Ação do brometo de sódio na atividade epileptiforme não-sináptica

• Ano de defesa: 2008
• Autor(a) principal: Carlesso, Fernanda Noal
• Orientador(a): Costa, Jaderson Costa da
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Pontifícia Universidade Católica do Rio Grande do Sul; Porto Alegre
• Palavras-chave em Português: MEDICINA; EPILEPSIA; ANTICONVULSIVOS; ANIMAIS DE LABORATÓRIO; FARMACOLOGIA
• Link de acesso: http://hdl.handle.net/10923/4538

Rationale: Bromide was the first therapeutic option in the treatment of refractory pediatric epilepsies. Despite this fact the pharmacological activity of bromides has not been profusely investigated and remains without a complete elucidation. The mechanism of action proposed suggests GABAergic activation. Bromides share ionic kinetics with chlorides. However, its activity on nonsynaptic mechanisms has not been studied yet. Purpose: This study aims to verify the effect of NaBr on epileptiform activity (EA) induced by suppression of nonsynaptic connections through perfusion with 0- Ca++ and high K+ artificial cerebrospinal fluid (ACSF). Methods and Results: The study involved experimental measures and simulation. Experiments were taken on hippocampal slices from Wistar rats (4 to 6 weeks old). The studied groups were NaBr (n=23), SITS (n=3), and control (n=3). After EA induction with 0- Ca++ and high K+ (8 mM) ACSF, Br- was applied by perfusion. We replaced choride for bromide in the following concentrations: NaCl 5, 7, 9 and 11 mM for NaBr 5, 7, 9 and 11 mM. SITS was also perfused (time: 20min). Br- reversely suppressed EA in the dentate gyrus (DG). Before full EA suppression, we observed the following changes in the extracellular field potentials (FP): (i) decrease of DC amplitude; (ii) transitory increase of population spikes amplitudes, followed by reduction until full suppression; (iii) decrease of event duration and inter-event interval. Simultaneously, we recorded the intrinsic optical signal (IOS). In accordance to FP recordings we observed decrease of event duration and inter-event interval. SITS response was similar to the NaBr one. IOS suggests partition in the region compreheding the events, pointing a reduction in spatial recruitment with NaBr. Simulations were based on mathematical modeling of subcellular and electrochemical mechanisms of neurons (sodium-potassium pump, ion channels, gap junctions, co-transporters, electrodiffusion, field effect and volume variation), comprehending a net of granular and glial cells connected to extracellular net. Reproduction of space-time behavior during blockade was possible with the assumption of competitive effect between Br- and Cl-, either in channels or contransports. Conclusion: NaBr at 9 mM is the minimum required concentration for full blockade of EA, with minimum extinction time. Computational simulations suggest two explanations for the inhibitory effect of NaBr on EA: (i) Br- competing with Cl-, decreasing permeability of the latter, which reduces efflux and influx during interical and ictal periods, respectively; (ii) Br- Nernst potential, that has inhibitory effects, favoring reduction in excitability. Possible involvement of voltage-dependent Cl- channels (FP and IOS recordings similar for NaBr and SITS).