Different microRNA profiles in chronic epilepsy versus acute seizure mouse models.
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ABSTRACT:
SUBMITTER: Kretschmann A
PROVIDER: S-EPMC4303710 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Redox modulation and S-nitrosylation of cysteine residues are the post-translational modifications of N-methyl-D-aspartate receptor (NMDAR) to regulate its functionality. Recently, we have reported that protein disulfide isomerase (PDI) reduces disulfide bond (S-S) to free thiol (-SH) on NMDAR. Since PDI is a modulator of S-nitrosylation on various proteins, it is noteworthy whether PDI affects S-nitrosylation of NMDAR in acute seizure and chronic epilepsy models. In the present study, we found that acute seizures in response to pilocarpine and spontaneous seizures in chronic epilepsy rats led to the reduction in S-nitrosylated thiol (SNO-thiol)-to-total thiol ratio on NMDAR, while they elevated nitric oxide (NO) level and S-nitrosylation on NMDAR. N-nitro-L-arginine methyl ester (L-NAME, a non-selective NOS inhibitor) did not affect seizure activities in both models, although it decreased SNO-thiol levels on NMDAR. However, PDI knockdown effectively inhibited pilocarpine-induced acute seizures and spontaneous seizures in chronic epilepsy rats, accompanied by increasing the SNO-thiol-to-total thiol ratio on NMDAR due to diminishing the amounts of total thiols on GluN1 and GluN2A. Therefore, these findings indicate that PDI may not be a NO donor or a denitrosylase for NMDAR, and that PDI knockdown may inhibit seizure activity by the S-nitrosylation-independent thiolation on NMDAR.
| S-EPMC6261974 | biostudies-literature
Project description:Epilepsy is not well controlled by current anti-seizure drugs (ASDs). High mobility group box 1 (HMGB1) is a DNA-binding protein in the nucleus regulating transcriptional activity and maintaining chromatin structure and DNA repair. In epileptic brains, HMGB1 is released by activated glia and neurons, interacting with various receptors like Toll-like receptor 4 (TLR4) and downstream glutamatergic NMDA receptor, thus enhancing neural excitability. But there is a lack of small-molecule drugs targeting the HMGB1-related pathways. In this study we evaluated the therapeutic potential of inflachromene (ICM), an HMGB-targeting small-molecule inhibitor, in mouse epilepsy models. Pentylenetetrazol-, kainic acid- and kindling-induced epilepsy models were established in mice. The mice were pre-treated with ICM (3, 10 mg/kg, i.p.). We showed that ICM pretreatment significantly reduced the severity of epileptic seizures in all the three epilepsy models. ICM (10 mg/kg) exerted the most apparent anti-seizure effect in kainic acid-induced epileptic status (SE) model. By immunohistochemical analysis of brain sections from kainic acid-induced SE mice, we found that kainic acid greatly enhanced HMGB1 translocation in the hippocampus, which was attenuated by ICM pretreatment in subregion- and cell type-dependent manners. Notably, in CA1 region, the seizure focus, ICM pretreatment mainly inhibited HMGB1 translocation in microglia. Furthermore, the anti-seizure effect of ICM was related to HMGB1 targeting, as pre-injection of anti-HMGB1 monoclonal antibody (5 mg/kg, i.p.) blocked the seizure-suppressing effect of ICM in kainic acid-induced SE model. In addition, ICM pretreatment significantly alleviated pyramidal neuronal loss and granule cell dispersion in kainic acid-induced SE model. These results demonstrate that ICM is an HMGB-targeting small molecule with anti-seizure potential, which may help develop a potential drug for treating epilepsy.
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Project description:PurposeAcute symptomatic seizures (ASyS) are common in critically ill patients. It is unknown how ASyS affect posthospitalization self-reported health compared to patients with established epilepsy.MethodsThis is a retrospective cohort study from 2010 to 2018. Patients were identified by an institutional epilepsy database (Ebase). Patient-reported outcome measures (PROMs) were completed as part of standard of care and included the number of seizures in the prior 4 weeks, Liverpool Seizure Severity Scale (LSSS) ictal score, quality of life in epilepsy (QOLIE)-10, Patient Health Questionnaire-9 scales, and the PROM Information System Global Health (PROMIS-GH) scale. Mixed-effects models were created to adjust for age, sex, and race and to examine score trajectory over the 1 year after baseline.ResultsA total of 15 311 established epilepsy patients and 317 patients with ASyS were identified. When compared to patients with epilepsy, patients with ASyS were older, mostly male, more often black, and had worse baseline scores on the QOLIE-10 (P < .001), PROMIS-GH Physical Health (P = .037), and LSSS Ictal (P = .006) scales. Patient-Reported Outcomes Measurement Information System Mental and Physical Health T-scores were worse than the general population (T-score = 50) for patients with both ASyS (44 and 42.5, respectively) and epilepsy (44.2 and 44.6, respectively). After adjusting for age, sex, and race, patients with ASyS reported 38% fewer seizures (P = .006) yet worse QOLIE-10 score (P = .034). We found that scores improved over time for all PROMs except for PROMIS-GH Mental Health.ConclusionCompared to patients with epilepsy, patients with ASyS had fewer seizures but worse epilepsy-specific quality of life. Independent of group status, scores generally improved over time.
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Project description:ObjectiveCortical excitability differs between treatment responders and nonresponders in new-onset epilepsy. Moreover, during the first 3 years of epilepsy, cortical excitability becomes more abnormal in nonresponders but normalizes in responders. Here, we study chronic active epilepsy, to examine whether cortical excitability continues to evolve over time, in association with epilepsy duration and treatment response.MethodsWe studied 28 normal subjects, 28 patients with moderately controlled epilepsy (≤4 seizures per year) and 40 patients with poorly controlled epilepsy (≥20 or more seizures per year). Resting motor threshold (RMT), active motor threshold (AMT), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF) and cortical silent period (CSP) were measured, using transcranial magnetic stimulation (TMS). Disease and treatment covariates were collected (age at onset of epilepsy, epilepsy duration, number of drugs prescribed, total drug load, sodium channel drug load).ResultsRMT and AMT were higher in patients than in normal subjects; RMT and AMT were higher in poorly controlled than moderately controlled patients. ICF at 12 msec and 15 msec were lower in poorly controlled patients than in normal subjects. Long-interval intracortical inhibition (LICI) at 50 msec was higher in poorly controlled compared to moderately controlled patients. These differences were not explained by antiepileptic drug (AED) treatment or duration of epilepsy. RMT and AMT increased with duration in the poorly controlled group, but did not increase with duration in the moderately controlled group.InterpretationCortical excitability differs markedly between moderately controlled and poorly controlled patients with chronic epilepsy, not explained by disease or treatment variables. Moreover, the evolution of cortical excitability over time differs, becoming more abnormal in the poorly controlled group.
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Project description:MicroRNA (miRNA) is believed to play a crucial role in the cause and treatment of epilepsy by controlling gene expression. However, it is still unclear how miRNA profiles change after multiple prolonged seizures and aggravation of brain injury in chronic epilepsy (CE). To investigate the role of miRNA in epilepsy, we utilized the CE rat models with pentylenetetrazol (PTZ) and miRNA profiles in the hippocampus. miRNA profiles were characterized using miRNA microarray analysis and were compared with the rats in the sham group, which received 0.9% physiological saline treatment at the same dose. Four up-regulated miRNAs (miR-139-3p, -770-5p, -127-5p, -331-3p) and 5 down-regulated miRNAs (miR-802-5p, -380-5p, -183-5p, -547-5p, -344a/-344a-5p) were found in the CE rats (fold change >1.5, P<0.05). Three of the dysregulated miRNAs were validated by quantitative real-time polymerase chain reaction, which revealed an outcome consistent with the initial results of the miRNA microarray analyses. Then, miR-344a agomir was intracerebroventricularly injected and followed by PTZ induction of CE models to investigate the effect of miR-344a in chronic neocortical epileptogenesis. After miRNA-344a agomir and scramble treatment, results showed a restoration of seizure behavior and a reduction in neuron damage in the cortex in miRNA-334a agomir treated rats. These data suggest that miRNA-344a might have a small modulatory effect on seizure-induced apoptosis signaling pathways in the cortex.
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Project description:Epilepsy is often associated with altered expression or function of ion channels. One example of such a channelopathy is the reduction of A-type potassium currents in the hippocampal CA1 region. The underlying mechanisms of reduced A-type channel function in epilepsy are unclear. Here, we show that inhibiting a single microRNA, miR-324-5p, which targets the pore-forming A-type potassium channel subunit Kv4.2, selectively increased A-type potassium currents in hippocampal CA1 pyramidal neurons in mice. Resting membrane potential, input resistance and other potassium currents were not altered. In a mouse model of acquired chronic epilepsy, inhibition of miR-324-5p reduced the frequency of spontaneous seizures and interictal epileptiform spikes supporting the physiological relevance of miR-324-5p-mediated control of A-type currents in regulating neuronal excitability. Mechanistic analyses demonstrated that microRNA-induced silencing of Kv4.2 mRNA is increased in epileptic mice leading to reduced Kv4.2 protein levels, which is mitigated by miR-324-5p inhibition. By contrast, other targets of miR-324-5p were unchanged. These results suggest a selective miR-324-5p-dependent mechanism in epilepsy regulating potassium channel function, hyperexcitability and seizures.
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Project description:The expression and functions of microRNAs (miRNAs) in chronic temporal lobe epilepsy (TLE), the most common type of refractory epilepsy in adults, are poorly understood currently. In this study, status epilepticus evoked by amygdala stimulation was used to establish rat chronic TLE model. Two months later, high-throughput sequencing was employed to investigate miRNA expression profile in rat hippocampus, and six miRNAs were confirmed to be differentially expressed. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that most of the target genes for these six miRNAs were associated with neuronal apoptosis. Meanwhile, the levels of miR-423-3p and miR-296-5p were correlated with the activity of caspase-3, an apoptosis indicator. Additionally, the loading of miR-423-3p was increased in RNA-induced silencing complex whilst caspase-6, a target of miR-423-3p, was reduced in chronic TLE rats. Collectively, our findings suggest that miRNAs may exert anti-apoptotic effects in chronic TLE.
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Project description:The GABA(A) receptor (GABA(A)R) α1 subunit mutation, A322D, causes autosomal dominant juvenile myoclonic epilepsy (JME). Previous in vitro studies demonstrated that A322D elicits α1(A322D) protein degradation and that the residual mutant protein causes a dominant-negative effect on wild type GABA(A)Rs. Here, we determined the effects of heterozygous A322D knockin (Het(α1)AD) and deletion (Het(α1)KO) on seizures, GABA(A)R expression, and motor cortex (M1) miniature inhibitory postsynaptic currents (mIPSCs) at two developmental time-points, P35 and P120. Both Het(α1)AD and Het(α1)KO mice experience absence seizures at P35 that persist at P120, but have substantially more frequent spontaneous and evoked polyspike wave discharges and myoclonic seizures at P120. Both mutant mice have increased total and synaptic α3 subunit expression at both time-points and decreased α1 subunit expression at P35, but not P120. There are proportional reductions in α3, β2, and γ2 subunit expression between P35 and P120 in wild type and mutant mice. In M1, mutants have decreased mIPSC peak amplitudes and prolonged decay constants compared with wild type, and the Het(α1)AD mice have reduced mIPSC frequency and smaller amplitudes than Het(α1)KO mice. Wild type and mutants exhibit proportional increases in mIPSC amplitudes between P35 and P120. We conclude that Het(α1)KO and Het(α1)AD mice model the JME subsyndrome, childhood absence epilepsy persisting and evolving into JME. Both mutants alter GABA(A)R composition and motor cortex physiology in a manner expected to increase neuronal synchrony and excitability to produce seizures. However, developmental changes in M1 GABA(A)Rs do not explain the worsened phenotype at P120 in mutant mice.
| S-EPMC4641014 | biostudies-literature
Project description:BACKGROUND:It is well known that patients with epilepsy have a high rate of psychiatric comorbidity. However, studies exploring epilepsy in psychiatric cohorts are scarce. The aim of this study was to examine the prevalence of seizure disorders in acute psychiatric inpatients. METHODS:This is a cross-sectional study performed in a catchment-area based acute psychiatric department. All patients (age > 18) admitted during September 2011 - March 2012 were eligible for inclusion. Consenting patients were screened for a life-time history of epilepsy or seizures using self-reported questionnaire data and diagnostic codes for epilepsy in hospital and National registries. Patients scoring positive to one or more of these screening criteria underwent a thorough diagnostic validation (chart review), and the seizure disorders were classified as epilepsy, acute symptomatic seizures and/or psychogenic non-epileptic seizures according to current definitions. RESULTS:A total of 380 out of 591 (64.3%) consecutively admitted patients consented to participate in the study. Eighty-nine patients (23.4%) scored positive to one or more screening criteria. Fifteen (3.9%) were classified with epilepsy, 21 (5.5%) with acute symptomatic seizures and 9 (2.4%) with psychogenic non-epileptic seizures. CONCLUSIONS:This is the first study to report on the prevalence of seizure disorders in acute psychiatric inpatients. The life-time prevalence of epilepsy in this cohort of patients is five - six times as high as reports in the general population. These findings underscore the need for the clinical psychiatrist to have comprehensive knowledge on the interface between epileptology and psychiatry. TRIALS REGISTRATION:ClinicalTrials.gov identifier NCT01415323 .
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Project description:Women with catamenial epilepsy often experience increased seizure burden near the time of ovulation (periovulatory) or menstruation (perimenstrual). To date, a rodent model of chronic temporal lobe epilepsy (TLE) that exhibits similar endogenous fluctuations in seizures has not been identified. Here, we investigated whether seizure burden changes with the estrous cycle in the intrahippocampal kainic acid (IHKA) mouse model of TLE. Adult female IHKA mice and saline-injected controls were implanted with EEG electrodes in the ipsilateral hippocampus. At one and two months post-injection, 24/7 video-EEG recordings were collected and estrous cycle stage was assessed daily. Seizures were detected using a custom convolutional neural network machine learning process. Seizure burden was compared within each mouse between diestrus and combined proestrus and estrus days (pro/estrus) at two months post-injection. IHKA mice showed higher seizure burden on pro/estrus compared with diestrus, characterized by increased time in seizures and longer seizure duration. When all IHKA mice were included, no group differences were observed in seizure frequency or EEG power. However, increased baseline seizure burden on diestrus was correlated with larger cycle-associated differences, and when analyses were restricted to mice that showed the severe epilepsy typical of the IHKA model, increased seizure frequency on pro/estrus was also revealed. Controls showed no differences in EEG parameters with cycle stage. These results suggest that the stages of proestrus and estrus are associated with higher seizure burden in IHKA mice. The IHKA model may thus recapitulate at least some aspects of reproductive cycle-associated seizure clustering.
| S-EPMC7642196 | biostudies-literature