CoordenaÃÃo de AperfeiÃoamento de NÃvel Superior / Epilepsy is the most common neurological disorder, affecting 50 million people worldwide, 40 million of them in developed countries. People of all races, genders, socioeconomic conditions and regions are affected. The pilocarpine (P400) is a cholinergic agonist characterized by inducing seizures evolving to status epilepticus, similar to human temporal lobe epilepsy. The pentylenetetrazole (PTZ) is a GABA antagonist that mimics the small-mal seizures (absence seizure) and tonic-clonic seizures in humans. The strychnine is a potent convulsant and acts mainly as a selective antagonist of postsynaptic inhibition mediated by glycine. Its main action is to increase the excitability of the spinal reflex . The convulsant picrotoxin is an agent that blocks chloride channels activated by gamma-aminobutyric acid. Convulsant agents were administered intraperitoneally, 10 minutes after intravenous administration of carbapenÃmcios With the development of this work, we found that pretreatment with imipenem or meropenem interfere with various neurotransmitter systems when animals are subjected to seizures induced by pilocarpine at a dose of 400mg/kg, 55mg/Kg at a dose of pentylenetetrazole, strychnine and picrotoxin 10mg/Kg 2mg/kg. This has been evidenced by increasing levels of excitatory amino acids such as glutamate and on the other hand, a decrease in levels of inhibitory amino acids such as GABA reinforcing the existence of a possible modulatory pathway of these amino acids in control and development of seizure occurs when pre-treatment with imipenem or meropenem. / Epilepsia à o mais freqÃente distÃrbio neurolÃgico, atingindo 50 milhÃes de pessoas no mundo, 40 milhÃes delas em paÃses desenvolvidos. Pessoas de todas as raÃas, sexos, condiÃÃes socioeconÃmicas e regiÃes sÃo acometidas. A pilocarpina (P400) à um agonista colinÃrgico que se caracteriza por induzir convulsÃes que evoluem para status epilÃpticus, similar à epilepsia do lobo temporal humana. O pentilenotetrazol (PTZ) à um antagonista GABA que mimetiza convulsÃes do pequeno-mal (crise de ausÃncia) e do tipo tÃnico-clÃnico em humanos. A estricnina à um potente convulsivante e atua, principalmente, como antagonista competitivo seletivo da inibiÃÃo pÃs-sinÃptica mediada pela glicina. Sua principal aÃÃo à o aumento da excitabilidade reflexa da medula. A picrotoxina à um agente convulsivante que bloqueia os canais de cloro ativados pelo Ãcido gama-aminobutÃrico. Os agentes convulsivantes foram administrados intraperitonialmente, apÃs 10 minutos da administraÃÃo intravenosa dos carbapenÃmcios Com o desenvolvimento deste trabalho, podemos observar que o prÃ-tratamento com imipenem ou meropenem interfere com vÃrios sistemas de neurotransmissores quando os animais sÃo submetidos à convulsÃo induzida pela pilocarpina na dose de 400mg/kg, pentilenotetrazol na dose de 55mg/Kg, estricnina 2mg/Kg e picrotoxina 10mg/Kg. Tal efeito foi evidenciado atravÃs do aumento nos nÃveis de aminoÃcidos excitatÃrios como o glutamato e, por outro lado, uma diminuiÃÃo nos nÃveis de aminoÃcidos inibitÃrios como o GABA reforÃando a existÃncia de uma possÃvel via modulatÃria desses aminoÃcidos no controle e desenvolvimento de crises epilÃpticas quando ocorre o prÃ-tratamento com imipenem/cilastatina ou meropenem.

The neurotoxic potential of intravenous administered benzylpenicillin (BPC) was studied in rabbits with intact blood-CNS barriers and rabbits with experimental E. coli meningitis. At onset of epileptogenic EEG activity or seizures, serum, CSF and brain tissue were collected for assay of BPC. Based on the fact that, in tissues, BPC seems to remain extracellularly, brain concentrations of BPC were expressed as brain tissue fluid (BTF) levels, calculated as lOx the concentration in whole brain tissue. Neurotoxicity could be precipitated in all rabbits. In normal rabbits BTF levels of BPC were considerably higher than those in CSF indicating a better penetration across the blood-brain barrier (BBB). BPC penetrated better to CSF and BTF in meningitic rabbits than in normal controls, suggesting some degree of damage of the BBB concomitant with meningeal inflammation. E. coli meningitis did not increase the neurotoxicity of BPC. In control rabbits the intracistemal injection of saline resulted in some degree of pleocytosis. Unmanipulated animals are therefore preferable as controls. Epileptogenic EEG-changes was the most precise of the two variables used for demonstration of neurotoxicity. EEG-changes were therefore used as neurotoxicity criterion in the following rabbit experiments. To evaluate the effect of uraemia alone and uraemia plus meningitis on the neurotoxity of BPC in rabbits, cephaloridine was used to induce uraemia. Meningitis was induced by intracistemal inoculation of a cephalosporinresistant strain of E. cloacae. Untreated  rabbits were used as controls. Uraemia resulted in increased BTF penetration of BPC, possibly explained by permeability changes in the BBB and/or decreased binding of BPC to albumin. Uraemia did not result in increased penetration of BPC into the CSF of non-meningitic rabbits. Uraemic non-meningitic rabbits had the highest BTF levels of BPC at the criterion, indicating that cephaloridine-induced renal failure increased the epileptogenic threshold in these rabbits. The combination of uraemia and meningitis increased the neurotoxicity of BPC since the criterion was reached at considerably lower BTF levels of BPC. Meningitis, either alone or together with uraemia, did not increase the neurotoxicity in comparison to control rabbits. Higher BTF levels of BPC were found in meningitic rabbits than in controls with intact blood-CNS barriers at onset of EEG-changes. In all groups of rabbits there was a pronounced variability of BPC levels in the CSF while the intra-group variations in BTF levels were much smaller. Thus, BTF and not CSF levels were decisive for the neurotoxicity of BPC. Using   the same EEG-model, the neurotoxic potential of imipenem/cilastatin (I) and a new penem derivative, FCE 22101 were compared in a cross-over study. Both I and FCE 22101 were significantly more neurotoxic than BPC. While BTF levels of the three antibiotics could be detected in all tested rabbits, detectable CSF levels were only found in one of twelve rabbits treated with I or FCE 22101, indicating that BTF concentrations rather than CSF ones are decisive for neurotoxicity of ß-lactam antibiotics. The EEG-model used was found to be a suitable model for cross-over studies of intravenously administered antibiotics. Using the "silent-second" as EEG-threshold, a CNS interaction between intraperitoneally administered BPC and intravenous thiopental was demonstrated in rats. The most probably site for this interaction is the organic acid transport system out of the CNS. Thiopental distribution in the rat brain seemed to depend not only on its lipid solubility. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 1988, härtill 5 uppsatser.</p> / digitalisering@umu