RESUMO
The effects of two classic antiepileptic drugs (carbamazepine and phenytoin), a potential antiepileptic (vinpocetine) and a monoamine-oxidase inhibitor (clorgyline) on the simultaneous changes (detected by HPLC) on Glu, Asp, dopamine and DOPAC inside and outside striatal isolated nerve endings were investigated. Under resting conditions phenytoin, carbamazepine and clorgyline increased dopamine release. Phenytoin and clorgyline increased internal dopamine and decreased DOPAC formation. Carbamazepine decreased internal dopamine and practically did not change DOPAC formation. Glu and Asp release was unchanged. Neurotransmitter release induced by the Na+ channel opener veratridine was reduced by all the antiepileptic drugs tested, except phenytoin which, like clorgyline, facilitated veratridine-induced dopamine release. We conclude that besides the antagonism exerted by carbamazepine, phenytoin and vinpocetine on excitatory neurotransmitters release triggered by Na+ channel activation, that might importantly contribute to their anticonvulsant action, they exert different actions on striatal dopamine distribution, that might explain their different side effect profiles.
Assuntos
Anticonvulsivantes/farmacologia , Catecolaminas/metabolismo , Corpo Estriado/efeitos dos fármacos , Inibidores da Monoaminoxidase/farmacologia , Terminações Nervosas/efeitos dos fármacos , Canais de Sódio/metabolismo , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Anticonvulsivantes/efeitos adversos , Ácido Aspártico/metabolismo , Carbamazepina/efeitos adversos , Carbamazepina/farmacologia , Clorgilina/efeitos adversos , Clorgilina/farmacologia , Corpo Estriado/metabolismo , Corpo Estriado/ultraestrutura , Dopamina/metabolismo , Glutamina/metabolismo , Técnicas In Vitro , Masculino , Inibidores da Monoaminoxidase/efeitos adversos , Terminações Nervosas/metabolismo , Fenitoína/efeitos adversos , Fenitoína/farmacologia , Ratos , Ratos Wistar , Agonistas de Canais de Sódio , Alcaloides de Vinca/efeitos adversos , Alcaloides de Vinca/farmacologiaRESUMO
OBJECTIVE: To compare the acute, chronic and post-treatment effects of the classic antiepileptic drug carbamazepine (CBZ) and the potential antiepileptic vinpocetine (VPC), successfully used in the treatment of brain vascular origin disorders, on 4-aminopyridine (4-AP)-induced increase in auditory threshold, brain-auditory-evoked-potentials (BAEPs) later waves alterations and epileptiform activity. METHODS: BAEP and EEG recordings before and following 4-AP (3mg/kg, i.p.) were obtained in guinea pigs. One week after, the animals received a daily injection (i.p.) of vehicle, 3mg/kg VPC or 17 mg/kg CBZ for 13 days. The acute and chronic effects before and following 4-AP were tested at the 1st and last days, respectively, and the post-treatment effect 1 month after the end of treatment. RESULTS: CBZ and 4-AP increased BAEPs threshold and BAEPs P4 wave latency. Chronic CBZ inhibited 4-AP-induced increase in P3 amplitude. In the VPC-treated group, all the 4-AP-induced BAEPs changes were prevented. Seizures were prevented in 50% and 75% of the animals by chronic CBZ and VPC, respectively. After acute VPC and after the end of VPC-treatment 4-AP failed to induce seizures in 50% of the animals. CONCLUSION: VPC inhibits 4-AP-induced seizures and hearing loss, even after post-treatment, at a concentration about 10 times lower than CBZ. SIGNIFICANCE: The complications in hearing that can accompany epilepsy can be prevented by VPC, indicating its advantage as an alternative antiepileptic.
Assuntos
Anticonvulsivantes/uso terapêutico , Carbamazepina/uso terapêutico , Perda Auditiva/tratamento farmacológico , Convulsões/tratamento farmacológico , Alcaloides de Vinca/uso terapêutico , 4-Aminopiridina , Estimulação Acústica/métodos , Animais , Limiar Auditivo/efeitos dos fármacos , Modelos Animais de Doenças , Interações Medicamentosas , Potenciais Evocados Auditivos/efeitos dos fármacos , Cobaias , Perda Auditiva/induzido quimicamente , Masculino , Psicoacústica , Convulsões/induzido quimicamente , Fatores de TempoRESUMO
The effect of carbamazepine, phenytoin, valproate, oxcarbazepine, lamotrigine and topiramate, that are among the most widely used antiepileptic drugs (AEDs), and of the new putative AED vinpocetine on the Ca(2+) channel-mediated release of [(3)H]Glu evoked by high K(+) in hippocampal isolated nerve endings was investigated. Results show that carbamazepine, oxcarbazepine and phenytoin reduced [(3)H]Glu release to high K(+) to about 30% and 55% at concentrations of 500 microM and 1500 microM, respectively; lamotrigine and topiramate to about 27% at 1500 microM; while valproate failed to modify it. Vinpocetine was the most potent and effective; 50 microM vinpocetine practically abolished the high K(+) evoked release of [(3)H]Glu. Comparison of the inhibition exerted by the AEDs on [(3)H]Glu release evoked by high K(+) with the inhibition exerted by the AEDs on [(3)H]Glu release evoked by the Na(+) channel opener, veratridine, shows that all the AEDs are in general more effective blockers of the presynaptic Na(+) than of the presynaptic Ca(2+) channel-mediated response. The high doses of AEDs required to control seizures are frequently accompanied by adverse secondary effects. Therefore, the higher potency and efficacy of vinpocetine to reduce the permeability of presynaptic ionic channels controlling the release of the most important excitatory neurotransmitter in the brain must be advantageous in the treatment of epilepsy.
Assuntos
Anticonvulsivantes/farmacologia , Canais de Cálcio/fisiologia , Ácido Glutâmico/metabolismo , Canais de Sódio/fisiologia , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Hipocampo/ultraestrutura , Masculino , Potássio/farmacologia , Ratos , Ratos Wistar , Bloqueadores dos Canais de Sódio/farmacologia , Tetrodotoxina/farmacologia , Trítio/metabolismo , ômega-Agatoxina IVA/farmacologiaRESUMO
Several of the most effective antiepileptic drugs are believed to stop the paroxysmal neuronal activity acting as Na(+) channel blockers. However, no single study comparing in parallel the potency and efficacy of the most commonly used antiepileptic drugs on brain Na(+) channel-mediated responses is available. In the present study the effects of increasing concentrations of carbamazepine, phenytoin, lamotrigine, oxcarbazepine and topiramate, which are among the most frequently used antiepileptic drugs, and of the new putative antiepileptic drug, vinpocetine, on the release of glutamate (Glu) elicited by the Na(+) channel opener, veratridine were investigated in hippocampal isolated nerve endings preloaded with the labeled excitatory amino acid neurotransmitter. The present results show that carbamazepine, phenytoin, lamotrigine and oxcarbazepine, in the range from 150 to 1500 microM, progressively inhibit [(3)H]Glu release induced by veratridine. Also vinpocetine progressively inhibits the veratridine-induced response, but in a much lower range of concentrations (from 1.5 to 15 microM), whereas topiramate only exerts a modest inhibition (20%) of Glu release to veratridine at the highest dose tested (1500 microM). These results indicate that the mechanism of action of several of the most widely used antiepileptic drugs involves reduction in cerebral presynaptic voltage sensitive Na(+) channels permeability. Considering that the high doses of antiepileptic drugs required to control seizures are frequently accompanied by adverse secondary effects, the higher potency of vinpocetine to reduce Na(+) channels permeability might be advantageous.
Assuntos
Anticonvulsivantes/farmacologia , Ácido Glutâmico/metabolismo , Hipocampo/ultraestrutura , Terminações Nervosas/efeitos dos fármacos , Canais de Sódio/fisiologia , Animais , Relação Dose-Resposta a Droga , Técnicas In Vitro , Masculino , Ratos , Ratos Wistar , Trítio/metabolismoRESUMO
OBJECTIVE: To characterize the acute and chronic effects of the antiepileptic drugs (AEDs): carbamazepine (CBZ), phenytoin (PHT), valproic acid (VPA) and vinpocetine (VPC), at doses 20, 6, 30 and 2mg/kg, respectively, on the latencies and amplitudes of the waves of brainstem auditory evoked potentials (BAEPs) elicited by a supra-threshold stimulus alongside BAEP threshold. METHODS: BAEPs elicited by a stimulus of high (100dB nHL) intensity and BAEP thresholds were obtained at 4 and 8kHz: before, after the start of treatment, and following 28 days of a daily injection of the AEDs. RESULTS: After the start of treatment BAEPs were unchanged. After the long term treatment, CBZ and PHT increased P3 and P4 wave peak latencies and reduced P4 amplitude. Chronic VPA did not modify BAEP waves, and chronic VPC reduced P3 and P4 latencies. P1 and P2 were unchanged. BAEP thresholds at 4 and 8kHz were increased by CBZ, PHT and VPA, and decreased by VPC. CONCLUSIONS: The chronic administration of several AEDs modifies BAEP waves of retro-cochlear origin. SIGNIFICANCE: Alterations in the generators of the later waves of BAEPs underlie, in most cases, the changes in hearing sensitivity produced by the long term treatment with AEDs at therapeutic relevant doses.
Assuntos
Anticonvulsivantes/farmacologia , Vias Auditivas/efeitos dos fármacos , Limiar Auditivo/efeitos dos fármacos , Tronco Encefálico/efeitos dos fármacos , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Estimulação Acústica , Animais , Vias Auditivas/fisiologia , Percepção Auditiva/efeitos dos fármacos , Percepção Auditiva/fisiologia , Limiar Auditivo/fisiologia , Tronco Encefálico/fisiologia , Carbamazepina/farmacologia , Eletrofisiologia , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Cobaias , Masculino , Condução Nervosa/efeitos dos fármacos , Condução Nervosa/fisiologia , Fenitoína/farmacologia , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Ácido Valproico/farmacologia , Alcaloides de Vinca/farmacologiaRESUMO
The single and combined effects of carbamazepine and vinpocetine on the release of the excitatory amino acid neurotransmitter glutamate, on the rise in internal Na+ (Na(i), as determined with SBFI), and on the rise in internal Ca2+ (Ca(i), as determined with fura-2) induced by an increased permeability of presynaptic Na+ channels, with veratridine, or by an increased permeability of presynaptic Ca2+ channels with high K+, were investigated in isolated hippocampal nerve endings. The present study shows that carbamazepine and vinpocetine, both inhibit dose dependently the release of preloaded [3H]Glu induced by veratridine. However, carbamazepine is two orders of magnitude less potent than vinpocetine. The calculated IC(50)'s for carbamazepine and vinpocetine to inhibit veratridine-induced [3H]Glu release are 200 and 2 microM, respectively. Consistently 150 microM carbamazepine and 1.5 microM vinpocetine reduce the veratridine-induced rise in Na(i) in a similar extent. The single effects of carbamazepine and of vinpocetine on the presynaptic Na+ channel mediated responses, namely the rise in Na(i) and the release of Glu induced by veratridine, are additive. Responses that depend on the entrance of external Ca2+ via presynaptic Ca2+ channels, such as the release of [3H]Glu and the rise in Ca(i) induced by high K+, are insensitive to 300 microM carbamazepine and slightly reduced by 5 microM vinpocetine. It is concluded that the additive effects of carbamazepine, which is one of the most common antiepileptic drugs, and vinpocetine that besides its known neuroprotective action and antiepileptic potential is a memory enhancer, may perhaps be advantageous in the treatment of epileptic patients.
Assuntos
Carbamazepina/farmacologia , Ácido Glutâmico/metabolismo , Hipocampo/efeitos dos fármacos , Canais Iônicos/efeitos dos fármacos , Terminações Pré-Sinápticas/efeitos dos fármacos , Alcaloides de Vinca/farmacologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Anticonvulsivantes/farmacologia , Cálcio/metabolismo , Canais de Cálcio/efeitos dos fármacos , Canais de Cálcio/metabolismo , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Hipocampo/metabolismo , Canais Iônicos/metabolismo , Masculino , Fármacos Neuroprotetores/farmacologia , Técnicas de Cultura de Órgãos , Terminações Pré-Sinápticas/metabolismo , Ratos , Ratos Wistar , Sódio/metabolismo , Canais de Sódio/efeitos dos fármacos , Canais de Sódio/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Veratridina/farmacologiaRESUMO
Here we investigate the effect of the neuroprotective drug, vinpocetine on the epileptic cortical activity, on the alterations of the later waves of brainstem auditory evoked potentials (BAEPs) and on the hearing decline induced by the convulsing agent, pentylenetetrazole (PTZ). Vinpocetine at doses from 2 to 10 mg/kg inhibits the tonic-clonic convulsions induced by PTZ (100 mg/kg). Vinpocetine injected at a dose of 2 mg/kg 4 h before PTZ completely prevents the characteristic electroencephalogram (EEG) changes induced by PTZ for the ictal and post-ictal periods. Vinpocetine also abolished the PTZ-induced changes in the amplitude and latency of the later waves of the BAEPs in response to pure tone burst monoaural stimuli (frequency 8 or 4 kHz intensity 100 dB), and the PTZ-induced increase in the BAEP threshold. These results show the antiepileptic potential of vinpocetine and indicate the capability of vinpocetine to prevent the changes in the BAEP waves associated with the hearing loss observed during generalized epilepsy.
Assuntos
Anticonvulsivantes/farmacologia , Córtex Cerebral/fisiopatologia , Epilepsia/fisiopatologia , Audição/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Alcaloides de Vinca/farmacologia , Animais , Córtex Cerebral/efeitos dos fármacos , Convulsivantes/farmacologia , Eletroencefalografia , Epilepsia/induzido quimicamente , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Cobaias , Perda Auditiva/induzido quimicamente , Perda Auditiva/prevenção & controle , Masculino , Pentilenotetrazol/farmacologiaRESUMO
For exploring a possible connection between the reduced hearing sensitivity and certain abnormalities in the auditory brainstem responses (ABRs) in generalized epilepsy, the effects of two convulsing agents, namely pentylenetetrazole (PTZ) and of 4-aminopyridine (4-AP), on: (1). the cortical activity (EEG), (2). the hearing threshold and (3). the amplitudes and latencies of the ABR waves evoked by a stimulus of high intensity (100 dB) were investigated in guinea pigs. All animals injected (i.p.) with 100mg/kg PTZ or with 2mg/kg 4-AP developed generalized seizures, followed by characteristic EEG patterns for the post-ictal period, that were accompanied by a marked reduction of the hearing sensitivity (as indicated by the elevated threshold of the ABR), as well as by retro-cochlear changes (as judged by the changes in the later ABR waves in response to 100 dB). For instance, both convulsing agents decreased the amplitude and increased the latency of P4, that is the wave component of the ABRs generated in the lateral superior olivary nucleus and while PTZ increased the latency of P3, the wave component of the ABRs generated in the medial superior olivary nucleus, 4-AP dramatically increased its amplitude. Comparison of recordings taken at specific times for the duration of the post-ictal period (i.e. within about 1h for PTZ and 2h for 4-AP) reveals that the extent of the changes on the EEG matches with the increase in the auditory threshold and with the extent of the changes on the later waves of the ABR elicited by 100 dB. These data indicate that changes in the activity of the lateral and the medial nuclei of the superior olivary complex (SOC) accompany the hearing loss and the post-ictal epileptic cortical activity.