Cortical hyperexcitability and epileptogenesis: Understanding the mechanisms of epilepsy - Part 2

Badawy, Radwa A.B.; Harvey, A. Simon; Macdonell, Richard

doi:10.1016/j.jocn.2008.10.001

Cited by 53 publications

(34 citation statements)

References 211 publications

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“…When compared with seizureprone pyramidal neurons in CA1 or CA3 or with hilar neurons, granular neurons in the DG are relatively more resistant to seizure-induced excitotoxicity. These granular neurons sprout mossy fibers, forming aberrant synapses on dendrites of neighboring granular neurons [19,20]. The newly formed excitatory circuit might support recurrent epileptiform activity during the postseizure period.…”

Section: Discussionmentioning

confidence: 99%

Variations in elemental compositions of rat hippocampal formation between acute and latent phases of pilocarpine-induced epilepsy: an X-ray fluorescence microscopy study

et al. 2012

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There is growing experimental evidence that tracing the elements involved in brain hyperexcitability, excitotoxicity, and/or subsequent neurodegeneration could be a valuable source of data on the molecular mechanisms triggering or promoting further development of epilepsy. The most frequently used experimental model of the temporal lobe epilepsy observed in clinical practice is the one based on pilocarpine-induced seizures. In the frame of this study, the elemental anomalies occurring for the rat hippocampal tissue in acute and silent periods after injection of pilocarpine in rats were compared. X-ray fluorescence microscopy was applied for the topographic and quantitative elemental analysis. The differences in the levels of elements such as P, S, K, Ca, Fe, Cu, and Zn between the rats 3 days (SE72) and 6 h (SE6) after pilocarpine injection as well as naive controls were examined. Comparison of SE72 and control groups showed, for specific areas of the hippocampal formation, lower levels of P, K, Cu, and Zn, and an increase in Ca accumulation. These results as well as further analysis of the differences between the SE72 and SE6 groups confirmed that seizure-induced excitotoxicity as well as mossy fiber sprouting are the mechanisms involved in the neurodegenerative processes which may finally lead to spontaneous seizures in the chronic period of the pilocarpine model. Moreover, in the light of the results obtained, Cu seems to play a very important role in the pathogenesis of epilepsy in this animal model. For all areas analyzed, the levels of this element recorded in the latent period were not only lower than those for controls but were even lower than the levels found in the acute period. The decreased hippocampal accumulation of Cu in the phase of behavior and EEG stabilization, a possible inhibitory effect of this element on excitatory amino acid receptors, and enhanced seizure susceptibility in Menkes disease (an inherited Cu transport disorder leading to Cu deficiency in the brain) suggest a neuroprotective role rather than neurodegenerative and proconvulsive roles of Cu in pilocarpine-induced epilepsy.

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Section: Discussionmentioning

confidence: 99%

Variations in elemental compositions of rat hippocampal formation between acute and latent phases of pilocarpine-induced epilepsy: an X-ray fluorescence microscopy study

et al. 2012

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“…As one of the cellular mechanisms of epileptogenesis [3], the excessive discharge of highly synchronized and hyperexcitable neurons in different brain areas, including the cerebral cortex, hippocampus and several subcortical structures, may induce different types of epileptic seizures [5][6][7]. Excessive excitatory neurotransmission (e.g., via the glutamatergic system) and/or a decrease in inhibitory neurotransmission (e.g., via the GABAergic system) may disrupt the excitatory/inhibitory balance, which may excite or exacerbate epileptic seizures [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

“…This refractory state is possibly due to seizureinduced adaptive mechanisms, such as overexpression of the P-glycoprotein and the multidrug-resistance-associated protein [10][11][12]. Although the pathomechanisms (mechanisms of pathological processes) of different types of epilepsies *Address correspondence to this author at the Department of Zoology, University of West Hungary, Savaria Campus, Szombathely, Károlyi Gáspár tér 4., 9700 Hungary; Tel: 0036 94/504 409; Fax: 0036 94/504 404; E-mail: zskovacs@ttk.nyme.hu have been elucidated [1][2][3][4][5][6][7][13][14][15][16][17][18], epilepsy treatment is mainly based on the suppression of symptoms by antiepileptic drugs [19,20], which have severe adverse effects [21,22]. Consequently, there is an urgent need to develop new therapeutic approaches to find safer and more effective antiepileptic strategies to prevent and cure epilepsy.…”

Section: Introductionmentioning

confidence: 99%

The Antiepileptic Potential of Nucleosides

Kovács¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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Despite newly developed antiepileptic drugs to suppress epileptic symptoms, approximately one third of patients remain drug refractory. Consequently, there is an urgent need to develop more effective therapeutic approaches to treat epilepsy. A great deal of evidence suggests that endogenous nucleosides, such as adenosine (Ado), guanosine (Guo), inosine (Ino) and uridine (Urd), participate in the regulation of pathomechanisms of epilepsy. Adenosine and its analogues, together with non-adenosine (non-Ado) nucleosides (e.g., Guo, Ino and Urd), have shown antiseizure activity. Adenosine kinase (ADK) inhibitors, Ado uptake inhibitors and Ado-releasing implants also have beneficial effects on epileptic seizures. These results suggest that nucleosides and their analogues, in addition to other modulators of the nucleoside system, could provide a new opportunity for the treatment of different types of epilepsies. Therefore, the aim of this review article is to summarize our present knowledge about the nucleoside system as a promising target in the treatment of epilepsy.

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“…Fortunately, the statistical power of the initial association remained significant after adjusting for the confounding factor, the etiology of epilepsy. In addition, given that the injuries that cause acquired epilepsy vary but share a common molecular mechanism for producing brain damage resulting in epileptogenesis, 36,37 the imbalance between excitatory and inhibitory neurotransmission due to an impaired GABA transporter reversal may not be lesion-specific, but rather a common mechanism underlying AED pharmacoresistance.…”

Section: Discussionmentioning

confidence: 99%

Association of a synonymous GAT3 polymorphism with antiepileptic drug pharmacoresistance

Kim

Cho

et al. 2011

J Hum Genet

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It would be likely that the genetic variants of the GTA3 gene encoding GAT-3, an astrocytic GABA transporter, may alter gammaaminobutyric acid (GABA) neurotransmission in the synaptic cleft in the epileptic brain and cause antiepileptic drugs (AEDs) pharmacoresistance. A candidate gene association analysis with fine mapping was performed to dissect the genetic contributions of GAT3 to AEDs pharmacoresistance. Two independent case sample sets were recruited (Samples 1 and 2), and each set was divided into two groups (drug-resistant and drug-responsive) according to the treatment outcomes with AEDs. Sample1 (n¼400) was used for the initial exploratory stage of the study and sample 2 (n¼435) was used for confirmation of the genetic association in the replication stage of the study. A GAT3 polymorphism (GAT3 c.1572 C4T, rs2272400) was nominally associated with AEDs pharmacoresistance (P CC vs P CT/TT ¼0.012, P allelic ¼0.01). The odds ratio (OR) for AED pharmacoresistance was 1.6 (95% confidence interval (CI), 1.11-2.24; P¼0.01) in the additive models of inheritance. The statistical significance remained after we adjusted for a confounding factor, the etiology of epilepsy, at 0.012 (adjusted OR: 1.73, 95% CI: 1.13-2.67) and used Bonferroni's correction for multiple comparisons at 0.048. Importantly, the positive association of c.1572 T was reproduced in the replication stage (P allelic ¼0.037, joint P-value of the replication¼0.001). The results suggest that GAT3 c.1572T may be one of the contributing factors with a modest effect on AEDs pharmacoresistance in the epileptic brain, shed light on a better understanding of the underlying mechanisms and serve as an impetus for new avenues of treatment for AEDs pharmacoresistance.

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Cortical hyperexcitability and epileptogenesis: Understanding the mechanisms of epilepsy - Part 2

Cited by 53 publications

References 211 publications

Variations in elemental compositions of rat hippocampal formation between acute and latent phases of pilocarpine-induced epilepsy: an X-ray fluorescence microscopy study

Variations in elemental compositions of rat hippocampal formation between acute and latent phases of pilocarpine-induced epilepsy: an X-ray fluorescence microscopy study

The Antiepileptic Potential of Nucleosides

Association of a synonymous GAT3 polymorphism with antiepileptic drug pharmacoresistance

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