[Advances in the physiopathology of epileptogenesis: molecular aspects].
OBJECTIVE
We review the molecular basis of epileptogenesis and the new perspectives in the treatment of epilepsy.


METHODS
Epileptogenesis are the molecular and cellular events producing the disordered firing of a subpopulation of neurons resulting in periodic seizures. Epilepsies may be due to genetic and acquired factors. Some idiopathic epilepsies are due to mutant genes coding voltage gated sodium and potassium channels, GABAA receptor chloride channels and nicotinic acetylcholine receptor sodium channels. Genetic defects also produce epilepsy secondary to either neuronal developmental or metabolic abnormalities, and may contribute to acquired epilepsy. Events observed in both animal and human acquired epilepsies are an increase in glutamate levels and NMDA receptor sensitivity, selective lost of pyramidal neurons, mossy fibre sprouting and neosinaptogenesis. There is also a reduction in inhibitory control due to lost of GABAergic interneurons, and a decrease in GABA levels and GABAA receptor sensitivity. Hyperexcitability may be also due to reduction in glial ATPasa activity, increase in astrocytes gap junctions, and decrease in extracellular calcium. Chandelier GABAergic interneuron microlesions and an hyperexcitable thalamus are key in spread of partial seizures. Absences may be caused by cortex hyperexcitability and genetic abnormalities in thalamic voltage gated T calcium channels. Brain stem is key in convulsive seizures. The role of voltage gated potassium, sodium and calcium channels, and GABAergic and glutamatergic neurotransmission in epileptogenesis and treatment of epilepsies are revised. The role of other neurotransmitters and neuromodulators, second messengers, and immediate early genes and neurotrophins are also commented.


CONCLUSIONS
Understanding the molecular basis of epileptogenesis should lead to the rational design of drugs both to prevent the development of epilepsy, and minimize hyperexcitability which may be the result of a genetic or acquired disorder.
Armijo
J A
JA
Servicio de Farmacología Clínica; Hospital Universitario Marqués de Valdecilla. Universidad de Cantabria, Santander, 39008, España. facasj@humv.es
Valdizán
E M
EM
De Las Cuevas
I
I
Cuadrado
A
A
D000818:Animals; D004827:Epilepsy / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D008959:Models, Neurological; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D018079:Receptors, GABA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D007473:Ion Channels; D018377:Neurotransmitter Agents; D018079:Receptors, GABA; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid