Prolonged prophylactic effects of gabapentin on status epilepticus-induced neocortical injury

Abstract

Long-term consequences of status epilepticus (SE) occur in a significant proportion of those who survive the acute episode. We developed an in vivo model of acute focal neocortical SE (FSE) to study long-term effects on local cortical structure and function and potential strategies to mitigate adverse consequences of SE. An acute 2 h episode of FSE was induced in anesthetized mice by epidural application of gabazine +4-aminopyridine over sensorimotor neocortex. Ten and 30 days later, the morphological and functional consequences of this single episode of FSE were studied using immunocytochemical and electrophysiological techniques. Results, focused on cortical layer V, showed astrogliosis, microgliosis, decreased neuronal density, and increased excitatory synapses, along with increased immunoreactivity for thrombospondin 2 (TSP2) and α2δ-1 proteins. In addition, neocortical slices, obtained from the area of prior focal seizure activity, showed abnormal epileptiform burst discharges along with increases in the frequency of miniature and spontaneous excitatory postsynaptic currents in layer V pyramidal cells, together with decreases in both parvalbumin immunoreactivity (PV-IR) and the frequency of miniature inhibitory postsynaptic currents in layer V pyramidal cells. Treatment with an approved drug, gabapentin (GBP) (ip 100 mg/kg/day 3 × /day for 7 days following the FSE episode), prevented the gliosis, the enhanced TSP2- and α2δ-1- IR and the increased excitatory synaptic density in the affected neocortex. This model provides an approach for assessing adverse effects of FSE on neocortical structure and function and potential prophylactic treatments.

Structural and functional abnormalities in thalamic neurons following neocortical focal status epilepticus

“…Previous results showed that there was an increase in activated astrocytes in cortical layer V of the epileptogenic area 10 and 30 days after FSE ( Perez-Ramirez et al, 2020 ). In the present study, we tested the hypothesis that astrogliosis would also be induced by FSE in downstream thalamic targets at these same time points.…”

“…FSE In neocortex results in increased frequency of mEPSCs and sEPSC onto layer V pyramidal cells, and IHC evidence of increased putative excitatory synapses ( Perez-Ramirez et al, 2020 ).To test whether FSE also increases the density of excitatory synapses of cortical origin in nRT, VPM, and VPL, we measured close appositions of presynaptic and postsynaptic markers VGLUT1 - PSD95-IR (putative excitatory synapses of cortical origin ( Fremeau Jr. et al, 2004 ). Ten days after the FSE, the percentage of the colocalization area between VGLUT1- and PSD95-IR per ROI was increased in each nucleus (yellow puncta in white circles in Fig.…”

“…Focal SE was induced as previously described ( Perez-Ramirez et al, 2020 ). Adult male and female mice (FVB/NJ Jax; P 80–120) were anesthetized (Ketamine/Xylazine 80/8 mg/kg), a small unilateral cranial opening (~2 mm) was made, and a gel foam pledget moistened with GABAzine (150 μM) and 4-aminopyridine (4AP, 150 μM) applied to the intact dura over the right sensorimotor cortex.…”

“…FSE in neocortex of mice results in activation of astrocytes and synaptogenic proteins, neuronal loss, increases in functional excitatory synaptic connectivity, hyperexcitability in neocortical networks in vitro, and loss of parvalbumin neurons in the area of convulsant drug application ( Perez-Ramirez et al, 2020 ). Previous reports have shown that prolonged neocortical seizures in rats can induce injury in downstream targets, such as the thalamus ( Collins and Olney, 1982 ), that might contribute to long-term consequences of FSE.…”

Pharmacological perspectives and mechanisms involved in epileptogenesis

“…Gabapentin and pregabalin showed antiepileptogenic effects in several models [51], mainly by decreasing exaggerated excitatory activity. In a kainate-induced SE model, gabapentin demonstrated a neuroprotective effect and inhibited epileptic [52].…”