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 Characterization of the Gene Expression Profile of Human Hippocampus in Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Julio Lachos ◽  
Michela Zattoni ◽  
Heinz-Gregor Wieser ◽  
Jean-Marc Fritschy ◽  
Thomas Langmann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Temporal Lobe Epilepsy ◽  
Gene Expression Profile ◽  
Temporal Lobe ◽  
Hippocampal Sclerosis ◽  
Mesial Temporal Lobe Epilepsy ◽  
Human Hippocampus ◽  
Mesial Temporal Lobe ◽  
Underlying Pathophysiology

One of the main putative causes of therapy refractory epilepsy in mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis is the overexpression of multidrug transporters (MDTs) at the blood-brain barrier (BBB). It steps up the removal of antiepileptic drugs (AEDs) out of the brain cells across the BBB resulting in a low concentration of AEDs within the target cells. Some of the mechanisms of AED resistance are most likely to be genetically determined. To obtain more information about the underlying pathophysiology of intractability in epilepsy, we compared the global gene expression profile of human hippocampus and hippocampal-derived microvascular endothelial cells from MTLE with HS patients and controls. At the level of MDT, a significant up-regulation was found for ABCB1 (P-gp), ABCB2, ABCB3, and ABCB4, which was mainly related to endothelial cells. The data on the MDT were validated and extended by quantitative RT-PCR. Surprisingly, inflammatory factors such as interleukins (IL-1α, IL-1β, IL-6, and IL-18) and cytokines (TNF-α and TGF-β1) were found to be up-regulated in hippocampal parenchyma. The overexpression of P-gp, IL-1β, and IL-6 was also confirmed by immunohistochemistry (IHC). Our results suggest that complex expression changes of ABC-transporters may play a decisive role in pharmacoresistance in MTLE. Further studies on the new and unexpected overexpression of inflammatory cytokines may unlock hitherto undiscovered pathways of the underlying pathophysiology of human MTLE.

Severity of depressive symptoms, hippocampal sclerosis, auditory memory, and side of seizure focus in temporal lobe epilepsy

2004 ◽  
Vol 5 (4) ◽  
pp. 522-531 ◽  
Author(s):  
Mario F. Dulay ◽  
Bruce K. Schefft ◽  
Jamison D. Fargo ◽  
Michael D. Privitera ◽  
Hwa-shain Yeh
Keyword(s):  
Depressive Symptoms ◽  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Hippocampal Sclerosis ◽  
Auditory Memory ◽  
Seizure Focus

scholarly journals Effects of febrile seizures in mesial temporal lobe epilepsy with hippocampal sclerosis on gene expression using bioinformatical analysis

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Yinchao Li ◽  
Chengzhe Wang ◽  
Peiling Wang ◽  
Xi Li ◽  
Liemin Zhou
Keyword(s):  
Gene Expression ◽  
Temporal Lobe Epilepsy ◽  
Ion Channel ◽  
Temporal Lobe ◽  
Febrile Seizure ◽  
Hippocampal Sclerosis ◽  
Febrile Seizures ◽  
Mesial Temporal Lobe Epilepsy ◽  
Channel Activity ◽  
Mesial Temporal Lobe

Abstract Background To investigate the effect of long-term febrile convulsions on gene expression in mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) and explore the molecular mechanism of MTLE-HS. Methods Microarray data of MTLE-HS were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between MTLE-HS with and without febrile seizure history were screened by the GEO2R software. Pathway enrichment and gene ontology of the DEGs were analyzed using the DAVID online database and FunRich software. Protein–protein interaction (PPI) networks among DEGs were constructed using the STRING database and analyzed by Cytoscape. Results A total of 515 DEGs were identified in MTLE-HS samples with a febrile seizure history compared to MTLE-HS samples without febrile seizure, including 25 down-regulated and 490 up-regulated genes. These DEGs were expressed mostly in plasma membrane and synaptic vesicles. The major molecular functions of those genes were voltage-gated ion channel activity, extracellular ligand-gated ion channel activity and calcium ion binding. The DEGs were mainly involved in biological pathways of cell communication signal transduction and transport. Five genes (SNAP25, SLC32A1, SYN1, GRIN1, and GRIA1) were significantly expressed in the MTLE-HS with prolonged febrile seizures. Conclusion The pathogenesis of MTLE-HS involves multiple genes, and prolonged febrile seizures could cause differential expression of genes. Thus, investigations of those genes may provide a new perspective into the mechanism of MTLE-HS.

scholarly journals Auras in temporal lobe epilepsy with hippocampal sclerosis: Relation to seizure focus laterality and post surgical outcome

2012 ◽  
Vol 24 (1) ◽  
pp. 120-125 ◽  
Author(s):  
Taíssa Ferrari-Marinho ◽  
Luís Otávio S.F. Caboclo ◽  
Murilo M. Marinho ◽  
Ricardo S. Centeno ◽  
Rafael S.C. Neves ◽  
...  
Keyword(s):  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Surgical Outcome ◽  
Hippocampal Sclerosis ◽  
Seizure Focus

Cnestis ferruginea Vahl ex DC (Connaraceae) downregulates expression of immediate early genes in kainic acid-induced temporal lobe epilepsy in mice

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Emmanuel S. Ojo ◽  
Ismail O. Ishola ◽  
Olasunmbo Afolayan ◽  
Ayorinde B. James ◽  
Benneth Ben-Azu ◽  
...  
Keyword(s):  
Temporal Lobe Epilepsy ◽  
Kainic Acid ◽  
Temporal Lobe ◽  
Hippocampal Sclerosis ◽  
Preventive Treatment ◽  
Immediate Early Genes ◽  
Immediate Early ◽  
Early Genes ◽  
Fos Protein ◽  
Oxide Synthase

Abstract Objectives This study investigates the influence of Cnestis ferruginea (CF) on kainic acid (KA)-induced immediate early genes (IEGs) associated with hippocampal sclerosis in temporal lobe epilepsy (TLE) in mice. Methods Animals were randomly divided into preventive treatment; vehicle (10 mL/kg, p.o.) or CF (400 mg/kg, p.o.) for three consecutive days before KA (5 mg/kg, i.p.) on days 4 and 5. In the reversal model, KA (5 mg/kg, i.p.) was administered on days 1 and 2 before CF (400 mg/kg) administration on days 3–5. Animals were euthanized on day 5, 6 h after KA exposure in preventive model and 1 h after CF administration in reversal model to estimate markers of IEGs. Results KA upregulated the expression of c-Fos protein by 3.32-, 9.45-, 8.13-, and 8.66-fold in the hippocampal CA1, CA2, CA3, and DG regions, respectively. Also, KA elevated inducible nitric oxide synthase protein expression by 10.9-, 10.6-, 9.78-, and 9.51-fold. Besides, mRNA expression of brain-derived neurotrophic factors and heat shock protein was increased by 2.38- and 1.39-fold, respectively, after exposure to KA which were attenuated by CF. Conclusions CF attenuated KA-induced IEGs and could be used as an adjunct in TLE.

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 Synaptic Reshaping and Neuronal Outcomes in the Temporal Lobe Epilepsy

2021 ◽  
Vol 22 (8) ◽  
pp. 3860
Author(s):  
Elisa Ren ◽  
Giulia Curia
Keyword(s):  
Animal Models ◽  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Current Knowledge ◽  
Focal Epilepsy ◽  
Ex Vivo ◽  
Hippocampal Sclerosis ◽  
Control Group ◽  
Epileptogenic Zone ◽  
Epileptiform Discharges

Temporal lobe epilepsy (TLE) is one of the most common types of focal epilepsy, characterized by recurrent spontaneous seizures originating in the temporal lobe(s), with mesial TLE (mTLE) as the worst form of TLE, often associated with hippocampal sclerosis. Abnormal epileptiform discharges are the result, among others, of altered cell-to-cell communication in both chemical and electrical transmissions. Current knowledge about the neurobiology of TLE in human patients emerges from pathological studies of biopsy specimens isolated from the epileptogenic zone or, in a few more recent investigations, from living subjects using positron emission tomography (PET). To overcome limitations related to the use of human tissue, animal models are of great help as they allow the selection of homogeneous samples still presenting a more various scenario of the epileptic syndrome, the presence of a comparable control group, and the availability of a greater amount of tissue for in vitro/ex vivo investigations. This review provides an overview of the structural and functional alterations of synaptic connections in the brain of TLE/mTLE patients and animal models.

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