS on modulating brain monoamine and oxidative stress in mice. The antiepileptic potential of DVS (10, 20, or 30 mg/kg/i.p.) in pentylenetetrazole (PTZ; 85 mg/kg) with i.p. route of administration, strychnine (STR; 75 mg/kg) with i.p. route, pilocarpine (400 mg/kg) with s.c. route and maximal electroshock MES-induced convulsion in mouse models. The activities of oxidative stress, i.e. superoxide dismutase (SOD), glutathione (GSH) and lipid peroxidation (LPO) as well as gamma-aminobutyric acid (GABA) in the brains of PTZ-induced convulsive mice. Treatment with DVS increased the latency to develop siezures and declined mortalities in rodents against PTZ, STR and pilocarpine-induced convulsions. Results of MES-leaded siezures revealed that DVS reduced tonic hind limb extension duration and mortalities significantly. Brain, SOD, GSH and GABA level were significantly (P<0.01) increased and LPO reduced significantly (P<0.01) after DVS treatment. Furthermore, the DVS did not show any motor coordination signs in the rotarod test. We demonstrated that the role of DVS in convulsion genesis in mice under control condition and attenuate the PTZ-induced oxidative damage.

O succinato de desvenlafaxina (DVS) inibe seletivamente a recaptação da serotonina e é aprovado para transtornos depressivos maiores. Esta pesquisa investigou a influência do DVS na modulação da monoamina cerebral e do estresse oxidativo em camundongos. O potencial antiepiléptico de DVS (10, 20 ou 30 mg / kg / i.p.) Em pentilenotetrazole (PTZ; 85 mg / kg) com i.p. via de administração, estricnina (STR; 75 mg / kg) com i.p. via, pilocarpina (400 mg / kg) com s.c. rota e convulsão induzida por MES de eletrochoque máximo em modelos de camundongos. As atividades de estresse oxidativo, ou seja, superóxido dismutase (SOD), glutationa (GSH) e peroxidação lipídica (LPO), bem como ácido gama-aminobutírico (GABA) nos cérebros de camundongos convulsivos induzidos por PTZ. O tratamento com DVS aumentou a latência para desenvolver crises e diminuiu a mortalidade em roedores contra convulsões induzidas por PTZ, STR e pilocarpina. Os resultados de siezures conduzidos por MES revelaram que o DVS reduziu significativamente a duração e a mortalidade da extensão tônica dos membros posteriores. Os níveis de cérebro, SOD, GSH e GABA aumentaram significativamente (P < 0,01) e o LPO reduziu significativamente (P < 0,01) após o tratamento com DVS. Além disso, o DVS não apresentou sinais de coordenação motora no teste do rotarod. Demonstramos o papel do DVS na gênese da convulsão em camundongos sob condição de controle e atenua o dano oxidativo induzido por PTZ.

Endogenous and exogenous serotonin, but not sumatriptan, ameliorate seizures and neuroinflammation in the pentylenetetrazole-induced seizure model in rats / A serotonina endógena e exógena, mas não o sumatriptano, melhora as convulsões e a neuroinflamação no modelo de convulsão induzida por pentilenotetrazol em ratos

ABSTRACT Background: Epilepsy has neuropsychiatric comorbidities such as depression, bipolar disorder, and anxiety. Drugs that target epilepsy may also be useful for its neuropsychiatric comorbidities. Objective: To investigate the effects of serotonergic modulation on pro-inflammatory cytokines and the seizures in pentylenetetrazole (PTZ)-induced seizure model in rats. Methods: Male Wistar rats were injected intraperitoneally with serotonin, selective serotonin reuptake inhibitor fluoxetine, 5-HT1B/D receptor agonist sumatriptan, or saline 30 min prior to PTZ treatment. Behavioral seizures were assessed by the Racine's scale. Concentrations of IL-1β, IL-6, and TNF-α in serum and brain tissue were determined by ELISA. Results: Serotonin and fluoxetine, but not sumatriptan, alleviated PTZ-induced seizures by prolonging onset times of myoclonic-jerk and generalized tonic-clonic seizures. The anti-seizure effect of fluoxetine was greater than that of serotonin. Likewise, serotonin and fluoxetine, but not sumatriptan, reduced PTZ-induced increases in the levels of IL-1β and IL-6 in both serum and brain tissue. None of the administered drugs including PTZ affected TNF-α concentrations. Conclusions: Our findings suggest that endogenous and exogenous serotonin exhibits anticonvulsant effects by suppressing the neuroinflammation. It seems that 5-HT1B/D receptors do not mediate anticonvulsant and anti-neuroinflammatory effects of serotonin.

RESUMO Antecedentes: A epilepsia apresenta comorbidades neuropsiquiátricas como depressão, transtorno bipolar e ansiedade. Os medicamentos que visam o tratamento da epilepsia podem ser úteis para a epilepsia e suas comorbidades neuropsiquiátricas. Objetivo: Investigar os efeitos da modulação serotonérgica em citocinas pró-inflamatórias e as convulsões no modelo de convulsão induzida por pentilenotetrazol (PTZ) em ratos. Métodos: Ratos Wistar machos foram injetados intraperitonealmente com serotonina, inibidor seletivo da recaptação da serotonina fluoxetina, sumatriptano agonista do receptor 5-HT1B / D ou solução salina 30 min antes do tratamento com PTZ. As crises comportamentais foram avaliadas pela escala de Racine. As concentrações de IL-1β, IL-6 e TNF-α no soro e tecido cerebral foram determinadas por ELISA. Resultados: A serotonina e a fluoxetina, mas não o sumatriptano, aliviaram as convulsões induzidas por PTZ ao prolongar os tempos de início das convulsões mioclônicas e tônico-clônicas generalizadas. O efeito anticonvulsivo da fluoxetina foi maior do que o da serotonina. Da mesma forma, a serotonina e a fluoxetina, mas não o sumatriptano, reduziram os aumentos induzidos por PTZ nos níveis de IL-1β e IL-6 no soro e no tecido cerebral. Nenhum dos medicamentos administrados, incluindo PTZ, alterou as concentrações de TNF-α. Conclusões: Nossos achados sugerem que a serotonina endógena e exógena exibe efeitos anticonvulsivantes por suprimir a neuroinflamação. Aparentemente, os receptores 5-HT1B / D não medeiam os efeitos anticonvulsivantes e anti-neuroinflamatórios da serotonina.

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.

1-triacontanol cerotate isolated from Marsilea quadrifolia Linn. safeguards hippocampal CA3 neurons and augments special memory deficit in chronic epileptic rats / Cerotato de 1-triacontanol aislado de Marsilea quadrifolia Linn. protege las neuronas CA3 del hipocampo y mejora el déficit de memoria especial en ratas epilépticas crónicas

SUMMARY: Currently many people with epilepsy do not have seizure control even with the best available medications. Moreover various antiepileptics have adverse cognitive impact with other side effect. Thus, need for new antiepileptic drugs still remains challenge. However, many of the natural components have antiepileptic action and this fact remains scientifically unexplored. This study was designed to check the behavioral and neuro-pathological outcome of 1-Triacontanol cerotate (1TAC), isolated from Marsilea quadrifolia Linn. (MQ) on chronic Pentylenetetrazol (PTZ) kindling model of epilepsy in rats. Two-month-old adult male Wistar rats (n=60) were randomly divided into six groups; Group I (Cage Control), II (Vehicle Control), III (Positive Control), IV (Standard drug treated), V (1TAC: 40 mg/kg) & VI (1TAC: 80 mg/kg). To induce kindling a 35 mg/kg dose of PTZ was injected i.p. in every 48 hrs for 30 days in Group III to VI. Spatial memory performance was tested using Morris water maze, following which brains were further processed for histopathological investigations. Interestingly, 1TAC was able to minimize the loss of pyramidal cells in hippocampal CA3 region. These cellular changes were behaviorally responded as improved special learning and memory, a better spatial navigation and object place configuration. The current study strongly implicates that 1TAC from MQ has potent neuroprotective role and augments special memory deficit in chronic epileptic rats. The isolated component which attenuates spatial memory performance could be beneficial outcome to retain cognitive blunting in chronic epilepsy.

RESUMEN: Actualmente, muchas personas con epilepsia no cuentan con un control adecuado de las convulsiones, incluso con los mejores medicamentos disponibles. Además, varios antiepilépticos tienen un impacto cognitivo adverso además de efectos secundarios. Por lo tanto, la necesidad de nuevos fármacos antiepilépticos sigue siendo un desafío. Sin embargo, muchos de los componentes naturales tienen acción antiepiléptica y este hecho permanece científicamente inexplorado. Este estudio se diseñó para verificar el resultado conductual y neuro-patológico del cerotato de 1-triacontanol (1TAC), aislado de Marsilea quadrifolia Linn. (MQ) en el modelo de epilepsia en ratas del pentilenetetrazol (PTZ) crónico (PTZ). Ratas Wistar adultas de dos meses de edad (n = 60) se dividieron aleatoriamente en seis grupos; Grupo I (Control de jaula), II (Control de vehículo), III (Control positivo), IV (Medicamento estándar de tratamiento), V (1TAC: 40 mg / kg) y VI (1TAC: 80 mg / kg). Para inducir la inflamación se inyectó una dosis de 35 mg / kg de PTZ i.p. en cada 48 horas durante 30 días en los grupos III a VI. El rendimiento de la memoria espacial se probó utilizando el laberinto de agua de Morris, después de lo cual se procesaron los cerebros para investigaciones histopatológicas. Curiosamente, 1TAC pudo minimizar la pérdida de células piramidales en la región CA3 del hipocampo. Estos cambios celulares respondieron de manera conductual como una mejora del aprendizaje especial y la memoria, una mejor navegación espacial y la configuración del lugar del objeto. El estudio actual implica fuertemente que 1TAC de MQ tiene un potente papel neuroprotector y mejora el déficit de memoria especial en ratas epilépticas crónicas. El componente aislado que atenúa el rendimiento de la memoria espacial podría ser un resultado beneficioso para retener la reducción cognitiva en la epilepsia crónica.

[Effect of dihydropyridine Ca[2+] channel blockers on PTZ-induced clonic seizures threshold in mice]

Several studies have shown that the dihydropyridine calcium channel blockers such as nimodipine, nifedipine, and amlodipine have anticonvulsant effect in a range of animal models. The aim of this study was to investigate the effects of nimodipine, nifedipine and amlodipine on PTZ-induced seizure threshold with further comparison of results in mice. In 2007, this experimental study was carried out in School of Veterinary Medicine of Tabriz Islamic Azad University. Male NMRI mice were randomly divided into groups of ten members. Mice were intraperitoneally pretreated with vehicle or dihydropyridines [0.5-20 mg/kg] before the determination of intravenously PTZ-induced seizure threshold. The PTZ seizure threshold was 33.4 +/- 0.42 mg/kg in control group. In animals pretreated with nimodipine, nifedipine and amlodipine, the PTZ seizure threshold dose-dependently increased, compared with vehicle group. Nimodipine and nifedipine were found to have the highest and lowest anticonvulsant effects, respectively. Our results suggest that the dihydropyridine Ca2+ channel blockers induce an anticonvulsant activity probably via an antagonistic effect on voltage-gated Ca2+ channels

effect of plasma testosteron on epileptiform seizures induced by pentylen tetrazole [PTZ] in normal and gonadectomized male rats

It has been verified that androgene concentration in epileptic men who were treated with antiepileptic drugs is decreased and this results in a decrease in sexual activities in such patients. Although there : are many investigations regarding the effects of antileptic drugs on the rate of serum androgenes and particularly testosteron, little is known about the probable effects of androgenes on epileptic seizures. In this study the effects of plasma level of testosteron on epileptiform seizures in three cases [normal, increased and decreased] induced with Pentylentetrazole [PTZ] in Wistar male rats were investigated. Wistar male rats with similar response and sesitivity to PTZ and epileptiform seizures were randomly assigned to the five following: groups [n=8 for each group]. 1[st] exprimental group: Intramuscular injection of testosteron [5 mg/Kg BW] and after 2 hours intraperitoneal injection of PTZ [25mg/Kg BW/for max. 3 times]; 2[nd] exprimental group: treatment with testosteron [0.5 mg/Kg BW] for 10 days and injections of PTZ thereafter; control group for 1[st] and 2[nd] experimental rats where they received sesame oil and then PTZ in a protocol precisely similar to the 1[st] and 2[nd] groups; 3[rd] exprimental group: PTZ injections and recording of epileptiform convulsions before gonadectomy [as control] and repeat of PTZ injections after 10 days. The last protocol was performed in two groups: gonadectomized, without any testosteron injections, and gonadectomized but with one dose of testoteron. The results show that increase in serum testosteron level does not affect epileptiform convulsions, whereas the reduction of testosteron level increases the partial seizures [p<0.001] and duration of tonic-clonic seizures [p<0.05]. Results of this study show that testosteron has an anticonvulsant effect and this effect might be through neurosteroid metabolites, where these metabolites affect on GABA A receptor complex

Effects of misoprostrol on pentylenetetrazol-induced seirures in mice

The effects of prostaglandin E - analogue misoprostol on the susceptibility to pentilenetetrazol (PTZ) - induced seizures were examined in mice. Misoprostol (200-800 mug/kg), given subcutaneously 45 min before the subconvulsive dose of PTZ (30 mg/kg, i.p) provoked dose-dependent clonic-tonic seizures (30 to 100 percent) and mortality in mice. At 300 g/kg, s.c., misoprostol pretreatment significantly (p<0.05) lowered the onset latency to first convulsion as well as the latency to mortality induced by a convulsive dose of PTZ (60 mg/kg, i.p.). At this dose misoprostol was found to lower the CD50 and Ld50 values for PTZ by 21 percent and 36 percent respectively. The results suggest that prostaglandins are likely to lower the threshold for convulsions.

Evaluación preliminar de los efectos neurofarmacológicos de Justicia pectoris / Preliminary evaluation of neuropharmacological effects of Justicia pectoris

Se realizaron ensayos preliminares de la decocción de Justicia pectoralis en ratones de la cepa C-57, donde se evaluaron los posible efectos de dichas decocciones sobre la conducta exploratoria, la conducta agresiva y las convulsiones inducidas por pentilentetrazol en ratones. También se estudió el efecto de J. pectoralis sobre la excitación producida por fenciclidina (droga esquizofrenomimética) en ratas infantiles. Los resultados obtenidos sugieren que Justicia pectoralis reduce la conducta agresiva y la actividad exploratoria en ratones, bloquea la excitación inducida por fenciclidina en ratas infantiles y no previene las convulsiones inducidas por pentilentetrazol

Influência de fármacos adjuvantes da anestesia locorregional na mortalidade pós-ictal pela lidocaína, bupivacaína e pentilenotetrazol / Influence of loco-regional anesthesia adjuvant drugs in post-ictal mortality by lidocaine, bupivacaine and pentylenetetraziol

Investigaram-se o envolvimento de drogas adjuvantes de anestesia locorregional na incidência da mortalidade pós-ictal das amidas anestésicas locais, a lidocaína e bupivacaína, em camundongos albinos, machos, comparando os resultados com animais em que se injetou pentilenotetrazol por via subcutânea. As drogas adjuvantes utilizadas no controle de efeitos colaterais dos anestésicos locais (tremores, bradicardia, hipotensäo arterial e outros) e agentes suplementares (ansiolíticos, hipnoanalgésicos e hipnóticos) foram injetados por via peritoneal, 15 minutos antes da administraçäo de DL50 dos anestésicos locais. Proporcionalmente as doses empregadas, fentanil, meperidina, metaraminol e quetamina, aumentaram a incidência da mortalidade. O diazepam bloqueou completamente a convulsäo clônica induzida pelo pentilenotetrazol, mas apresentou um efeito duplo quando relacionado com as amidas. Baixas doses (0,2 mg.kg-1) aumentaram e altas doses (10 mg.kg-1) diminuíram a mortalidade pós-ictal. O tiopental e a atropina diminuíram a incidência da mortalidade, enquanto que a administraçäo isolada de oxigênio e droperidol näo tiveram nenhuma influência significativa. Estes resultados sugerem que os opiáceos e sistema colinérgico provavelmente exercem influência facilitatória e que o sistema do ácido gama-amino-butírico tem efeito inibitório nas vias cerebrais envolvidas na gênese e propagaçäo das convulsöes induzidas pela lidocaína e bupivacaína, diferentemente das convulsöes induzidas pelo pentilenotetrazol, onde somente as drogas sinérgicas ao GABA apresentam influência inibitória. Estas diferenças na efetividade do diazepam, tiopental e atropina em modificar as convulsöes e mortalidade pós-ictal induzidas pela lidocaína, bupivacaína e pentilenotetrazol podem estar relacionadas a diferentes mecanismos de açäo