Febrile seizures and mechanisms of epileptogenesis: insights from an animal model.

Temporal lobe epilepsy (TLE) is the most prevalent type of human epilepsy, yet the causes for its development, and the processes involved, are not known. Most individuals with TLE do not have a family history, suggesting that this limbic epilepsy is a consequence of acquired rather than genetic causes. Among suspected etiologies, febrile seizures have frequently been cited. This is due to the fact that retrospective analyses of adults with TLE have demonstrated a high prevalence (20-->60%) of a history of prolonged febrile seizures during early childhood, suggesting an etiological role for these seizures in the development of TLE. Specifically, neuronal damage induced by febrile seizures has been suggested as a mechanism for the development of mesial temporal sclerosis, the pathological hallmark of TLE. However, the statistical correlation between febrile seizures and TLE does not necessarily indicate a causal relationship. For example, preexisting (genetic or acquired) 'causes' that result independently in febrile seizures and in TLE would also result in tight statistical correlation. For obvious reasons, complex febrile seizures cannot be induced in the human, and studies of their mechanisms and of their consequences on brain molecules and circuits are severely limited. Therefore, an animal model was designed to study these seizures. The model reproduces the fundamental key elements of the human condition: the age specificity, the physiological temperatures seen in fevers of children, the length of the seizures and their lack of immediate morbidity. Neuroanatomical, molecular and functional methods have been used in this model to determine the consequences of prolonged febrile seizures on the survival and integrity of neurons, and on hyperexcitability in the hippocampal-limbic network. Experimental prolonged febrile seizures did not lead to death of any of the seizure-vulnerable populations in hippocampus, and the rate of neurogenesis was also unchanged. Neuronal function was altered sufficiently to promote synaptic reorganization of granule cells, and transient and long-term alterations in the expression of specific genes were observed. The contribution of these consequences of febrile seizures to the epileptogenic process is discussed

EFFECTS of MORPHINE and NALOXONE ON PILOCARPINE-INDUCED CONVULSIONS in RATS

ESCOLA PAULISTA MED,EXPTL NEUROL LAB,BR-04023 São Paulo,SP,BRAZILESCOLA PAULISTA MED,EXPTL NEUROL LAB,BR-04023 São Paulo,SP,BRAZILESCOLA PAULISTA MED,EXPTL NEUROL LAB,BR-04023 São Paulo,SP,BRAZILWeb of Scienc

REVIEW - CHOLINERGIC MECHANISMS and EPILEPTOGENESIS - the SEIZURES INDUCED BY PILOCARPINE - A NOVEL EXPERIMENTAL-MODEL of INTRACTABLE EPILEPSY

MED SCH LUBLIN,DEPT PHARMACOL,PL-20090 LUBLIN,POLANDESCOLA PAULISTA MED,DEPT NEUROL & NEUROSURG,EXPTL NEUROL LAB,BR-04023 São Paulo,SP,BRAZILESCOLA PAULISTA MED,DEPT NEUROL & NEUROSURG,EXPTL NEUROL LAB,BR-04023 São Paulo,SP,BRAZILWeb of Scienc

EFFECTS of AMINOPHYLLINE and 2-CHLOROADENOSINE ON SEIZURES PRODUCED BY PILOCARPINE in RATS - MORPHOLOGICAL and ELECTROENCEPHALOGRAPHIC CORRELATES

ESCOLA PAULISTA MED,DEPT NEUROL & NEUROSURG,EXPTL NEUROL LAB,BR-04023 São Paulo,SP,BRAZILESCOLA PAULISTA MED,DEPT NEUROL & NEUROSURG,EXPTL NEUROL LAB,BR-04023 São Paulo,SP,BRAZILWeb of Scienc

Paradoxical anticonvulsant activity of the excitatory amino acid N-methyl-D-aspartate in the rat caudate-putamen.

We used limbic seizures induced in rats by systemic injection of the cholinergic agonist pilocarpine (380 mg/kg; i.p.) to study the neuronal pathways within the basal ganglia that modulate seizure threshold. N-Methyl-D-aspartate (N-Me-D-Asp) is an excitatory amino acid derivative that is a powerful convulsant agent when injected into the cerebral cortex, amygdala, or hippocampus in rats. Bilateral microinjections of N-Me-D-Asp into the caudate-putamen, however, protected against limbic seizures induced by pilocarpine (injected systemically), with an ED50 of 0.7 nmol (range 0.5-1.0 nmol). Lesioning the caudate-putamen (by bilateral microinjection of the excitotoxin ibotenate) converted subconvulsant doses of pilocarpine into convulsant ones. The anticonvulsant action of N-Me-D-Asp in the caudate-putamen was reversed by blocking gamma-aminobutyrate-mediated inhibition in the substantia nigra pars reticulata or in the entopeduncular nucleus. The results suggest that the caudate-putamen and its gamma-aminobutyrate-dependent efferent pathways modulate the threshold for seizures in the limbic forebrain