jasplakinolide and Seizures

Clasmatodendrosis is an irreversible astroglial degenerative change, which includes extensive swelling and vacuolization of cell bodies and disintegrated and beaded processes. Since alteration in F-actin level influences on the formation of vacuoles/vesicles during exocytosis/endocytosis in astrocytes, we investigated whether F-actin polymerization involves clasmatodendrosis in the rat hippocampus following status epilepticus (SE). In the present study, vacuoles in clasmatodendrotic astrocytes showed LAMP-1 and LC3-II (a marker for autophagy) immunoreactivity. These findings reveal that clasmatodendrosis may be lysosome-derived autophagic astroglial death. Jasplakinolide (an F-actin stabilizer) infusion significantly decreased the size and the number of medium/large-sized vacuoles in each clasmatodendritic astrocyte accompanied by enhancement of phalloidin signals, as compared to vehicle-infusion. In contrast, latrunculin A (an F-actin-depolymerizing agent) infusion increased the size and the number of medium/large-sized vacuoles, which were dissociated adjacent to cell membrane. Therefore, our findings suggest that F-actin stabilization may inhibit lysosome-derived autophagic astroglial death during clasmatodendrosis.

Topics: Actins; Animals; Antineoplastic Agents; Astrocytes; Autophagy; Biomarkers; Bridged Bicyclo Compounds, Heterocyclic; Cell Death; Depsipeptides; Lysosomes; Male; Rats; Rats, Sprague-Dawley; Seizures; Thiazolidines

The molecular basis for developing epilepsy remains under debate. It is hypothesized that increased excitatory synaptic activity might activate the N-methyl-D-aspartate receptor/Ca(2+) transduction pathway, which induces long-lasting plasticity changes leading to recurrent epileptiform discharges. To determine if these effects are caused by disruption of F-actin in the dendritic spines, we have perfused the hippocampus of conscious rats with the F-actin-depolymerizing agent latrunculin Aand the actin filament stabilizer jasplakinolide. Single perfusions of latrunculin Aand jasplakinolide decrease and increase picrotoxin seizure threshold, respectively. Repeated perfusions of both latrunculin Aand jasplakinolide induce epileptic seizures and a long-term increase in neuronal excitability. These results suggest that actin disruption might not be just a consequence but also a possible cause of epileptic seizures. We propose a new experimental model in rats to study the biochemical changes that might lead to chronic seizures and a method for testing new antiepileptic drugs.

Topics: Actins; Animals; Anticonvulsants; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Convulsants; Depsipeptides; Hippocampus; Male; Microdialysis; Picrotoxin; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Seizures; Thiazolidines