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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.

SUBMITTER: Perez-Ramirez MB

PROVIDER: S-EPMC8083016 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Status epilepticus (SE) is a life-threatening emergency that can result in de novo development or worsening of epilepsy. We tested the hypothesis that the aberrant cortical output during neocortical focal status epilepticus (FSE) would induce structural and functional changes in the thalamus that might contribute to hyperexcitability in the thalamocortical circuit. We induced neocortical FSE by unilateral epidural application of convulsant drugs to the somatosensory cortex of anesthetized mice of both sexes. The resulting focal EEG ictal episodes were associated with behavioral seizures consisting of contralateral focal myoclonic activity and persisted for 2-3 h. Ten and 30 days later, brains were processed for either immunohistochemistry (IHC) or in vitro slice recordings. Sections from the center of the thalamic reticular nucleus (nRT, see methods), the ventral posterolateral nucleus (VPL), and the ventral posteromedial nucleus (VPM) from the ventrobasal nucleus (VB) were used to measure density of NeuN-immunoreactive neurons, GFAP-reactive astrocytes, and colocalized areas for VGLUT1 + PSD95- and VGLUT2 + PSD95-IR, presumptive excitatory synapses of cortical and thalamic origins. Whole-cell voltage-clamp recordings were used to measure spontaneous EPSC frequency in these nuclei. We found that the nRT showed no decrease in numbers of neurons or evidence of reactive astrogliosis. In contrast, there were increases in GFAP-IR and decreased neuronal counts of NeuN positive cells in VB. Dual IHC for VGLUT1-PSD95 and VGLUT2-PSD95 in VB showed increased numbers of excitatory synapses, likely of both thalamic and cortical origins. The frequency, but not the amplitude of sEPSCs was increased in nRT and VB neurons. SIGNIFICANCE STATEMENT: Previous reports have shown that prolonged neocortical seizures can induce injury to downstream targets that might contribute to long-term consequences of FSE. Effects of FSE in thalamic structures may disrupt normal thalamo-cortical network functions and contribute to behavioral abnormalities and post-SE epileptogenesis. Our results show that a single episode of focal neocortical SE in vivo has chronic consequences including cell loss in VB nuclei and increased excitatory connectivity in intra-thalamic and cortico-thalamic networks. Additional experiments will assess the functional consequences of these alterations and approaches to mitigate cell loss and alterations in synaptic connectivity.

Project description:Acute intoxication with tetramethylenedisulfotetramine (TETS) can trigger status epilepticus (SE) in humans. Survivors often exhibit long-term neurological effects, including electrographic abnormalities and cognitive deficits, but the pathogenic mechanisms linking the acute toxic effects of TETS to chronic outcomes are not known. Here, we use advanced in vivo imaging techniques to longitudinally monitor the neuropathological consequences of TETS-induced SE in two different mouse strains. Adult male NIH Swiss and C57BL/6J mice were injected with riluzole (10 mg/kg, i.p.), followed 10 min later by an acute dose of TETS (0.2 mg/kg in NIH Swiss; 0.3 mg/kg, i.p. in C57BL/6J) or an equal volume of vehicle (10% DMSO in 0.9% sterile saline). Different TETS doses were administered to trigger comparable seizure behavior between strains. Seizure behavior began within minutes of TETS exposure and rapidly progressed to SE that was terminated after 40 min by administration of midazolam (1.8 mg/kg, i.m.). The brains of vehicle and TETS-exposed mice were imaged using in vivo magnetic resonance (MR) and translocator protein (TSPO) positron emission tomography (PET) at 1, 3, 7, and 14 days post-exposure to monitor brain injury and neuroinflammation, respectively. When the brain scans of TETS mice were compared to those of vehicle controls, subtle and transient neuropathology was observed in both mouse strains, but more extensive and persistent TETS-induced neuropathology was observed in C57BL/6J mice. In addition, one NIH Swiss TETS mouse that did not respond to the midazolam therapy, but remained in SE for more than 2 h, displayed robust neuropathology as determined by in vivo imaging and confirmed by FluoroJade C staining and IBA-1 immunohistochemistry as readouts of neurodegeneration and neuroinflammation, respectively. These findings demonstrate that the extent of injury observed in the mouse brain after TETS-induced SE varied according to strain, dose of TETS and/or the duration of SE. These observations suggest that TETS-intoxicated humans who do not respond to antiseizure medication are at increased risk for brain injury.

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

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