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1.
Molecules ; 26(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34205930

RESUMO

BACKGROUND: Neurotic disturbances, anxiety, neurosis-like disorders, and stress situations are widespread. Benzodiazepine tranquillizers have been found to be among the most effective antianxiety drugs. The pharmacological action of benzodiazepines is due to their interaction with the supra-molecular membrane GABA-a-benzodiazepine receptor complex, linked to the Cl-ionophore. Benzodiazepines enhance GABA-ergic transmission and this has led to a study of the role of GABA in anxiety. The search for anxiolytics and anticonvulsive agents has involved glutamate-ergic, 5HT-ergic substances and neuropeptides. However, each of these well-known anxiolytics, anticonvulsants and cognition enhancers (nootropics) has repeatedly been reported to have many adverse side effects, therefore there is an urgent need to search for new drugs able to restore damaged cognitive functions without causing significant adverse reactions. OBJECTIVE: Considering the relevance of epilepsy diffusion in the world, we have addressed our attention to the discovery of new drugs in this field Thus our aim is the synthesis and study of new compounds with antiepileptic (anticonvulsant) and not only, activity. METHODS: For the synthesis of compounds classical organic methods were used and developed. For the evaluation of biological activity some anticonvulsant and psychotropic methods were used. RESULTS: As a result of multistep reactions 26 new, five-membered heterocyclic systems were obtained. PASS prediction of anticonvulsant activity was performed for the whole set of the designed molecules and probability to be active Pa values were ranging from 0.275 to 0.43. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures, anti-thiosemicarbazides effect as well as some psychotropic effect. The biological assays evidenced that some of the studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of compounds is low and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity it was found that the selected compounds have an activating behavior and anxiolytic effects on the models of "open field" and "elevated plus maze" (EPM). The data obtained indicate the anxiolytic (anti-anxiety) activity of the derivatives of pyrimidines, especially pronounced in compounds 6n, 6b, and 7c. The studied compounds increase the latent time of first immobilization on the model of "forced swimming" (FST) and exhibit some antidepressant effect similarly to diazepam. Docking studies revealed that compound 6k bound tightly in the active site of GABAA receptor with a value of the scoring function that estimates free energy of binding (ΔG) at -7.95 kcal/mol, while compound 6n showed the best docking score and seems to be dual inhibitor of SERT transporter as well as 5-HT1A receptor. CONCLUSIONS: Тhe selected compounds have an anticonvulsant, activating behavior and anxiolytic effects, at the same time exhibit some antidepressant effect.


Assuntos
Azepinas/administração & dosagem , Azepinas/síntese química , Pirimidinas/administração & dosagem , Pirimidinas/síntese química , Convulsões/tratamento farmacológico , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/síntese química , Ansiolíticos/química , Ansiolíticos/farmacologia , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Azepinas/química , Azepinas/farmacologia , Modelos Animais de Doenças , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Pentilenotetrazol/efeitos adversos , Pirimidinas/química , Pirimidinas/farmacologia , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo , Ratos , Receptores de GABA-A/química , Receptores de GABA-A/metabolismo , Convulsões/induzido quimicamente , Convulsões/fisiopatologia
2.
Int J Mol Sci ; 21(23)2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33291789

RESUMO

BACKGROUND: Epilepsy is a chronic neurological disorder characterized by the recurrence of seizures. One-third of patients with epilepsy may not respond to antiseizure drugs. PURPOSE: We aimed to examine whether D-limonene, a cyclic monoterpene, exhibited any antiseizure activity in the pentylenetetrazole (PTZ)-induced kindling mouse model and in vitro. METHODS: PTZ kindling mouse model was established by administering PTZ (30 mg/kg) intraperitoneally to mice once every 48 h. We performed immunoblot blots, immunohistochemistry (IHC), and high-performance liquid chromatography (HPLC) analysis after the behavioral study. RESULTS: An acute injection of PTZ (60 mg/kg) induced seizure in mice, while pretreatment with D-limonene inhibited PTZ-induced seizure. Repeated administration of PTZ (30 mg/kg) increased the seizure score gradually in mice, which was reduced in D-limonene (10 mg/kg)-pretreated group. In addition, D-limonene treatment increased glutamate decarboxylase-67 (GAD-67) expression in the hippocampus. Axonal sprouting of hippocampal neurons after kindling was inhibited by D-limonene pretreatment. Moreover, D-limonene reduced the expression levels of Neuronal PAS Domain Protein 4 (Npas4)-induced by PTZ. Furthermore, the adenosine A2A antagonist SCH58261 and ZM241385 inhibited anticonvulsant activity and gamma-aminobutyric acid (GABA)ergic neurotransmission-induced by D-limonene. CONCLUSION: These results suggest that D-limonene exhibits anticonvulsant activity through modulation of adenosine A2A receptors on GABAergic neuronal function.


Assuntos
Neurônios GABAérgicos/metabolismo , Limoneno/farmacologia , Pentilenotetrazol/efeitos adversos , Receptor A2A de Adenosina/metabolismo , Convulsões/etiologia , Convulsões/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Convulsivantes/administração & dosagem , Convulsivantes/efeitos adversos , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/metabolismo , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Camundongos , Plasticidade Neuronal/efeitos dos fármacos , Pentilenotetrazol/administração & dosagem , Fosforilação , Ratos , Convulsões/fisiopatologia
3.
Neuron ; 108(1): 193-208.e9, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-32853550

RESUMO

The mammalian genome has hundreds of nuclear-encoded tRNAs, but the contribution of individual tRNA genes to cellular and organismal function remains unknown. Here, we demonstrate that mutations in a neuronally enriched arginine tRNA, n-Tr20, increased seizure threshold and altered synaptic transmission. n-Tr20 expression also modulated seizures caused by an epilepsy-linked mutation in Gabrg2, a gene encoding a GABAA receptor subunit. Loss of n-Tr20 altered translation initiation by activating the integrated stress response and suppressing mTOR signaling, the latter of which may contribute to altered neurotransmission in mutant mice. Deletion of a highly expressed isoleucine tRNA similarly altered these signaling pathways in the brain, suggesting that regulation of translation initiation is a conserved response to tRNA loss. Our data indicate that loss of a single member of a tRNA family results in multiple cellular phenotypes, highlighting the disease-causing potential of tRNA mutations.


Assuntos
Neurônios/metabolismo , RNA de Transferência de Arginina/genética , Convulsões/genética , Transmissão Sináptica/genética , Animais , Eletrochoque/efeitos adversos , Antagonistas de Receptores de GABA-A/efeitos adversos , Camundongos , Pentilenotetrazol/efeitos adversos , Iniciação Traducional da Cadeia Peptídica/genética , RNA de Transferência de Isoleucina/genética , RNA-Seq , Receptores de GABA-A/genética , Convulsões/induzido quimicamente , Convulsões/etiologia , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
4.
J Mol Histol ; 51(5): 503-518, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32729055

RESUMO

Abnormal synchronous activity in neurons generates epileptic seizures. Antiepileptic drugs (AEDs) are effective in 70% of patients, but this percentage is drastically lower in developing countries. Sparteine is a quinolizidine alkaloid synthesized from most Lupine species and has a probable anticonvulsive effect. For this reason, the objective of the present work was to study the anticonvulsant effect of sparteine using a dose-effect curve and to determine its effectiveness against seizures using behavioral, electroencephalographic, morphological and molecular data. Wistar rats were grouped into control [saline solution (0.9%), pentylenetetrazole (90 mg/kg), and sparteine (13, 20 and 30 mg/kg), intraperitoneal (i.p.)] and experimental (sparteine + pentylenetetrazole) groups. The rats were implanted with surface electrodes to register electrical activity, and convulsive behavior was evaluated according to Velisek's scale. The rats were perfused to obtain brain slices for cresyl violet staining and cellular density quantification as well as for immunohistochemistry for NeuN and GFAP. Other animals were used to determine the hippocampal mRNA expression of the M2 and M4 acetylcholine receptors by qPCR. Sparteine exhibited a better anticonvulsant effect at a dose of 30 mg/kg (i.p.) than at the other doses used. This anticonvulsant effect was characterized by a decrease in the severity of convulsive behavior, 100% survival, an inhibitory effect on epileptiform activity 75 min after pentylenetetrazole administration, and the conservation of the cellular layers of CA1, CA3 and the dentate gyrus (DG); however, astrogliosis was observed after 30 mg/kg sparteine treatment. In addition, sparteine treatment increased the mRNA expression of the M4 receptor three hours after administration. According to our findings, the effective dose of sparteine as an anticonvulsant agent by i.p. injection is 30 mg/kg. The astrogliosis that was observed after sparteine administration may be a compensatory mechanism to diminish excitability and maintain neuronal homeostasis, possibly through redistributing potassium and glutamate. The increase in the mRNA expression of the M4 receptor may suggest the participation of the M4 receptor in the anticonvulsive effect of sparteine, as the activation of this receptor may inhibit acetylcholine release and facilitate the subsequent release of GABA. However, the precise mechanisms by which sparteine produces these effects are not known, and therefore, further experiments are necessary.


Assuntos
Anticonvulsivantes/farmacologia , Pentilenotetrazol/efeitos adversos , Convulsões/tratamento farmacológico , Convulsões/etiologia , Esparteína/farmacologia , Animais , Comportamento Animal , Biomarcadores , Encéfalo/metabolismo , Encéfalo/patologia , Gerenciamento Clínico , Modelos Animais de Doenças , Suscetibilidade a Doenças , Eletroencefalografia , Imunofluorescência , Imuno-Histoquímica , Masculino , Ratos , Convulsões/diagnóstico
5.
Toxicol Appl Pharmacol ; 399: 115033, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32387339

RESUMO

N-(2-hydroxyphenyl)-2-propylpentamide (HO-AAVPA) is a novel arylamide derivative of valproic acid (VPA) designed in silico, with better antioxidant and antiproliferative effect on cancer cell lines than VPA. This study was aimed to evaluate the anticonvulsant activity, the toxicity and teratogenicity produced in HO-AAVPA-treated CD1 mice using VPA as positive control. With the maximal electroshock (MES)- and pentylenetetrazole (PTZ)-induced seizure models, HO-AAVPA reduced the time of hind limb extension, stupor and recovery, the number of clonic and tonic seizures and the mortality rate in a dose-dependent manner, obtaining an ED50 of 370 and 348 mg/kg for MES and PTZ, respectively. On the rotarod test, mice administered with 600 mg/kg HO-AAVPA manifested reduced locomotor activity (2.78%); while HO-AAVPA at 300 mg/kg and VPA at 500 mg/kg gave a similar outcome (∼60%). The LD50 of 936.80 mg/kg herein found for HO-AAVPA reflects moderate toxicity. Concerning teratogenicity, the administration of HO-AAVPA to pregnant females at 300 and 600 mg/kg on gestation day (GD) 8.5 generated less visceral and skeletal alterations in the fetuses, as well as, minor rate of modifications in the expression pattern of the neuronal marker Tuj1 and endothelial marker PECAM1 in embryos, that those induced by VPA administration. Altered embryonic development occurred with less frequency and severity with HO-AAVPA at 600 mg/kg than VPA at 500 mg/kg. In conclusion, the protective effect against convulsions provided by HO-AAVPA was comparable to that of VPA in the MES and PZT seizure models, showed lower toxicity and less damage to embryonic and fetal development.


Assuntos
Amidas/efeitos adversos , Amidas/farmacologia , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/farmacologia , Pentanos/efeitos adversos , Pentanos/farmacologia , Ácido Valproico/efeitos adversos , Ácido Valproico/farmacologia , Animais , Antioxidantes/efeitos adversos , Antioxidantes/farmacologia , Biomarcadores/metabolismo , Eletrochoque/métodos , Endotélio/efeitos dos fármacos , Endotélio/metabolismo , Feminino , Dose Letal Mediana , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Pentilenotetrazol/efeitos adversos , Pentilenotetrazol/farmacologia , Gravidez , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/metabolismo
6.
Cell Mol Neurobiol ; 40(8): 1283-1295, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32107753

RESUMO

Aquaporin 4 (AQP4), a water-specific channel protein locating on the astrocyte membrane, has been found to be antagonist, agonist and undergone closely related to epilepsy. Our previous study showed that inhibition of an N-methyl-D-aspartate receptor (NMDAR) subunit NR2A can suppress epileptic seizures, suggesting that AQP4 is potentially involved in NR2A-mediated epilepsy treatment. In this study, we aimed to explore the relevance of AQP4 in NR2A-mediated seizures treatment in pentylenetetrazol (PTZ)-induced rat models. We performed electroencephalogram (EEG) recording and examined AQP4 expression at mRNA and protein levels, and the downstream molecules of AQP4 as well. It showed that AQP4 expression was increased after the induction of seizures. Lateral ventricle pretreatment of NR2A inhibitor could mitigate the PTZ-induced seizures severity and counterbalance the increase of AQP4 expression. In contrast, NR2A activator that resulted in seizures aggravation could further augment the seizure-related elevations of AQP4 expression. Pharmacological inhibition of AQP4 alone could also suppress the PTZ-induced seizure activities, with decreased expressions of NF-κB p65, interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α in the brain. The results indicated that increased expression of AQP4 might be an important mechanism involved in NR2A of NMDAR-mediated treatment for epileptic seizures, enlightening a potentially new target for seizures treatment.


Assuntos
Aquaporina 4/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Convulsões/tratamento farmacológico , Animais , Aquaporina 4/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Pentilenotetrazol/efeitos adversos , Pentilenotetrazol/metabolismo , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsões/metabolismo
7.
Neuroscience ; 425: 112-122, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31785360

RESUMO

In several tauopathies such as Alzheimer's disease (AD), an increased incidence of seizures is observed. Tau, one of the major proteins implicated in AD pathology, is an important regulator of neural network excitability and might participate in the underlying epileptic cascade. However, the mechanisms underlying this relationship are not fully elucidated. We aim to investigate this mechanism by analyzing seizure susceptibility to the convulsant pentylenetetrazole (PTZ) in a novel rodent tauopathy model. A single dose of PTZ was systemically injected in Tau58/4 transgenic mice. To investigate whether young and aged heterozygous (HET) mice exhibit a higher susceptibility to seizures in comparison with wild-type (WT) littermates, video electroencephalography (EEG) in combination with behavioral scoring according to a modified Racine scale was used. The employment of different dosage groups enabled us to characterize the dose range reliably inducing seizures. Here, we report an increased seizure susceptibility in young but not in old HET Tau58/4 mice. Young HET animals displayed more severe seizures and had a reduced latency to the first seizure compared to WTs. Also, age-related differences in susceptibility could be demonstrated for both genotypes. Identification and targeting of secondary diseases such as epilepsy, which aggravate dementia and lead to earlier institutionalization, is key. This study finds that tau pathology itself is sufficient to alter seizure susceptibility in a rodent model, indicating that the disease process is crucial in the emergence of epilepsy in patients with tauopathy.


Assuntos
Convulsões/metabolismo , Convulsões/fisiopatologia , Tauopatias/metabolismo , Tauopatias/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Convulsivantes/farmacologia , Modelos Animais de Doenças , Eletroencefalografia/métodos , Epilepsia/induzido quimicamente , Epilepsia/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pentilenotetrazol/efeitos adversos , Pentilenotetrazol/farmacologia , Convulsões/induzido quimicamente
8.
Epilepsy Behav ; 102: 106683, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760199

RESUMO

Among neurotransmitter systems affected by status epilepticus (SE) in adult rats are both GABAergic systems. To analyze possible changes of GABAA and GABAB systems in developing rats lithium-pilocarpine SE was induced at postnatal day 12 (P12). Seizures were elicited by a GABAA antagonist pentylenetetrazol (PTZ) 3, 6, 9, and 13 days after SE (i.e., in P15, P18, P21, and P25 rats), and their possible potentiation by a GABAB receptor antagonist CGP46381 was studied. Pilocarpine was replaced by saline in control animals (lithium-paraldehyde [LiPAR]). Pentylenetetrazol in a dose of 50 mg/kg s.c. elicited generalized seizures in nearly all 15-day-old naive rats and in 40% of 18-day-old ones but not in older animals. After SE, PTZ no longer elicited seizures in these two younger groups, i.e., sensitivity of GABAA system was diminished. The GABAB antagonist exhibited proconvulsant effect in P15 and P18 SE as well as LiPAR rats returning the incidence of PTZ-induced seizures to values of control animals. A decrease in the incidence of minimal clonic seizures was seen in P21 LiPAR animals; these seizures in the oldest group were not affected. Change of the effect from proconvulsant to anticonvulsant (or at least to no action) took place before postnatal day 21. Both SE and LiPAR animals exhibited similar changes but their intensity differed, effects in LiPAR controls were usually more expressed than in SE rats.


Assuntos
Anticonvulsivantes/uso terapêutico , Antagonistas de Receptores de GABA-A/metabolismo , Antagonistas de Receptores de GABA-B/metabolismo , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/metabolismo , Animais , Animais Recém-Nascidos , Interações Medicamentosas/fisiologia , Antagonistas de Receptores de GABA-B/efeitos adversos , Masculino , Pentilenotetrazol/efeitos adversos , Ácidos Fosfínicos/efeitos adversos , Ácidos Fosfínicos/metabolismo , Ratos , Ratos Wistar , Estado Epiléptico/tratamento farmacológico
9.
Rev Assoc Med Bras (1992) ; 65(9): 1188-1192, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618336

RESUMO

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-1ß) 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-1ß 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-1ß concentrations, ghrelin reduced the increases evoked by PTZ. While VIP further increased PTZ-evoked CGRP levels, it diminished IL-1ß concentrations. However, obestatin did not change CGRP, SP, and IL-1ß 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.


Assuntos
Convulsivantes/efeitos adversos , Neuropeptídeos/efeitos dos fármacos , Pentilenotetrazol/efeitos adversos , Hormônios Peptídicos/farmacologia , Convulsões/induzido quimicamente , Animais , Biomarcadores/sangue , Peptídeo Relacionado com Gene de Calcitonina/sangue , Peptídeo Relacionado com Gene de Calcitonina/efeitos dos fármacos , Modelos Animais de Doenças , Grelina/farmacologia , Inflamação , Interleucina-1beta/sangue , Interleucina-1beta/efeitos dos fármacos , Masculino , Mioclonia , Distribuição Aleatória , Ratos Wistar , Convulsões/metabolismo , Substância P/sangue , Substância P/efeitos dos fármacos , Fatores de Tempo , Peptídeo Intestinal Vasoativo/farmacologia
10.
J Food Biochem ; 43(12): e13070, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31576588

RESUMO

The aim was to evaluate the diuretic and neuropharmacological actions of d-pinitol and describe a possible mechanism of action. The diuretic effects of d-pinitol were evaluated using mice placed in metabolic cages. The sedative, anxiolytic-like, antidepressant-like, and anticonvulsant effects of 1-100 mg/kg d-pinitol were assessed. The possible mechanisms of action of the anxiolytic-like, antidepressant-like, and anticonvulsant effects of d-pinitol were evaluated using inhibitors. d-pinitol lacked diuretic effects. However, d-pinitol showed the highest anxiolytic-like actions (ED50  = 70 mg/kg p.o. in mice) in the cylinder exploratory test and the highest antidepressant-like activity in the forced swimming test (ED50  = 26 mg/kg p.o. in mice). d-pinitol (100 mg/kg) exerted anticonvulsant actions in the pentylenetetrazole-induced seizures test. The pre-treatment with 2 mg/kg flumazenil reverted the anxiolytic-like actions and the anticonvulsant effects of d-pinitol, whereas the pre-treatment with 1 mg/kg yohimbine and 0.05 mg/kg prazosin abolished the antidepressant effects of d-pinitol. PRACTICAL APPLICATIONS: d-pinitol (3-O-methyl-d-chiro-inositol) is a polyol found in many fruits, as well as in many members of the Leguminosae and Fabaceae families. The results propose that this compound could contribute in the treatment of anxiety, depression, and convulsions. The findings suggest the possible participation of the GABAergic system in the anxiolytic-like and anticonvulsant actions of d-pinitol, whereas the noradrenergic system is probably involved in the antidepressant effects of d-pinitol. This study provides new information about other pharmacological uses for d-pinitol.


Assuntos
Ansiolíticos/farmacologia , Anticonvulsivantes/farmacologia , Antidepressivos/farmacologia , Flumazenil/efeitos adversos , Hipnóticos e Sedativos/farmacologia , Inositol/análogos & derivados , Pentilenotetrazol/efeitos adversos , Convulsões/induzido quimicamente , Ioimbina/efeitos adversos , Animais , Inositol/análise , Camundongos , Camundongos Endogâmicos BALB C , Neurofarmacologia
11.
Eur J Pharmacol ; 863: 172684, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31545983

RESUMO

The design of new pharmacologically active compounds with affinity to melatonin receptors has become an area of great interest during the last decade. Recently, we reported that newly synthesized melatonin derivatives, containing aroylhydrazone moiety in the indole scaffold, with the highest affinity to the elaborated pharmacophore model, possess an anticonvulsant activity in the maximal electroshock (MES) and 6Hz test in mice. We aimed further to explore the effect of these melatonin derivatives and the role of melatonin receptors on seizure threshold measured by the timed intravenous pentylenetetrazole (iv PTZ) infusion test in mice. Carbamazepine (CBZ) and melatonin were used as positive controls. Three out of six compounds, 3c, 3f, and 3e, respectively, dose-dependently increased the PTZ-induced seizure thresholds for myoclonic twitch, clonic, and tonic seizures comparable to the effect of CBZ and melatonin. The anticonvulsant effect of 3c, 3f, and 3e was blocked by the non-selective melatonin receptor antagonist luzindol suggesting the involvement of melatonin receptors in the activity of these compounds. Also docking study of 3c, 3f and 3e in the melatonin-binding site of melatonin receptor confirm the possible mechanism of action of these compounds involving melatonin receptors. Our previous and present results suggest that 3c, 3f, and 3e can be considered promising agents with anticonvulsant activity on melatonin receptors in the brain.


Assuntos
Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Melatonina/química , Melatonina/farmacologia , Pentilenotetrazol/efeitos adversos , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Administração Intravenosa , Animais , Anticonvulsivantes/metabolismo , Anticonvulsivantes/uso terapêutico , Interações Medicamentosas , Masculino , Melatonina/metabolismo , Melatonina/uso terapêutico , Camundongos , Simulação de Acoplamento Molecular , Pentilenotetrazol/administração & dosagem , Conformação Proteica , Receptor MT1 de Melatonina/química , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/química , Receptor MT2 de Melatonina/metabolismo , Convulsões/metabolismo , Triptaminas/farmacologia
12.
Rev. Assoc. Med. Bras. (1992) ; 65(9): 1188-1192, Sept. 2019. graf
Artigo em Inglês | LILACS | ID: biblio-1041067

RESUMO

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.


Assuntos
Animais , Masculino , Pentilenotetrazol/efeitos adversos , Convulsões/induzido quimicamente , Neuropeptídeos/efeitos adversos , Convulsivantes/efeitos adversos , Hormônios Peptídicos/farmacologia , Convulsões/metabolismo , Fatores de Tempo , Peptídeo Intestinal Vasoativo/farmacologia , Biomarcadores/sangue , Distribuição Aleatória , Substância P/efeitos adversos , Substância P/sangue , Peptídeo Relacionado com Gene de Calcitonina/efeitos adversos , Peptídeo Relacionado com Gene de Calcitonina/sangue , Ratos Wistar , Modelos Animais de Doenças , Interleucina-1beta/efeitos adversos , Interleucina-1beta/sangue , Grelina/farmacologia , Inflamação , Mioclonia
13.
J Food Sci ; 84(7): 1703-1711, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31218711

RESUMO

We evaluated the effect of krill oil (KO) supplement on seizures induced by pentylenetetrazole (PTZ) in animals with previous febrile seizures (FSs) induced by hyperthermia to determine its effectiveness in seizure susceptibility and as an anticonvulsant. Male Wistar rats with FS separated into water (W, 1 mL), palm oil (PO, 300 mg/kg, total volume 1 mL), or KO (300 mg/kg, total volume 1 mL) groups. All drugs were administered chronically via the intragastric route. Electrical activity was recorded by intracranial EEG simultaneously with convulsive behavior. All animals' brains were processed by immunofluorescence against GFAP, NeuN, and connexins (Cx); cellular quantification was performed in hippocampus and pyramidal or granular layer thickness was evaluated with cresyl violet (CV) staining. The results showed a significant delay in convulsive behavior and a slight increased survival time after PTZ administration in the group treated with KO compared with PO and W groups. The epileptiform activity showed high amplitude and frequency, with no significant differences between groups, nor were there differences in the number and duration of discharge trains. KO and PO increased the number of astrocytes and the number of neurons compared with the W group. KO and PO decreased the expression of Cx36 without affecting Cx43 expression or the thickness of layers. Based on these data, we consider it important to perform more experiments to determine the anticonvulsant role of KO, taking into account the partial effect found in this study. KO could be used as a coadjuvant of traditional anticonvulsive treatments. PRACTICAL APPLICATION: In this study was evaluated the anticonvulsive effect of a chronic krill oil (KO) supplement in animals with seizures. Results showed that KO had partial anticonvulsive effects measured by EEG activity and convulsive behavior analysis. These data justify further research that looks at KO supplementation as a prospective coadjuvant of pharmacologic management of seizure disorder.


Assuntos
Anticonvulsivantes/administração & dosagem , Euphausiacea/química , Hipocampo/efeitos dos fármacos , Óleos Vegetais/administração & dosagem , Convulsões Febris/tratamento farmacológico , Animais , Conexina 43/genética , Conexina 43/metabolismo , Conexinas/genética , Conexinas/metabolismo , Proteínas de Ligação a DNA , Suplementos Nutricionais/análise , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/metabolismo , Humanos , Masculino , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Pentilenotetrazol/efeitos adversos , Ratos , Ratos Wistar , Convulsões Febris/induzido quimicamente , Convulsões Febris/genética , Convulsões Febris/metabolismo
14.
Artigo em Inglês | MEDLINE | ID: mdl-30975378

RESUMO

Over the past few years, there has been a tremendous increase in interest of general population toward food-based therapies for management of chronic clinical conditions due to their lesser adverse effects with prolonged use over pharmacotherapies. Foods enriched with omega-3 fatty acids have shown some promising results in case of epilepsy. The present study was envisioned to investigate the effect of early exposure of α-linolenic acid (ALA), an essential omega-3 fatty acid in developing zebrafish (Danio rerio) embryos toward pentylenetetrazol (PTZ)-induced seizure susceptibility. The healthy wild-type zebrafish embryos were incubated in system water or system water containing different ALA concentrations (1-20 µM) till 7 dpf (days post fertilization). Each larva at 7 dpf was placed in 8 mM PTZ solution and seizure event was recorded. ALA incubation at 10 µM and 20 µM concentrations showed a dose-dependent reduction in PTZ-mediated hyperactive responses in larvae indicated by a marked decrease in total distance travelled and speed, as compared to vehicle control. Furthermore, both the treated groups showed increase in the latency to PTZ-induced clonus-like seizures in larvae, as compared to vehicle control. ALA incubated larvae at 10 µM and 20 µM concentrations also showed a significant reduction in c-fos mRNA level. A marked increase in the level of ALA and docosahexaenoic acid was also observed in the larvae incubated at highest effective concentration of ALA. The present study concluded that embryonic exposure of ALA reduced PTZ-induced seizures in zebrafish larva.


Assuntos
Convulsivantes/farmacologia , Larva/efeitos dos fármacos , Pentilenotetrazol/farmacologia , Convulsões/induzido quimicamente , Peixe-Zebra/embriologia , Ácido alfa-Linoleico/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Convulsivantes/efeitos adversos , Suplementos Nutricionais , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/metabolismo , Epilepsia/dietoterapia , Feminino , Expressão Gênica/efeitos dos fármacos , Masculino , Pentilenotetrazol/efeitos adversos , Proteínas Proto-Oncogênicas c-fos/genética , RNA Mensageiro/genética , Natação , Ácido alfa-Linoleico/metabolismo
15.
Mol Med Rep ; 19(4): 3255-3262, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816469

RESUMO

Repulsive guidance molecule a (RGMa) is a membrane­associated glycoprotein that regulates axonal guidance and inhibits axon outgrowth. In our previous study, we hypothesized that RGMa may be involved in temporal lobe epilepsy (TLE) via the repulsive guidance molecule a (RGMa)­focal adhesion kinase (FAK)­Ras signaling pathway. To investigate the role of RGMa in epilepsy, recombinant RGMa protein and FAK inhibitor 14 was intracerebroventricularly injected into a pentylenetetrazol (PTZ) kindling model and Timm staining, co­immunoprecipitation and western blotting analyses were subsequently performed. The results of the present study revealed that intracerebroventricular injection of recombinant RGMa protein reduced the phosphorylation of FAK (Tyr397) and intracerebroventricular injection of FAK inhibitor 14 reduced the interaction between FAK and p120GAP, as wells as Ras expression. Recombinant RGMa protein and FAK inhibitor 14 exerted seizure­suppressant effects; however, recombinant RGMa protein but not FAK inhibitor 14 suppressed mossy fiber sprouting in the PTZ kindling model. Collectively, these results demonstrated that RGMa may be considered as a potential therapeutic agent for epilepsy, and that RGMa may exert the aforementioned biological effects partly via the FAK­p120GAP­Ras signaling pathway.


Assuntos
Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Glicoproteínas de Membrana/metabolismo , Fibras Musgosas Hipocampais/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Convulsões/metabolismo , Convulsões/fisiopatologia , Transdução de Sinais , Proteína p120 Ativadora de GTPase/metabolismo , Proteínas ras/metabolismo , Animais , Modelos Animais de Doenças , Proteínas Ligadas por GPI , Expressão Gênica , Masculino , Glicoproteínas de Membrana/administração & dosagem , Fibras Musgosas Hipocampais/fisiopatologia , Proteínas do Tecido Nervoso/administração & dosagem , Pentilenotetrazol/efeitos adversos , Fosforilação , Ligação Proteica , Ratos , Proteínas Recombinantes , Convulsões/tratamento farmacológico , Convulsões/etiologia , Transdução de Sinais/efeitos dos fármacos , Proteínas ras/genética
16.
Molecules ; 24(3)2019 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-30696059

RESUMO

Epilepsy is a common clinical syndrome characterized by sudden and recurrent attacks and temporary central nervous system dysfunction caused by excessive discharge of neurons in the brain. Amber, a fossilized organic substance formed by the resins of conifers and leguminous plants, was prescribed to tranquilize the mind in China. In this paper, the antiepileptic effect of amber was evaluated by a pentylenetetrazole (PTZ)-induced epileptic model. An untargeted metabolomics approach was applied to investigate metabolic changes in the epileptic model, which was based on HILIC-UHPLC-MS/MS multivariate statistical analysis and metabolism network analysis. The outcome of this study suggested that 35 endogenous metabolites showed marked perturbations. Moreover, four metabolism pathways were mainly involved in epilepsy. After treatment by amber, the endogenous metabolites had a marked tendency to revert back to the situation of the control group which was consistent with phenobarbital. This study characterized the pentylenetetrazole-induced epileptic model and provided new evidence for the sedative effect of amber.


Assuntos
Âmbar/farmacologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Epilepsia/induzido quimicamente , Epilepsia/metabolismo , Hipnóticos e Sedativos/farmacologia , Metaboloma , Metabolômica , Animais , Comportamento Animal , Cromatografia Líquida , Modelos Animais de Doenças , Imuno-Histoquímica , Redes e Vias Metabólicas , Metabolômica/métodos , Camundongos , Neurônios/metabolismo , Pentilenotetrazol/efeitos adversos , Espectrometria de Massas por Ionização por Electrospray
17.
Arch Toxicol ; 93(1): 189-206, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30334080

RESUMO

We previously reported a novel toxic peptide identified from the anthozoan Protopalythoa variabilis transcriptome which is homologous to a novel structural type of sodium channel toxin isolated from a parental species (Palythoa caribaeorum). The peptide was named, according to its homologous, as Pp V-shape α-helical peptide (PpVα) in the present study. Through molecular docking and dynamics simulation, linear and hairpin folded PpVα peptides were shown to be potential voltage-gated sodium channel blockers. Nowadays, sodium channel blockers have been the mainstream of the pharmacological management of epileptic seizures. Also, sodium channel blockers could promote neuronal survival by reducing sodium influx and reducing the likelihood of calcium importation resulting in suppressing microglial activation and protecting dopaminergic neurons from degeneration. The folded PpVα peptide could decrease pentylenetetrazol (PTZ)-induced c-fos and npas4a expression level leading to reverse PTZ-induced locomotor hyperactivity in zebrafish model. In vitro, the folded PpVα peptide protected PC12 cells against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity via activating heme oxygenase-1 (HO-1) and attenuating inducible nitric oxide synthase (iNOS) expression. In vivo, PpVα peptide suppressed the 6-OHDA-induced neurotoxicity on the locomotive behavior of zebrafish and, importantly, prevented the 6-OHDA-induced excessive ROS generation and subsequent dopaminergic neurons loss. This study indicates that the single S-S bond folded PpVα peptide arises as a new structural template to develop sodium channel blockers and provides an insight on the peptide discovery from cnidarian transcriptome to potentially manage epilepsy and neurodegenerative disorders.


Assuntos
Antozoários/química , Anticonvulsivantes/farmacologia , Fármacos Neuroprotetores/farmacologia , Peptídeos/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Canais de Sódio Disparados por Voltagem/metabolismo , Sequência de Aminoácidos , Animais , Heme Oxigenase (Desciclizante)/metabolismo , Locomoção , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Óxido Nítrico Sintase Tipo II/metabolismo , Oxidopamina/efeitos adversos , Células PC12 , Pentilenotetrazol/efeitos adversos , Peptídeos/síntese química , Estrutura Terciária de Proteína , Ratos , Espécies Reativas de Oxigênio/metabolismo , Peixe-Zebra
18.
Int. j. morphol ; 37(1): 265-272, 2019. graf
Artigo em Inglês | LILACS | ID: biblio-990037

RESUMO

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.


Assuntos
Animais , Masculino , Ratos , Marsileaceae/química , Epilepsia/tratamento farmacológico , Álcoois Graxos/administração & dosagem , Região CA3 Hipocampal/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Pentilenotetrazol/efeitos adversos , Doença Crônica , Ratos Wistar , Células Piramidais , Epilepsia/induzido quimicamente , Ácidos Graxos , Álcoois Graxos/isolamento & purificação , Teste do Labirinto Aquático de Morris , Hipocampo/efeitos dos fármacos
19.
Phytomedicine ; 50: 1-7, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30466968

RESUMO

BACKGROUND: Our previous studies on Asterothamnus centrali-asiaticus Novopokr. (ACN) and Arenaria kansuensis Maxim. (AKM) had led to the isolation of some phytochemical constituents and evaluation of anticonvulsant effect based on their extracts. ACN and AKM have been widely used in traditional Tibetan herbs for neuropsychiatric diseases and cardiopulmonary disorders. PURPOSE: The purpose is to investigate structure-activity relationships of flavonoids isolated from ACN and AKM, for binding to the benzodiazepine site (BZ-S) of γ-aminobutyric acid type A (GABAA) receptor complex, and to search for anticonvulsant compounds without undesirable effects such as myorelaxation and sedation. STUDY DESIGN AND METHODS: The affinities of these flavonoids for the BZ-S of GABAA receptors were determined by [3H]flunitrazepam binding to mouse cerebellum membranes in vitro. And the anticonvulsant, myorelaxant and sedative effects were determined by pentylenetetrazol (PTZ)-induced seizure and electrogenic seizure protection, rotarod test and locomotor activity test, respectively. RESULTS: Fifteen and thirteen flavonoids were isolated from ACN and AKM, respectively. Structure-activity relationships analysis indicated that 6-and/or 8-OMe flavones exhibited the most potent binding affinity to GABAA receptors. Furthermore, 2',4',5,7-tetrahydroxy-5',6-dimethoxyflavone (DMF, IC50 value of 0.10 µM), a flavone isolated from ACN, presented high anticonvulsant activity against chemical-induced seizures and electrogenic seizures, without myorelaxation and sedation. CONCLUSION: This study suggested that these flavones, especially DMF, are new BZ receptor ligands and prospective therapeutic candidates for seizures.


Assuntos
Anticonvulsivantes/farmacologia , Arenaria (Planta)/química , Asteraceae/química , Flavonoides/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Receptores de GABA-A/metabolismo , Convulsões/tratamento farmacológico , Animais , Anticonvulsivantes/isolamento & purificação , China , Flavonoides/isolamento & purificação , Flunitrazepam , Masculino , Medicina Tradicional Tibetana , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Pentilenotetrazol/efeitos adversos , Extratos Vegetais/farmacologia , Estudos Prospectivos , Convulsões/induzido quimicamente
20.
J Toxicol Sci ; 43(11): 671-684, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30405000

RESUMO

Thalidomide was originally developed to treat primary neurological and psychiatric diseases. There are reports of anticonvulsant effects of thalidomide in rats and antiepileptic effects in patients. Hence, thalidomide (100, 200 and 400 mg/kg) was herein administered to mice to evaluate possible protection against seizures induced by the systemic administration of neurotoxins: 10 mg/kg of 4-aminopyridine (4-AP), 90 mg/kg of pentylenetetrazol (PTZ), or 380 mg/kg of pilocarpine. The effect of an NO and COX inhibitor (7-NI and ibuprofen, respectively) was also examined. The results show that thalidomide (1) induces the typical sedative effects, (2) has no anticonvulsant effect in mice treated with 4-AP, and (3) has anticonvulsant effect (400 mg/kg) in mice treated with PTZ and pilocarpine. It was found that 7-NI has an anticonvulsant effect in the pilocarpine model and that thalidomide's effect is not enhanced by its presence. However, thalidomide (200 mg/kg) plus 7-NI or ibuprofen tend to have a toxic effect in PTZ model. On the other hand, the combination of thalidomide and 7-NI or ibuprofen protects against pilocarpine-induced seizures. In conclusion, thalidomide did not exert an anticonvulsant effect for clonic-tonic type convulsions (4-AP), but it did so for seizures induced by PTZ and pilocarpine (representing absence seizures and status epilepticus, respectively). NO and prostaglandins were involved in the convulsive process elicited by pilocarpine.


Assuntos
Anticonvulsivantes , Neurotoxinas/efeitos adversos , Pentilenotetrazol/efeitos adversos , Pilocarpina/efeitos adversos , Convulsões/prevenção & controle , Talidomida/administração & dosagem , Talidomida/farmacologia , 4-Aminopiridina/efeitos adversos , Doença Aguda , Animais , Modelos Animais de Doenças , Quimioterapia Combinada , Ibuprofeno/administração & dosagem , Indazóis/administração & dosagem , Masculino , Camundongos Endogâmicos , Óxido Nítrico , Convulsões/induzido quimicamente
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