Effects of Dexamethasone on Remodeling of the Hippocampal Synaptic Filamentous Actin Cytoskeleton in a Model of Pilocarpine-induced Status Epilepticus

Abstract

The filamentous actin (F-actin) cytoskeleton is progressively damaged after status epilepticus (SE), which is related to delayed neuronal death, aberrant recurrent circuits and epileptogenesis. Glucocorticoids regulate dendritic spine remodeling by acting on glucocorticoid receptors and the dynamics of the F-actin cytoskeleton. Our previous study showed that administration of dexamethasone (DEX) in the latent period of the pilocarpine epileptic model reduces damage to the hippocampal filamentous actin cytoskeleton and the loss of hippocampal neurons and aids in maintaining the synaptic structures, but it is not sufficient to stop epileptogenesis. In this work, we focused on the role of glucocorticoids in regulating the hippocampal F-actin cytoskeleton during SE. We examined the abundance of synaptic F-actin, analyzed the hippocampal F-actin/G-actin (F/G) ratio and pCofilin, and evaluated the number of hippocampal neurons and pre/postsynaptic markers in pilocarpine-induced status epilepticus mice with or without administration of dexamethasone (DEX). We found that the latency of Stage 3 seizures increased, the mortality decreased, the damage to the synaptic F-actin cytoskeleton in the hippocampal subfields was significantly attenuated, and a greater number of postsynaptic structures were retained in the hippocampal subfields after treatment with DEX. These results indicate that treatment with dexamethasone stabilizes the synaptic F-actin cytoskeleton and reduces the damage to the brain due to SE. This approach is expected to be beneficial in alleviating delayed neuron damage and the process of epileptogenesis.

Hippocampal glucocorticoid receptors modulate status epilepticus severity

“…Supporting a pro-convulsant role, adrenalectomy reduces susceptibility to kainic acid-induced seizures, while exogenous CORT and dexamethasone (a GR agonist) increase susceptibility ( Lee et al, 1989 ; Talmi et al, 1995 ; Roberts and Keith, 1995 ; O’toole et al, 2014 ). Other studies, however, support an anti-convulsant role, with glucocorticoid treatment reducing the severity of seizures induced by chemoconvulsants ( Yang et al, 2020 ; Marchi et al, 2011 ). Moreover, several investigators report no effect of manipulating glucocorticoid levels on seizure severity following chemoconvulsant challenge ( Benkovic et al, 2009 ; Garcia-Garcia et al, 2017 ; Stein and Sapolsky, 1988 ).…”

Parameters of Oxidative Stress and Behavior in Animals Treated with Dexametasone and Submitted to Pentylenetetrazol Kindling

“…There was a reduction in the latency time for the beginning of seizure demonstrating the possible anticonvulsant effect of DEXA on the animal model of pilocarpine. 19 …”

The rearrangement of actin cytoskeleton in mossy fiber synapses in a model of experimental febrile seizures

“…As described previously ( 16 , 25 ), hippocampal neurons in subfields dentate gyrus (DG), CA3 and CA1 were labeled by anti-NeuN antibody. Slices were pretreated with 10% normal donkey serum containing 0.3% Triton X-100 at room temperature for 30 min and then were treated with monoclonal anti-NeuN antibody (ab177487, Abcam, United States; 1:100) at 4°C overnight.…”