RESUMO
The objective of present work was to enquire the potential use of embelin-loaded nanolipid carriers for brain targeting. The average particle size and polydispersity index (PDI) of optimized formulation (F19) were found to be 152 ± 19.7 nm and 0.143 ± 0.023, respectively. Nanolipid carrier (NLC) was also significantly attenuated pentylenetetrazole (PTZ)-induced biochemical parameters in comparison to plain embelin that results in an increase in the level of malondialdehyde (MDA), nitrite, and reduction in the level of glutathione. From the results, it was concluded that embelin-NLCs developed as a beneficial carrier to achieve sustained release and brain targeting through nasal route.
Assuntos
Benzoquinonas/farmacocinética , Encéfalo/efeitos dos fármacos , Portadores de Fármacos , Nanopartículas/química , Palmitatos/química , Administração Intranasal , Animais , Benzoquinonas/sangue , Benzoquinonas/farmacologia , Encéfalo/metabolismo , Convulsivantes/antagonistas & inibidores , Convulsivantes/farmacologia , Composição de Medicamentos , Liberação Controlada de Fármacos , Feminino , Glutationa/agonistas , Glutationa/metabolismo , Masculino , Malondialdeído/antagonistas & inibidores , Malondialdeído/metabolismo , Nanopartículas/metabolismo , Nitritos/antagonistas & inibidores , Nitritos/metabolismo , Tamanho da Partícula , Pentilenotetrazol/antagonistas & inibidores , Pentilenotetrazol/farmacologia , Poloxâmero/química , Ratos , Ratos Wistar , Distribuição TecidualRESUMO
OBJECTIVE: There is an urge to identify new molecules which can modulate process of epileptogenesis, since currently available drugs act symptomatically and one-third of the patients remain refractory to the disease. Hence, the present study was conducted to evaluate the effects of Resveratrol (RESV) on epileptogenesis in pentylenetetrazole (PTZ)-induced kindling in mice. METHOD: Swiss albino mice were administered RESV (10, 20 and 40â mg/kg,p.o) in acute study. On the seventh day animals were subjected to various neurological and neurobehavioral tests viz, Increasing Current Electroshock Test (ICES), PTZ-induced seizures, passive avoidance response, and elevated plus maze test. For the development of kindling PTZ was administered in a dose of 25â mg/kg, i.p. on every alternate day and RESV in all the three doses was administered daily. Seizure score was continuously monitored till the development of kindling and cognition tests were performed in the end of the study. The animals were sacrificed and levels of inflammatory biomarkers viz., IL-1ß, interleukin-1 receptor antagonist (IL1-Ra), IL-6, and TNF-α were assessed in the hippocampus and cortex of the kindled animals. RESULTS: RESV in all three doses increased the seizure threshold to hind limb extension in the ICES test. RESV in all the tested doses suppressed the development of kindling and reduced the levels of IL-1ß, IL1-Ra, IL-6, and TNF-α in kindled mice. CONCLUSION: RESV suppressed the development of kindling in mice and decreased the levels of inflammatory biomarkers in their hippocampus. RESV modified brain inflammation during epileptogenesis and found to possess nootropic activity in the kindled mice.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Anticonvulsivantes/uso terapêutico , Córtex Cerebral/metabolismo , Suplementos Nutricionais , Hipocampo/metabolismo , Convulsões/prevenção & controle , Estilbenos/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anticonvulsivantes/administração & dosagem , Antioxidantes/administração & dosagem , Antioxidantes/uso terapêutico , Aprendizagem da Esquiva/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/imunologia , Convulsivantes/antagonistas & inibidores , Convulsivantes/toxicidade , Encefalite/induzido quimicamente , Encefalite/imunologia , Encefalite/metabolismo , Encefalite/prevenção & controle , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Excitação Neurológica/efeitos dos fármacos , Excitação Neurológica/imunologia , Excitação Neurológica/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/imunologia , Neurônios/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/uso terapêutico , Pentilenotetrazol/antagonistas & inibidores , Pentilenotetrazol/toxicidade , Distribuição Aleatória , Resveratrol , Convulsões/induzido quimicamente , Convulsões/imunologia , Convulsões/metabolismo , Estilbenos/administração & dosagemRESUMO
The mTORC1 complex integrates different inputs from intracellular and extracellular signals to control various cellular processes. Therefore, any disruption in the mTORC1 pathway could promote different neurological disorders. mTORC1 overactivation has been verified in different genetic and acquired epilepsy animal models. Therefore, inhibitors of this complex could have both antiepileptogenic and antiseizure effects. In our study, we investigated the effects of rapamycin pretreatment on pentylenetetrazole (PTZ)-induced seizures in zebrafish. Our results have shown that the latency to reach the tonic-clonic stage (stage III) of progressive behavioral alterations shown during PTZ-induced seizures was prolonged in larval (7days post fertilization, 7dpf), juvenile (45days post fertilization, 45dpf) and adult (6-8months) zebrafish after pretreatment with rapamycin. Furthermore, rapamycin pretreatment did not alter the locomotor activity in zebrafish. Therefore, the results obtained in our study indicate that rapamycin pretreatment is an important mechanism to control the progress of seizures in zebrafish throughout different developmental stages (larval, juvenile, and adult). Taken as a whole, our data support that rapamycin has immediate antiseizure effects and could be a potential alternative therapy for seizure control in epilepsy.
Assuntos
Anticonvulsivantes/farmacologia , Convulsivantes/antagonistas & inibidores , Convulsivantes/toxicidade , Pentilenotetrazol/antagonistas & inibidores , Pentilenotetrazol/toxicidade , Convulsões/prevenção & controle , Sirolimo/farmacologia , Peixe-Zebra/fisiologia , Animais , Modelos Animais de Doenças , Larva/efeitos dos fármacos , Alvo Mecanístico do Complexo 1 de Rapamicina , Atividade Motora/efeitos dos fármacos , Complexos Multiproteicos/metabolismo , Convulsões/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Peixe-Zebra/crescimento & desenvolvimento , Proteínas de Peixe-Zebra/metabolismoRESUMO
INTRODUCTION: Orexin has been shown to be involved in a number of physiological and behavioral processes including, feeding and metabolism, reward, nociception, and anxiety. Furthermore, orexin can cause increased neuronal excitability that gives rise to epileptic activity. The distribution of orexin receptor expression in the hippocampus, suggests a possible importance of orexin in the control of seizures in the temporal lobe epilepsy. Therefore, in this study, the effect of hippocampal orexin 1 and 2 receptors on seizure and glutamate and GABA (gamma-aminobutyric acid) contents was explored. MATERIALS AND METHODS: Orexin 1 receptor (OX1R) antagonist (SB) and OX2R antagonist (TCS) were administrated bilaterally through separate cannulae into both hippocampi. Behavioral convulsions were provoked by intravenous pentylenetetrazol (PTZ) application model. The amount of total hippocampal glutamate and GABA contents was then measured by a biochemical method. RESULTS: SB (50 nmol) infusion reduced seizure stage, duration and decreased glutamate while GABA content was increased. SB (200 nmol) also reduced seizure stage, duration and glutamate content, without change of GABA content. TCS (20 nmol) infusion reduced seizure stage and duration without concomitant change in glutamate and GABA contents. Further, TCS (40 nmol) did neither affect the seizure nor the GABA, while decreased glutamate content. Co-administration of SB (50 nmol) with TCS (40 nmol) and also SB (200 nmol) with TCS (40 nmol) reduced seizure stage, duration and glutamate, but increased GABA content. CONCLUSION: It is concluded that OX1R and OX2R antagonists reduce convulsive intensity, partially through alterations of hippocampal glutamate and GABA contents.
Assuntos
Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Pentilenotetrazol/antagonistas & inibidores , Convulsões/induzido quimicamente , Convulsões/metabolismo , Animais , Benzoxazóis/administração & dosagem , Benzoxazóis/farmacologia , Convulsivantes/farmacologia , Ácido Glutâmico/metabolismo , Isoquinolinas/administração & dosagem , Isoquinolinas/farmacologia , Masculino , Microinjeções , Naftiridinas , Pentilenotetrazol/farmacologia , Piridinas/administração & dosagem , Piridinas/farmacologia , Ratos , Ureia/administração & dosagem , Ureia/análogos & derivados , Ureia/farmacologia , Ácido gama-Aminobutírico/metabolismoRESUMO
Cognitive impairment, the most common and severe comorbidity of epilepsy, greatly diminishes the quality of life. However, current therapeutic interventions for epilepsy can also cause untoward cognitive effects. Thus, there is an urgent need for new kinds of agents targeting both seizures and cognition deficits. Oxidative stress is considered to play an important role in epileptogenesis and cognitive deficits, and antioxidants have a putative antiepileptic potential. Metformin, the most commonly prescribed antidiabetic oral drug, has antioxidant properties. This study was designed to evaluate the ameliorative effects of metformin on seizures, cognitive impairment and brain oxidative stress markers observed in pentylenetetrazole-induced kindling animals. Male C57BL/6 mice were administered with subconvulsive dose of pentylenetetrazole (37 mg/kg, i.p.) every other day for 14 injections. Metformin was injected intraperitoneally in dose of 200mg/kg along with alternate-day PTZ. We found that metformin suppressed the progression of kindling, ameliorated the cognitive impairment and decreased brain oxidative stress. Thus the present study concluded that metformin may be a potential agent for the treatment of epilepsy as well as a protective medicine against cognitive impairment induced by seizures.
Assuntos
Antioxidantes/farmacologia , Excitação Neurológica/efeitos dos fármacos , Metformina/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Convulsivantes/antagonistas & inibidores , Convulsivantes/toxicidade , Glutationa/metabolismo , Deficiências da Aprendizagem/induzido quimicamente , Deficiências da Aprendizagem/fisiopatologia , Deficiências da Aprendizagem/prevenção & controle , Masculino , Malondialdeído/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/fisiopatologia , Transtornos da Memória/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Pentilenotetrazol/antagonistas & inibidores , Pentilenotetrazol/toxicidade , Convulsões/induzido quimicamente , Convulsões/fisiopatologia , Convulsões/prevenção & controleRESUMO
A novel class of drugs - potassium (K(+)) channel openers or activators - has recently been shown to cause anticonvulsive and neuroprotective effects by activating hyperpolarizing K(+) currents, and therefore, may show efficacy for treating tinnitus. This study presents measurements of the modulatory effects of four K(+) channel openers on the spontaneous activity and action potential waveforms of neuronal networks. The networks were derived from mouse embryonic auditory cortices and grown on microelectrode arrays. Pentylenetetrazol was used to create hyperactivity states in the neuronal networks as a first approximation for mimicking tinnitus or tinnitus-like activity. We then compared the pharmacodynamics of the four channel activators, retigabine and flupirtine (voltage-gated K(+) channel KV7 activators), NS1619 and isopimaric acid ("big potassium" BK channel activators). The EC50 of retigabine, flupirtine, NS1619, and isopimaric acid were 8.0, 4.0, 5.8, and 7.8µM, respectively. The reduction of hyperactivity compared to the reference activity was significant. The present results highlight the notion of re-purposing the K(+) channel activators for reducing hyperactivity of spontaneously active auditory networks, serving as a platform for these drugs to show efficacy toward target identification, prevention, as well as treatment of tinnitus.
Assuntos
Vias Auditivas/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Canais de Potássio/agonistas , Animais , Córtex Auditivo/efeitos dos fármacos , Linhagem Celular , Convulsivantes/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Pentilenotetrazol/antagonistas & inibidores , Pentilenotetrazol/farmacologia , Zumbido/induzido quimicamente , Zumbido/prevenção & controleRESUMO
RATIONALE: In order to improve upon the pharmacological properties of the neuroactive steroid ganaxolone, it was used as the starting point in the design of novel neurosteroids that replace the 17ß-acetyl side chain with an isoxazole bioisostere. OBJECTIVES: UCI-50027 (3-[3α-hydroxy-3ß-methyl-5α-androstan-17ß-yl]-5-(hydroxymethyl)isoxazole) was designed as an orally active neuroactive steroid specifically targeted at the gamma-aminobutyric acid(A) receptor (GABAAR). METHODS: UCI-50027 was tested in vitro in Xenopus oocytes expressing human GABAARs and in vivo as an anticonvulsant, for ataxic effects and for anxiolytic activity. RESULTS: In vitro, UCI-50027 dose-dependently enhanced the activity of GABA at human α1ß2γ2L, α2ß1γ2L, and α4ß3δ GABAARs. Consistent with its action as a positive allosteric modulator (PAM), it had no direct activity in the absence of GABA. UCI-50027 protected against acute pentylenetetrazol (PTZ)-induced convulsions with an ED50 of 6 mg/kg p.o. In the rotarod (RR) paradigm in mice, the AD50 (the ataxic dose where half of the animals fail the RR test) was found to be 38 mg/kg p.o., giving a therapeutic index (TI = RR AD50/PTZ ED50)â¼6 versus 2.8 for ganaxolone. In the mouse-elevated plus maze (EPM) model for anxiety, UCI-50027 showed a minimum effective dose (MED) ≤0.3 mg/kg p.o. Thus, the TI (TI = RR AD50/EPM MED) for the compound as an anxiolytic is ≥127 versus 3.3 for ganaxolone. CONCLUSIONS: UCI-50027 is an orally active neuroactive steroid with pharmacological activity consistent with a GABAAR PAM that has an improved separation between anticonvulsant/anxiolytic and rotarod effects, potent activity as an anticonvulsant and anxiolytic when compared to ganaxolone.
Assuntos
Androstanos/farmacologia , Neurotransmissores/farmacologia , Animais , Ansiolíticos/farmacologia , Anticonvulsivantes/farmacologia , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Neurotransmissores/farmacocinética , Técnicas de Patch-Clamp , Pentilenotetrazol/antagonistas & inibidores , Equilíbrio Postural/efeitos dos fármacos , Pregnanolona/análogos & derivados , Pregnanolona/farmacocinética , Pregnanolona/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/efeitos dos fármacos , XenopusRESUMO
RATIONALE: Androsterone [(3α,5α)-3-hydroxyandrostan-17-one; 5α,3α-A] and its 5ß-epimer etiocholanolone [(3α,5ß)-3-hydroxyandrostan-17-one; 5ß,3α-A)], the major excreted metabolites of testosterone, are neurosteroid positive modulators of GABAA receptors. Such neurosteroids typically show enantioselectivity in which the natural form is more potent than the corresponding unnatural enantiomer. For 5α,3α-A and 5ß,3α-A, the unnatural enantiomers are more potent at GABAA receptors than the natural forms. OBJECTIVES: The aim of this study was to compare the anticonvulsant potencies and time courses of 5α,3α-A and 5ß,3α-A with their enantiomers in mouse seizure models. METHODS: Steroids were administered intraperitoneally to male NIH Swiss mice 15 min (or up to 6 h in time course experiments) prior to administration of an electrical stimulus in the 6-Hz or maximal electroshock (MES) seizure tests or the convulsant pentylenetetrazol (PTZ). RESULTS: In the 6-Hz test, the ED50 values of ent-5α,3α-A was 5.0 mg/kg whereas the value for 5α,3α-A was 12.1 mg/kg; the corresponding values in the PTZ seizure test were 22.8 and 51.8 mg/kg. Neurosteroid GABAA receptor-positive allosteric modulators are generally weak in the MES seizure test and this was confirmed in the present study. However, the atypical relative potency relationship was maintained with ED50 values of 140 and 223 mg/kg for ent-5α,3α-A and 5α,3α-A, respectively. Similar relationships were obtained for the 5ß-isomers, except that the enantioselectivity was accentuated. In the 6-Hz and PTZ tests, the ED50 values of ent-5ß,3α-A were 11.8 and 20.4 mg/kg whereas the values for 5ß,3α-A were 57.6 and 109.1 mg/kg. Protective activity in the 6-Hz test of ent-5α,3α-A persisted for somewhat longer (~5 h) than for 5α,3α-A (~4 h); protection by ent-5ß,3α-A also persisted longer (~3 h) than for 5ß,3α-A (~2 h). CONCLUSIONS: The unnatural enantiomers of 17-keto androgen class neurosteroids have greater in vivo potency and a longer duration of action than their natural counterparts. The more prolonged duration of action of the unnatural enantiomers could reflect reduced susceptibility to metabolism. Unnatural enantiomers of androgen class neurosteroids could have therapeutic utility and may provide advantages over the corresponding natural isomers due to enhanced potency and improved pharmacokinetic characteristics.
Assuntos
Androsterona/farmacologia , Anticonvulsivantes/farmacologia , Etiocolanolona/farmacologia , Neurotransmissores/farmacologia , Androsterona/química , Animais , Comportamento Animal/efeitos dos fármacos , Convulsivantes/farmacologia , Relação Dose-Resposta a Droga , Discinesia Induzida por Medicamentos/psicologia , Eletrochoque , Etiocolanolona/química , Masculino , Camundongos , Neurotransmissores/química , Pentilenotetrazol/antagonistas & inibidores , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Resveratrol is a polyphone chemical found in a number of plant species, including peanuts and grapes, but with significant amounts in red wine. In normal plant physiology, Resveratrol is produced as a defensive response to injury or parasitic attacks. Resveratrol has diverse biological properties and actions with potential clinical applications, including anti-inflammatory, antioxidant, anti proliferative, and neuroprotective effects. AIM: The aim of the present study was to explore the effect and mechanism of Resveratrol in Pentylenetetrazole (PTZ) induced kindling in rats. MATERIALS AND METHODS: In a PTZ kindled Wistar rat model, different doses of Resveratrol (25mg/kg, 50mg/kg and 75 mg/kg) were administered orally 30 min before the PTZ injection. The PTZ injection was given on alternate day till the animal became fully kindled or till 10 weeks. The following parameters were compared between control and various experimental groups: the course of kindling, stages of seizures, histopathological scoring of hippocampus, antioxidant parameters, DNA fragmentation and caspase-3 expression in the hippocampus, and neuron-specific enolase in the blood. One way ANOVA followed by Bonferroni post hoc analysis and Fischer's Exact test were used for statistical analyses. THE RESULTS: In the present study, Resveratrol showed dose-dependent anti-seizure effect. Resveratrol (75 mg/kg) significantly increased the latency to myoclonic jerks, clinic seizures as well as generalized tonic-clinic seizures, improved the seizure score and decreased the number of myoclonic jerks. PTZ induced kindling caused a significant neuronal injury, oxidative stress and apoptosis which were reversed by pretreatment with Resveratrol in a dose-dependent manner. CONCLUSION: Our study suggests that Resveratrol has a potential antiepileptogenic effect on PTZ-induced kindling in rats. The possible underlying mechanisms of Resveratrol as an antiepileptic agent may be due to its antioxidative property and neuroprotective effect.
Assuntos
Anticonvulsivantes/farmacologia , Antioxidantes/farmacologia , Convulsivantes/farmacologia , Excitação Neurológica/efeitos dos fármacos , Pentilenotetrazol/antagonistas & inibidores , Pentilenotetrazol/farmacologia , Convulsões/patologia , Convulsões/prevenção & controle , Estilbenos/farmacologia , Animais , Caspase 3/biossíntese , Hipocampo/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fosfopiruvato Hidratase/biossíntese , Ratos , Resveratrol , Convulsões/induzido quimicamenteRESUMO
A novel series of 2-(substituted-imino)thiazolidin-4-ones were synthesized and evaluated for anticonvulsant activity using the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (Sc-PTZ) assays and their neurotoxicity was measured by the rotarod test. The results of these tests demonstrated that 2-(4-(pentyloxy)phenylimino)thiazolidin-4-one (5d) was the most potent anticonvulsant, with ED50 value of 18.5 mg/kg and 15.3 mg/kg in the MES and Sc-PTZ tests, and protective index (PI=TD50/ED50) values of 10.6 and 12.8 respectively. 5d was much safer than a reference drug Carbamazepine.
Assuntos
Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacologia , Tiazolidinas/síntese química , Tiazolidinas/farmacologia , Animais , Anticonvulsivantes/toxicidade , Carbamazepina/farmacologia , Convulsivantes/farmacologia , Avaliação Pré-Clínica de Medicamentos , Eletrochoque , Feminino , Indicadores e Reagentes , Masculino , Camundongos , Pentilenotetrazol/antagonistas & inibidores , Pentilenotetrazol/farmacologia , Equilíbrio Postural/efeitos dos fármacosRESUMO
We investigated the anticonvulsant effect of acute Fuzi total alkaloid (FTA) in seizure induced by the GABAA-receptor antagonist pentylenetetrazole (PTZ). FTA significantly increased the seizure latency and decreased the mortality in PTZ-treated mice. Administration of PTZ increased c-Fos expression in the hippocampus, medial prefrontal cortex, and piriform cortex; and this PTZ-induced effect was inhibited by FTA in a dose-dependent manner. Furthermore, the effects of FTA on PTZ-induced seizure and c-Fos expression were reversed by the GABAA/benzodiazepine receptor-selective antagonist flumazenil. These findings suggest that the anticonvulsant effects of FTA may be related to modulation of GABAA-benzodiazepine receptor complex.
Assuntos
Anticonvulsivantes/farmacologia , Antagonistas de Receptores de GABA-A , Pentilenotetrazol , Fitoterapia , Extratos Vegetais/farmacologia , Receptores de GABA-A/metabolismo , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Animais , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Diterpenos , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas , Flumazenil/farmacologia , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Pentilenotetrazol/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-fos/metabolismo , Convulsões/metabolismoRESUMO
Danshen or Chinese red sage (Salvia miltiorrhiza, Bunge) is used by traditional Chinese medicine (TCM) practitioners to treat neurological, cardiovascular, and cerebrovascular disorders and is included in some TCM formulations to control epileptic seizures. In this study, acetonic crude extracts of danshen inhibited pentylenetetrazol (PTZ)-induced seizure activity in zebrafish larvae. Subsequent zebrafish bioassay-guided fractionation of the extract resulted in the isolation of four major tanshinones, which suppressed PTZ-induced activity to varying degrees. One of the active tanshinones, tanshinone IIA, also reduced c-fos expression in the brains of PTZ-exposed zebrafish larvae. In rodent seizure models, tanshinone IIA showed anticonvulsive activity in the mouse 6-Hz psychomotor seizure test in a biphasic manner and modified seizure thresholds in a complex manner for the mouse i.v. PTZ seizure assay. Interestingly, tanshinone IIA is used as a prescription drug in China to address cerebral ischemia in patients. Here, we provide the first in vivo evidence demonstrating that tanshinone IIA has anticonvulsant properties as well.
Assuntos
Abietanos/administração & dosagem , Anticonvulsivantes/administração & dosagem , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa/métodos , Pentilenotetrazol/antagonistas & inibidores , Convulsões/tratamento farmacológico , Abietanos/fisiologia , Abietanos/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Animais , Anticonvulsivantes/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Modelos Animais de Doenças , Progressão da Doença , Fertilização in vitro/efeitos dos fármacos , Injeções Intraventriculares , Larva/efeitos dos fármacos , Masculino , Camundongos , Microinjeções , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/uso terapêutico , Pentilenotetrazol/administração & dosagem , Pentilenotetrazol/toxicidade , Extratos Vegetais/administração & dosagem , Extratos Vegetais/uso terapêutico , Raízes de Plantas/química , Proteínas Proto-Oncogênicas c-fos/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-fos/biossíntese , Salvia miltiorrhiza/química , Convulsões/diagnóstico , Convulsões/mortalidade , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/uso terapêutico , Peixe-Zebra/embriologiaRESUMO
In the present study, the effect of medroxyprogesterone (MPA) is evaluated for its effect on pentylenetetrazole (PTZ) kindling model of epileptogenesis in mice followed by evaluation on kindling-induced changes in cognitive and motor functions. To explore whether the effects are mediated via progesterone receptors, a selective antagonist of progesterone (mifepristone, MIF) was also taken. Kindling was induced by once every 2 days treatment with PTZ (25 mg/kg, i.p.) for 5 weeks. The seizure severity during induction of kindling and % incidence of animals kindled at the end of 5 weeks were recorded. The motor function was assessed using a grip strength meter, whereas spatial memory was assessed in a cross maze. MPA (5 and 10 mg/kg, i.p.) significantly reduced the seizure severity scores and produced a significant decrease in the incidence of animals kindled at the end of 5 weeks (P<0.01). A higher efficacy was observed against male mice as compared with females following MPA. MIF neither reduced nor delayed the development of PTZ-induced kindling in mice. Also, it couldn't reverse the antiepileptogenic effects of MPA. On grip strength test (GST) and spontaneous alternation behavior (SAB), a significant decline in GST and % alternation was observed in kindled mice which was reversed by pre-treatment with MPA. MIF, however, could reverse only the reduced % alternation and not grip strength (GS) in PTZ-kindled animals. The study shows that MPA has antiepileptogenic effects against development of PTZ-induced kindling in mice that may not be mediated via progesterone receptors.
Assuntos
Anticonvulsivantes/farmacologia , Epilepsia/tratamento farmacológico , Excitação Neurológica/efeitos dos fármacos , Medroxiprogesterona/farmacologia , Receptores de Progesterona/agonistas , Animais , Anticoncepcionais Orais Sintéticos/farmacologia , Convulsivantes/antagonistas & inibidores , Convulsivantes/toxicidade , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Epilepsia/fisiopatologia , Feminino , Excitação Neurológica/fisiologia , Masculino , Camundongos , Pentilenotetrazol/antagonistas & inibidores , Pentilenotetrazol/toxicidade , Receptores de Progesterona/fisiologiaRESUMO
The concentration of kynurenic acid (KYNA) in the cerebrospinal fluid, which is in the nanomolar range, is known to decrease in epilepsy. The experimental data suggest that treatment with L: -KYN dose dependently increases the concentration of the neuroprotective KYNA in the brain, which itself hardly crosses the blood-brain barrier. However, it is suggested that new synthetic KYNA analogs may readily cross the blood-brain barrier. In this study, we tested the hypothesis that a new KYNA analog administered systemically in a sufficient dose results in a decreased population spike activity recorded from the pyramidal layer of area CA1 of the hippocampus, and also provides protection against pentylenetetrazole-induced epileptiform seizures.
Assuntos
Ácido Cinurênico/análogos & derivados , Ácido Cinurênico/uso terapêutico , Cinurenina , Pentilenotetrazol/toxicidade , Convulsões/prevenção & controle , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Ácido Cinurênico/farmacologia , Masculino , Pentilenotetrazol/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Convulsões/induzido quimicamente , Convulsões/fisiopatologiaRESUMO
A series of 1,2,4-trisubstituted-1H- imidazole derivatives (4a-o) was synthesized by reacting 2,4-disubstituted-1H-imidazoles (3a-o) with chlorobenzene in the presence of triethylamine. Phenylglyoxal (2) was reacted with different aromatic aldehydes in the presence of ammonium acetate and glacial acetic acid to afford the disubstituted imidazoles (3a-o). The structures of the synthesized compounds were confirmed on the basis of their elemental analysis and spectral data results. Anticonvulsant activity was shown by majority of the synthesized compounds in the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens when given i.p. to mice. In anticonvulsant screening, only one compound 4k showed potent activity comparable to that of standard drugs phenytoin and carbamazepine. Compounds 4a, 4c, 4e, 41 and 4n passed the rotorod test successfully without any sign of neurological deficit.
Assuntos
Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacologia , Imidazóis/síntese química , Imidazóis/farmacologia , Síndromes Neurotóxicas/patologia , Animais , Anticonvulsivantes/toxicidade , Avaliação Pré-Clínica de Medicamentos , Eletrochoque , Feminino , Imidazóis/toxicidade , Indicadores e Reagentes , Masculino , Camundongos , Pentilenotetrazol/antagonistas & inibidores , Equilíbrio Postural/efeitos dos fármacos , Convulsões/induzido quimicamente , Convulsões/prevenção & controle , Relação Estrutura-AtividadeRESUMO
Vitamin C helps to prevent brain oxidative stress and participate in the synthesis of progesterone. It also possesses a progesterone-like effect and acts synergistically with progesterone on the brain. Progesterone and its metabolites, but also vitamin C have been associated with anticonvulsant effects. We evaluated the progesterone concentration 30min and 24h after the last administration of vitamin C (500mg/kg, i.p. for five days). We also evaluated how vitamin C altered pentylenetetrazol (PTZ)-induced seizures by measuring the onset latency of seizures, percentage of incidence and mortality as well as amino acid levels after seizures. Vitamin C treatment alone increased basal progesterone concentrations to 531% after 30min compared to 253% after 24h. Furthermore, vitamin C significantly increased the latency to the first myoclonic, clonic and tonic seizure induced by PTZ (80mg/kg, i.p.) and decreased the percentage of incidence of clonic and tonic seizures as well as the mortality rate. Changes in tissue concentration of amino acids were primarily observed at 24h after vitamin C treatment. Our results suggest that vitamin C together with progesterone and/or its metabolites are involved in the protection against PTZ-induced seizures in immature rats.
Assuntos
Anticonvulsivantes , Ácido Ascórbico/farmacologia , Convulsivantes/antagonistas & inibidores , Pentilenotetrazol/antagonistas & inibidores , Convulsões/prevenção & controle , Vitaminas/farmacologia , Animais , Ácido Aspártico/metabolismo , Química Encefálica/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Epilepsias Mioclônicas/induzido quimicamente , Epilepsias Mioclônicas/prevenção & controle , Epilepsia Tônico-Clônica/induzido quimicamente , Epilepsia Tônico-Clônica/prevenção & controle , Feminino , Glutamatos/metabolismo , Glutamina/metabolismo , Masculino , Progesterona/metabolismo , Ratos , Ratos Sprague-Dawley , Convulsões/induzido quimicamente , Convulsões/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
A series of new 3-hydroxy-6-hydroxymethyl/methyl-2-substituted 4H-pyran-4-ones were synthesized and prepared by the reaction of kojic acid or allomaltol with piperidine derivatives and formaline as potential anticonvulsant compounds. The structure of the synthesized compounds was confirmed using the elemental analysis results and the spectroscopic techniques such as IR, 1H-NMR, and ESI-MS. Anticonvulsant activities were examined by maximal electroshock (MES) and subcutaneous Metrazol (scMet)-induced seizure tests. Neurotoxicity was determined by the rotorod toxicity test. All these tests were performed in accordance with the procedures of the Antiepileptic Drug Development (ADD) program. According to the activity studies and at all doses, 3-hydroxy-2-[(4-hydroxy-4-phenylpiperidin-1-yl)methyl]-6-methyl-4H-pyran-4-one (compound 1), 2-{[4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl]methyl}-3-hydroxy-6-methyl-4H-pyran-4-one (compound 6), 2-[(4-acetyl-4-phenylpiperidin-1-yl)methyl]-3-hydroxy-6-(hydroxymethyl)-4H-pyran-4-one (compound 11), and 2-{[4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl] methyl}-3-hydroxy-6-hydroxymethyl-4H-pyran-4-one (compound 12) were found to have anticonvulsant activity against MES-induced seizures at 4 h. Also, 2-{[4-(4-bromophenyl)-4-hydroxypiperidin-1-yl]methyl}-3-hydroxy-6-(hydroxymethyl)-4H-pyran-4-one (compound 8) was determined to be the most active compound against scMet-induced seizures at all doses at 0.5 and 4 h. In the rotorod neurotoxicity screening, all compounds showed no toxicity at all doses.
Assuntos
Anticonvulsivantes/síntese química , Anticonvulsivantes/uso terapêutico , Piperidinas/síntese química , Piperidinas/uso terapêutico , Pironas/química , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Química Farmacêutica/métodos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Eletrochoque , Masculino , Camundongos , Pentilenotetrazol/antagonistas & inibidores , Piperidinas/química , Piperidinas/farmacologia , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
OBJECTIVES: The aim of the study was to evaluate the correlation between colitis and susceptibility to seizures. METHODS: Colitis was induced in Wistar rats by a single intracolonic administration of trinitrobenzene sulfonic acid (TNBS; 20 mg in 35% ethanol). The control group were given intracolonic vehicle. One group of rats with colitis were treated with thalidomide (150 mg/kg p.o.) daily for 14 days. The other colitis group received vehicle only. On day 15, seizure susceptibility was tested by administration of pentylenetetrazole (40 mg/kg i.p.). Colonic tissue was collected for estimation of morphological score, and malondialdehyde, superoxide dismutase, catalase and glutathione peroxidase. Tumour necrosis factor (TNF)-alpha levels were measured in serum and brain samples. KEY FINDINGS: The colitis group showed a significant increase in seizure score and reduction in onset time compared with the control group. Thalidomide was protective against seizures, resulting in decreased seizure score and significantly delaying the onset of seizures. Thalidomide also provided significant protection against TNBS-induced colonic damage in terms of morphological and histological score and levels of lipid peroxidation, superoxide dismutase, catalase and glutathione peroxidase in colonic tissue. The level of TNF-alpha in serum was also reduced significantly whereas brain TNF-alpha level was reduced but not significantly. CONCLUSIONS: TNBS-induced colitis increased seizure susceptibility to a subconvulsive dose of pentylenetetrazole; the immunomodulator thalidomide was protective.
Assuntos
Colite , Convulsões , Fator de Necrose Tumoral alfa/fisiologia , Animais , Encéfalo/metabolismo , Catalase/metabolismo , Colite/induzido quimicamente , Colite/complicações , Colite/metabolismo , Colite/patologia , Colo/metabolismo , Colo/patologia , Modelos Animais de Doenças , Feminino , Glutationa Peroxidase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Pentilenotetrazol/antagonistas & inibidores , Ratos , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/complicações , Convulsões/tratamento farmacológico , Convulsões/fisiopatologia , Superóxido Dismutase/metabolismo , Talidomida/farmacologia , Talidomida/uso terapêutico , Ácido Trinitrobenzenossulfônico , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismoRESUMO
It is believed that a deficiency of androgens, including free testosterone, may promote the development of convulsions. The present study revealed differences in the action of androsterone (AND), a major excreted metabolite of testosterone and a neurosteroid, in three commonly used seizure models in mice. AND administered intraperitoneally exhibited dose-dependent protection against tonic-clonic convulsions caused by maximal electroshock (MES) with ED(50) (effective dose(50)) of 227 mg/kg. The compound also inhibited the convulsive action of pentylenetetrazole (PTZ), increasing its CD(50) (convulsive dose(50)) for clonic convulsions from 77.2 (PTZ + saline) to 93.9 (p < 0.05) for PTZ + AND 40 mg/kg and 113.9 mg/kg (p < 0.001) for PTZ + AND 60 mg/kg. In mice pretreated with 60 mg/kg AND, the CD(50) for PTZ-induced tonic convulsions increased from 102 to 127.6 mg/kg (p < 0.01). Surprisingly, doses of 50 and 100 mg/kg AND lowered the CD(50) for kainate (KA)-induced convulsions from 40.8 to 28.7 (p < 0.05) and 25.4 mg/kg (p < 0.001), respectively. In summary, for two of the mouse seizure models, our findings confirmed previous studies that demonstrated protective activity of AND. However, the potentiation of KA-induced convulsions by AND was somewhat unexpected and suggested that AND may also possess proconvulsant activity.
Assuntos
Androsterona/uso terapêutico , Modelos Animais de Doenças , Camundongos , Convulsões/prevenção & controle , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Eletrochoque/métodos , Ácido Caínico/agonistas , Masculino , Pentilenotetrazol/antagonistas & inibidores , Convulsões/induzido quimicamenteRESUMO
Typical N-methyl-D-aspartate (NMDA) receptor antagonists exhibit anticonvulsant action and unwanted effects, even in developing rats. Therefore, we studied the actions of the low-affinity, noncompetitive antagonist memantine and the NR2B-specific antagonist ifenprodil. Seizures (minimal clonic and generalized tonic-clonic) were elicited with pentylenetetrazol (100mg/kg subcutaneously) in rats 7, 12, 18, and 25 days old pretreated with memantine (2.5-40 mg/kg intraperitoneally) or ifenprodil (10-60 mg/kg intraperitoneally). The effects of both drugs were studied in open field and motor performance tests in 12-, 18-, and 25-day-old rats. Memantine suppressed generalized tonic-clonic seizures in all age groups; minimal seizures were potentiated. Ifenprodil abolished the tonic phase of generalized tonic-clonic seizures in 7-, 12-, and 18-day-old rats only; minimal seizures remained untouched. Memantine induced locomotor hyperactivity and compromised motor performance in all age groups. Ifenprodil exerted these effects only in 12-day-old rats; older animals were less active in open field tests. Memantine exhibits both anti- and pro-convulsant and behavioral effects typical of NMDA antagonists. Ifenprodil exerted the same effects in 12-day-old rats, but its anticonvulsant action in 18-day-old rats was accompanied by a decrease in locomotion.