latrunculin-a and Epilepsy

Latrunculin A microperfusion in rat hippocampus has shown to be an effective model of acute and chronic seizures for neurochemical studies. The intervention over early synaptic plasticity changes after the epileptogenesis onset represents a big challenge on the design of a suitable therapy to impair the epilepsy development. We previously suggested that receptor location might be essential for controlling neuronal excitability, and that disruption of local cytoskeletal dynamics followed by drastic changes in the synaptic/extrasynaptic ratio of NMDA, AMPA receptors and their subsequent downstream signalling may play an important role in the pathogenesis of seizures. In the present study, we performed a pharmacological intervention in the Latrunculin model by using Ascomicin (ASC) and Phenytoin (PHT). We pointed out the inhibitory action of ASC over the protein phosphatase 2B (PP2B). PP2B pathological mechanism involves changes in actin cytoskeleton and showed to avoid those subsequent changes previously observed in PSD components. On the contrary, PHT didn't seem to modify the F-actin depolymerization process induced, showing a similar redistribution pattern from the PSD towards the extrasynaptic site of several molecular components with more or less dependence on actin for their location, including glutamate receptors. Overall, we propose that the early intervention over changes on the synapse during the epileptogenic process might represent the best approach to avoid the onset of chronic refractory seizures our model. On this regard, the therapeutic potential of ASC, FK506 and derivatives should be further explored as a possible tool in the intervention over epilepsy and other brain diseases.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Calcineurin Inhibitors; Epilepsy; Hippocampus; Infusion Pumps; Male; Microdialysis; Rats; Rats, Sprague-Dawley; Tacrolimus; Thiazolidines

Changes in the membrane distribution of N-methyl-D-aspartate (NMDA) glutamate receptors seem to produce dramatic modifications in neuronal excitability and other properties of the neuron. In order to determine in vivo if these effects are due to the binding of extracellular glutamate and glycine to NMDA extrasynaptic receptors, we perfused the hippocampus of freely moving rats with the actin depolymerizant agent latrunculin A (4 microM) through microdialysis probes. One month later, continuous microperfusion of glutamate (1 mM) or glycine (1 mM) was used to induce epileptic seizures in the animals pretreated with latrunculin A. Glutamate microperfusion induced seizures in 50% of the animals studied, and glycine induced seizures in 75% of the rats. However, no effect was observed on control rats, or on those animals previously treated with picrotoxin. Simultaneous microperfusion of 100 microM MK-801 significantly reduced the number and duration of seizures induced by both glutamate and glycine. This study demonstrates that the application of latrunculin A results in long-term changes in susceptibility to the epileptogenic action of glutamate and glycine.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Dizocilpine Maleate; Drug Interactions; Epilepsy; Excitatory Amino Acid Antagonists; Glutamic Acid; Glycine; Hippocampus; Male; Microdialysis; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Thiazoles; Thiazolidines