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Electroencephalography and behavior patterns during experimental status epilepticus.

ABSTRACT: OBJECTIVE:To characterize the evolution of behavioral and electrographic seizures in an experimental electrical stimulation-based model of status epilepticus (SE) in C57Bl/6 mice, and to relate SE to various outcomes, including death and epileptogenesis. METHODS:SE was induced by continuous hippocampal stimulation and was evaluated by review of electroencephalographic recordings, spectral display, and behavior. RESULTS:Seizures were initially locked to the electrical trains but later became independent of them. Following the end of stimulation, autonomous seizures continued for >5 minutes in 85% of the animals. There was ongoing 2-3-Hz rhythmic, high-amplitude, slow spike-wave discharges (HASDs) associated with purposeless, repetitive, continuously circling and exploratory behavior. There were high-amplitude fast discharges (HAFDs) associated with worsening of behavioral seizures that were interspersed with the ongoing HASDs. Death during SE occurred in 23% of the animals, and it was preceded by a stage 5 behavioral seizure. In the waning stage of SE, severe seizures and HAFDs dissipated, HASDs slowed down, and normal behavior was restored in most animals. Epilepsy developed in 33% of the animals monitored after SE. SIGNIFICANCE:The electrical stimulation model of SE can be used to study mechanisms of SE and its adverse consequences, including death and epileptogenesis.

SUBMITTER: Lewczuk E

PROVIDER: S-EPMC5825005 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Electroencephalography and behavior patterns during experimental status epilepticus.

Lewczuk Ewa E Joshi Suchitra S Williamson John J Penmetsa Mouna M Shan Sarah S Kapur Jaideep J

Epilepsia 20171206 2

<h4>Objective</h4>To characterize the evolution of behavioral and electrographic seizures in an experimental electrical stimulation-based model of status epilepticus (SE) in C57Bl/6 mice, and to relate SE to various outcomes, including death and epileptogenesis.<h4>Methods</h4>SE was induced by continuous hippocampal stimulation and was evaluated by review of electroencephalographic recordings, spectral display, and behavior.<h4>Results</h4>Seizures were initially locked to the electrical trains ...[more]

PMID: 29214651

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Project description:BackgroundStatus epilepticus (SE) is an acute, prolonged epileptic crisis with a mortality rate of 20-30%; the underlying mechanism is not completely understood. We assessed the hypothesis that brain stem cardiovascular dysregulation occurs during SE because of oxidative stress in rostral ventrolateral medulla (RVLM), a key nucleus of the baroreflex loop; to be ameliorated by brain-derived neurotrophic factor (BDNF) via an antioxidant action.Methodology/principal findingsIn a clinically relevant experimental model of temporal lobe SE (TLSE) using Sprague-Dawley rats, sustained hippocampal seizure activity was accompanied by progressive hypotension that was preceded by a reduction in baroreflex-mediated sympathetic vasomotor tone; heart rate and baroreflex-mediated cardiac responses remained unaltered. Biochemical experiments further showed concurrent augmentation of superoxide anion, phosphorylated p47(phox) subunit of NADPH oxidase and mRNA or protein levels of BDNF, tropomyosin receptor kinase B (TrkB), angiotensin AT1 receptor subtype (AT1R), nitric oxide synthase II (NOS II) or peroxynitrite in RVLM. Whereas pretreatment by microinjection bilaterally into RVLM of a superoxide dismutase mimetic (tempol), a specific antagonist of NADPH oxidase (apocynin) or an AT1R antagonist (losartan) blunted significantly the augmented superoxide anion or phosphorylated p47(phox) subunit in RVLM, hypotension and the reduced baroreflex-mediated sympathetic vasomotor tone during experimental TLSE, pretreatment with a recombinant human TrkB-Fc fusion protein or an antisense bdnf oligonucleotide significantly potentiated all those events, alongside peroxynitrite. However, none of the pretreatments affected the insignificant changes in heart rate and baroreflex-mediated cardiac responses.Conclusions/significanceWe conclude that formation of peroxynitrite by a reaction between superoxide anion generated by NADPH oxidase in RVLM on activation by AT1R and NOS II-derived NO leads to a reduction in baroreflex-mediated sympathetic vasomotor tone during experimental TLSE; to be ameliorated by the upregulated BDNF/TrkB signaling via inhibition of p47(phox) phosphorylation. This information offers a new vista in devising therapeutic strategy towards minimizing mortality associated with TLSE.

Project description:Women with epilepsy commonly have premature onset of menopause. The decrease in estrogen levels is associated with increased occurrence of neurodegenerative processes and cognitive decline. Previously, we found that estradiol (E2) replacement in ovariectomized (OVX) female rats significantly reduced the seizure-related damage in the sensitive hilar region of hippocampal dentate gyrus (DG). However, the complex mechanisms by which E2 empowers the genomic fabrics of neurotransmission to resist damaging effects of status epilepticus (SE) are still unclear. We determined the protective effects of the estradiol replacement against kainic acid-induced SE-associated transcriptomic alterations in the DG of OVX rats. Without E2 replacement, SE altered expression of 44% of the DG genes. SE affected all major functional pathways, including apoptosis (61%), Alzheimer's disease (47%), cell cycle (59%), long-term potentiation (62%), and depression (55%), as well as synaptic vesicle cycle (62%), glutamatergic (53%), GABAergic (49%), cholinergic (52%), dopaminergic (55%), and serotonergic (49%) neurotransmission. However, in rats with E2 replacement the percentage of significantly affected genes after SE was reduced to the average 11% (from 8% for apoptosis to 32% for GABAergic synapse). Interestingly, while SE down-regulated most of the synaptic receptor genes in oil-injected females it had little effect on these receptors after E2-replacement. Our novel Pathway Protection analysis indicated that the E2-replacement prevented SE-related damage from 50% for GABA to 75% for dopaminergic transmission. The 15% synergistic expression between genes involved in estrogen signaling (ESG) and neurotransmission explains why low E2 levels result in down-regulation of neurotransmission. Interestingly, in animals with E2-replacement, SE switched 131 synergistically expressed ESG-neurotransmission gene pairs into antagonistically expressed gene pairs. Thus, the ESG pathway acts like a buffer against SE-induced alteration of neurotransmission that may contribute to the E2-mediated maintenance of brain function after the SE injury in postmenopausal women. We also show that the long-term potentiation is lost in OVX rats following SE but not in those with E2 replacement. The electrophysiological findings in OVX female rats with SE are corroborated by the high percentage of long-term potentiation regulated genes (62%) in oil-injected while only 13% of genes were regulated following SE in E2-replaced rats.

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Electroencephalography and behavior patterns during experimental status epilepticus.

Publications

Electroencephalography and behavior patterns during experimental status epilepticus.

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