scholarly journals High concordance between hippocampal transcriptome of the intraamygdala kainic acid model and human temporal lobe epilepsy

2020 ◽  
Author(s):  
Giorgia Conte ◽  
Alberto Parras ◽  
Mariana Alves ◽  
Ivana Ollà ◽  
Laura de Diego-Garcia ◽  
...  
Keyword(s):  
Gene Expression ◽  
Status Epilepticus ◽  
Temporal Lobe Epilepsy ◽  
Kainic Acid ◽  
Temporal Lobe ◽  
Calcium Signalling ◽  
Experimental Models ◽  
Drug Resistant ◽  
The Brain ◽  
Models Of Epilepsy

AbstractObjectivePharmacoresistance and the lack of disease-modifying actions of current anti-seizure drugs persist as major challenges in the treatment of epilepsy. Experimental models of chemoconvulsant-induced status epilepticus remain the models of choice to discover potential anti-epileptogenic drugs but doubts remain as to the extent to which they model human pathophysiology. The aim of the present study was to compare the molecular landscape of the intraamygdala kainic acid model of status epilepticus in mice with findings in resected brain tissue from patients with drug-resistant temporal lobe epilepsy (TLE).MethodsStatus epilepticus was induced via intraamygdala microinjection of kainic acid in C57BL/6 mice and gene expression analysed via microarrays in hippocampal tissue at acute and chronic time-points. Results were compared to reference datasets in the intraperitoneal pilocarpine and intrahippocampal kainic acid model and to human resected brain tissue (hippocampus and cortex) from patients with drug-resistant TLE.ResultsIntraamygdala kainic acid injection in mice triggered extensive dysregulation of gene expression which was ∼3-fold greater shortly after status epilepticus (2729 genes) when compared to epilepsy (412). Comparison to samples of patients with TLE revealed a particular high correlation of gene dysregulation during established epilepsy. Pathway analysis found suppression of calcium signalling to be highly conserved across different models of epilepsy and patients. CREB was predicted as one of the main up-stream transcription factors regulating gene expression during acute and chronic phases and inhibition of CREB reduced seizure severity in the intraamygdala kainic acid model.SignificanceOur findings suggest the intraamygdala kainic acid model faithfully replicates key molecular features of human drug-resistant temporal lobe epilepsy and provides potential rationale target approaches for disease-modification through new insights into the unique and shared gene expression landscape in experimental epilepsy.Key point boxMore genes show expression changes shortly following intraamygdala kainic acid-induced status epilepticus when compared to established epilepsy.The intraamygdala kainic acid mouse model mimics closely the gene expression landscape in the brain of patients with temporal lobe epilepsy.Supressed calcium signalling in the brain as common feature across experimental models of epilepsy and patients with temporal lobe epilepsy.CREB is a major up-stream transcription factor during early changes following status epilepticus and once epilepsy is established.

scholarly journals Induction of the Nrf2 Pathway by Sulforaphane Is Neuroprotective in a Rat Temporal Lobe Epilepsy Model

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1702
Author(s):  
Sereen Sandouka ◽  
Tawfeeq Shekh-Ahmad
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Status Epilepticus ◽  
Temporal Lobe Epilepsy ◽  
Antioxidant Capacity ◽  
Temporal Lobe ◽  
Epileptiform Activity ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
The Brain

Epilepsy is a chronic disease of the brain that affects over 65 million people worldwide. Acquired epilepsy is initiated by neurological insults, such as status epilepticus, which can result in the generation of ROS and induction of oxidative stress. Suppressing oxidative stress by upregulation of the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) has been shown to be an effective strategy to increase endogenous antioxidant defences, including in brain diseases, and can ameliorate neuronal damage and seizure occurrence in epilepsy. Here, we aim to test the neuroprotective potential of a naturally occurring Nrf2 activator sulforaphane, in in vitro epileptiform activity model and a temporal lobe epilepsy rat model. Sulforaphane significantly decreased ROS generation during epileptiform activity, restored glutathione levels, and prevented seizure-like activity-induced neuronal cell death. When given to rats after 2 h of kainic acid-induced status epilepticus, sulforaphane significantly increased the expression of Nrf2 and related antioxidant genes, improved oxidative stress markers, and increased the total antioxidant capacity in both the plasma and hippocampus. In addition, sulforaphane significantly decreased status epilepticus-induced neuronal cell death. Our results demonstrate that Nrf2 activation following an insult to the brain exerts a neuroprotective effect by reducing neuronal death, increasing the antioxidant capacity, and thus may also modify epilepsy development.

scholarly journals Manganese-enhanced magnetic resonance imaging in the acute phase of the pilocarpine-induced model of epilepsy

2012 ◽  
Vol 10 (2) ◽  
pp. 247-252 ◽  
Author(s):  
Jackeline Moraes Malheiros ◽  
Beatriz Monteiro Longo ◽  
Alberto Tannús ◽  
Luciene Covolan
Keyword(s):  
Status Epilepticus ◽  
Magnetic Resonance ◽  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Acute Phase ◽  
Cell Activation ◽  
Experimental Models ◽  
Magnetic Resonance Images ◽  
Control Group ◽  
Experimental Conditions

Magnetic resonance images are useful in the study of experimental models of temporal lobe epilepsy. The manganese-enhanced MRI (MEMRI) technique is of interest since it combines the effects caused by manganese on the increased contrast in activated cell populations, when competing with calcium in synaptic transmission. Thus, the purpose of this study was to investigate the temporal evolution of the contrast related to manganese in the acute phase of temporal lobe epilepsy induced by systemic pilocarpine and compare it to the expression of the c-Fos protein. During this phase, the intensity of the MEMRI signal was analyzed at three different time points (5, 15 or 30 minutes) after the onset of status epilepticus (SE). The group that was maintained in status epilepticus for 30 minutes showed a decrease in intensity of the signal in CA1 and the dentate gyrus (DG). There were no differences between the control group and the other groups treated with pilocarpine. The expression of the protein, c-Fos, in the same animals showed that even in the short-duration status epilepticus (5 minutes), there was already maximal cellular activation in subregions of the hippocampus (DG, CA1 and CA3). Under the experimental conditions tested, our data suggest that the MEMRI signal was not sensitive for the identification of detectable variations of cell activation in the acute phase of the pilocarpine model. Our findings are not consistent with the idea that manganese contrast reflects primarily alterations in cellular activity during SE when other signal-modifying elements can act.

scholarly journals Kainic Acid-Induced Post-Status Epilepticus Models of Temporal Lobe Epilepsy with Diverging Seizure Phenotype and Neuropathology

2017 ◽  
Vol 8 ◽  
Author(s):  
Daniele Bertoglio ◽  
Halima Amhaoul ◽  
Annemie Van Eetveldt ◽  
Ruben Houbrechts ◽  
Sebastiaan Van De Vijver ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Temporal Lobe Epilepsy ◽  
Kainic Acid ◽  
Temporal Lobe

scholarly journals Administration of Simvastatin after Kainic Acid-Induced Status Epilepticus Restrains Chronic Temporal Lobe Epilepsy

PLoS ONE ◽  
2011 ◽  
Vol 6 (9) ◽  
pp. e24966 ◽  
Author(s):  
Chuncheng Xie ◽  
Jiahang Sun ◽  
Weidong Qiao ◽  
Dunyue Lu ◽  
Lanlan Wei ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Temporal Lobe Epilepsy ◽  
Kainic Acid ◽  
Temporal Lobe

scholarly journals Drug-Resistant Temporal Lobe Epilepsy Alters the Expression and Functional Coupling to Gαi/o Proteins of CB1 and CB2 Receptors in the Microvasculature of the Human Brain

2021 ◽  
Vol 14 ◽  
Author(s):  
María de los Ángeles Nuñez-Lumbreras ◽  
José Luis Castañeda-Cabral ◽  
María Guadalupe Valle-Dorado ◽  
Vicente Sánchez-Valle ◽  
Sandra Orozco-Suárez ◽  
...  
Keyword(s):  
Protein Expression ◽  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
High Efficiency ◽  
Drug Resistant ◽  
Protein Activation ◽  
Cb2 Receptors ◽  
The Brain ◽  
Temporal Neocortex ◽  
Cb1 And Cb2 Receptors

Cannabinoid receptors 1 and 2 (CB1 and CB2, respectively) play an important role in maintaining the integrity of the blood–brain barrier (BBB). On the other hand, BBB dysfunction is a common feature in drug-resistant epilepsy. The focus of the present study was to characterize protein expression levels and Gαi/o protein-induced activation by CB1 and CB2 receptors in the microvascular endothelial cells (MECs) isolated from the brain of patients with drug-resistant mesial temporal lobe epilepsy (DR-MTLE). MECs were isolated from the hippocampus and temporal neocortex of 12 patients with DR-MTLE and 12 non-epileptic autopsies. Immunofluorescence experiments were carried out to determine the localization of CB1 and CB2 receptors in the different cell elements of MECs. Protein expression levels of CB1 and CB2 receptors were determined by Western blot experiments. [35S]-GTPγS binding assay was used to evaluate the Gαi/o protein activation induced by specific agonists. Immunofluorescent double-labeling showed that CB1 and CB2 receptors colocalize with tight junction proteins (claudin-5, occludin, and zonula occludens-1), glial fibrillary acidic protein and platelet-derived growth factor receptor-β. These results support that CB1 and CB2 receptors are expressed in the human isolated microvessels fragments consisting of MECs, astrocyte end feet, and pericytes. The hippocampal microvasculature of patients with DR-MTLE presented lower protein expression of CB1 and CB2 receptors (66 and 43%, respectively; p < 0.001). However, its Gαi/o protein activation was with high efficiency (CB1, 251%, p < 0.0008; CB2, 255%, p < 0.0001). Microvasculature of temporal neocortex presented protein overexpression of CB1 and CB2 receptors (35 and 41%, respectively; p < 0.01). Their coupled Gαi/o protein activation was with higher efficiency for CB1 receptors (103%, p < 0.006), but lower potency (p < 0.004) for CB2 receptors. The present study revealed opposite changes in the protein expression of CB1 and CB2 receptors when hippocampus (diminished expression of CB1 and CB2) and temporal neocortex (increased expression of CB1 and CB2) were compared. However, the exposure to specific CB1 and CB2 agonists results in high efficiency for activation of coupled Gαi/o proteins in the brain microvasculature of patients with DR-MTLE. CB1 and CB2 receptors with high efficiency could represent a therapeutic target to maintain the integrity of the BBB in patients with DR-MTLE.

scholarly journals Lateralized phenotypic differences in females in the intrahippocampal kainic acid mouse model of temporal lobe epilepsy

2021 ◽  
Author(s):  
Cathryn A. Cutia ◽  
Leanna K. Leverton ◽  
Xiyu Ge ◽  
Rana Youssef ◽  
Lori T. Raetzman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Weight Gain ◽  
Temporal Lobe Epilepsy ◽  
Kainic Acid ◽  
Temporal Lobe ◽  
Dorsal Hippocampus ◽  
Hippocampal Sclerosis ◽  
Endocrine Dysfunction ◽  
Seizure Focus ◽  
Reproductive Endocrine

AbstractClinical evidence indicates that patients with temporal lobe epilepsy (TLE) often show differential outcomes of comorbid conditions dependent on the lateralization of the seizure focus. However, whether a left or right seizure focus produces differential effects on comorbid outcomes has not been investigated in a rodent model of chronic recurrent seizures. Here, we used the intrahippocampal kainic acid (IHKA) mouse model of TLE to determine whether targeting of left or right dorsal hippocampus for injection produces different outcomes in hippocampal sclerosis, body weight gain, and multiple measures of reproductive endocrine dysfunction in female mice. At one, two, and four months after injection, in vivo measurements of estrous cycles and weight were followed by ex vivo examination of hippocampal sclerosis, circulating ovarian hormone and corticosterone levels, ovarian morphology, and pituitary gene expression. IHKA mice with right-targeted injection (IHKA-R) showed greater granule cell dispersion and pituitary Fshb expression compared to mice with left-targeted injection (IHKA-L). By contrast, pituitary expression of Lhb and Gnrhr were higher in IHKA-L mice compared to IHKA-R, but these values were not different from respective saline-injected controls. IHKA-L mice also showed an increased rate of weight gain compared to IHKA-R mice. Disruptions to estrous cyclicity, however, were similar in both IHKA-L and IHKA-R mice. These findings indicate that although major reproductive endocrine dysfunction phenotypes present similarly after targeting left or right dorsal hippocampus in the IHKA model of TLE, distinct latent mechanisms based on lateralization of seizure focus may contribute to produce similar emergent reproductive endocrine outcomes.Significance StatementPeople with epilepsy often develop comorbidities dependent on the side of the brain in which the seizures originate. However, the mechanisms linking laterality of seizure initiation side to different comorbidities are unknown. Here, we examined whether injection of kainic acid in the left or right hippocampus, a model of temporal lobe epilepsy, produces differential effects on hippocampal damage, weight gain, and measurements of female reproductive endocrine function in female mice. We found that hippocampal sclerosis, pituitary gene expression, and weight gain are influenced by the side of injection. These results are the first demonstration of changes in pituitary gene expression in a model of epilepsy and indicate that the hemisphere targeted in the intrahippocampal kainic acid model impacts phenotypic outcomes.

scholarly journals Polyadenylation of mRNA as a novel regulatory mechanism of gene expression in temporal lobe epilepsy

Brain ◽  
2020 ◽  
Vol 143 (7) ◽  
pp. 2139-2153
Author(s):  
Alberto Parras ◽  
Laura de Diego-Garcia ◽  
Mariana Alves ◽  
Edward Beamer ◽  
Giorgia Conte ◽  
...  
Keyword(s):  
Gene Expression ◽  
Status Epilepticus ◽  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Gene Expression Regulation ◽  
Tail Length ◽  
Cytoplasmic Polyadenylation ◽  
Additional Layer ◽  
Mrna Polyadenylation ◽  
First Time

Abstract Temporal lobe epilepsy is the most common and refractory form of epilepsy in adults. Gene expression within affected structures such as the hippocampus displays extensive dysregulation and is implicated as a central pathomechanism. Post-transcriptional mechanisms are increasingly recognized as determinants of the gene expression landscape, but key mechanisms remain unexplored. Here we show, for first time, that cytoplasmic mRNA polyadenylation, one of the post-transcriptional mechanisms regulating gene expression, undergoes widespread reorganization in temporal lobe epilepsy. In the hippocampus of mice subjected to status epilepticus and epilepsy, we report >25% of the transcriptome displays changes in their poly(A) tail length, with deadenylation disproportionately affecting genes previously associated with epilepsy. Suggesting cytoplasmic polyadenylation element binding proteins (CPEBs) being one of the main contributors to mRNA polyadenylation changes, transcripts targeted by CPEBs were particularly enriched among the gene pool undergoing poly(A) tail alterations during epilepsy. Transcripts bound by CPEB4 were over-represented among transcripts with poly(A) tail alterations and epilepsy-related genes and CPEB4 expression was found to be increased in mouse models of seizures and resected hippocampi from patients with drug-refractory temporal lobe epilepsy. Finally, supporting an adaptive function for CPEB4, deletion of Cpeb4 exacerbated seizure severity and neurodegeneration during status epilepticus and the development of epilepsy in mice. Together, these findings reveal an additional layer of gene expression regulation during epilepsy and point to novel targets for seizure control and disease-modification in epilepsy.

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