Is the underlying cause of epilepsy a major prognostic factor for recurrence?

Semah, F.; Picot, Marie‐Christine; Adam, Claude; Broglin, D.; Arzimanoglou, Alexis; Bazin, Brigitte; Cavalcanti, Desirée Rosa; Baulac, Michel

doi:10.1212/wnl.51.5.1256

Cited by 971 publications

(646 citation statements)

References 23 publications

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“…Temporal lobe epilepsy (TLE) is a common form of epilepsy that is often difficult to treat (Hauser and Kurland, 1975;Hauser et al, 1991;Semah et al, 1998). Previous in vitro and in vivo studies have shown that exogenously applied CB receptor agonists, such as D 9 THC and WIN 55, 212-2 are antiepileptic in a number of animal seizure models.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of endocannabinoid metabolism attenuates enhanced hippocampal neuronal activity induced by kainic acid

Coomber

O’Donoghue

Mason

2008

Synapse

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The endogenous cannabinoid system regulates neuronal excitability. The effects of inhibiting fatty acid amide hydrolase (FAAH), the enzyme responsible for metabolism of the endocannabinoid anandamide, on kainic acid (KA)-induced neuronal activity were investigated in the rat in vivo, using the selective FAAH inhibitor URB597. Hippocampal neuronal ensemble unit activity was recorded in isoflurane-anesthetized rats using 16-wire microelectrode arrays. Separate groups of rats were administered with single doses of KA alone, KA and URB597 (0.3 or 1 mg kg 21 , i.p.), or URB597 (1 mg kg 21 ) alone. The role of the cannabinoid CB1 receptor in mediating the effects of URB597 was explored using the CB1 selective antagonists AM251, either alone or prior to KA and URB597 (1 mg kg 21 ) administration, and SR141716A, administered prior to KA and URB597 (1 mg kg 21 ). Neuronal firing and burst firing rates were examined in animals with confirmed dorsal hippocampal placements. KA induced an increase in both firing and burst firing rates, effects which were attenuated by URB597 in a dose-related manner. Pretreatment with AM251 or SR141716A partly attenuated the URB597-mediated effects on firing and burst firing rate. Rats treated with AM251 or URB597 alone did not exhibit any significant change in either firing or burst firing rates compared with basal activity. These results suggest that the inhibition of endocannabinoid metabolism can suppress hyperexcitability in the rat hippocampus, partly via a CB1 receptormediated mechanism. Synapse 62: 746-755, 2008. V

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Section: Discussionmentioning

confidence: 99%

Inhibition of endocannabinoid metabolism attenuates enhanced hippocampal neuronal activity induced by kainic acid

Coomber

O’Donoghue

Mason

2008

Synapse

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“…Seizure severity was graded according to a modified Racine scale. 4,14 Fifteen minutes after kainate injection, the mice were injected intraperitoneally with a combination of [1-13 C]glucose (543 mg/kg) and [1,[2][3][4][5][6][7][8][9][10][11][12][13] C]acetate (504 mg/kg) and after another 15 minutes, the brains of the mice were subjected to microwave fixation at 4 kW for 1.7 seconds (model GA5013, Gerling Applied Engineering, Modesto, CA, USA). This is the most humane euthanization method instantly inactivating proteins in the brain.…”

Section: Metabolic Studiesmentioning

confidence: 99%

“…If [4,[5][6][7][8][9][10][11][12][13] C]a-ketoglutarate remains in the astrocytic TCA cycle for further metabolism via this pathway, it will, after condensation with unlabeled acetyl CoA, give rise to [3-13 C]-and [1,2-13 C]a-ketoglutarate in the subsequent turn, which may give rise to glutamate and glutamine displaying the same labeling patterns. Based on the distinct 13 C labeling in glutamine after the first and second turn of TCA cycle metabolism, a number indicative of astrocytic TCA cycle activity can be calculated by relating the amount of isotopomers generated in the second turn of TCA cycle metabolism to the amount of that generated in the first turn, i.e., ( [1,[2][3][4][5][6][7][8][9][10][11][12][13] …”

Section: Nuclear Magnetic Resonance Spectroscopymentioning

confidence: 99%

“…In glutamatergic neurons, this [4,[5][6][7][8][9][10][11][12][13] C]glutamate may be released upon depolarization. Otherwise, [4,[5][6][7][8][9][10][11][12][13] C]glutamate may be converted to [4,[5][6][7][8][9][10][11][12][13] C]a-ketoglutarate for further TCA cycle metabolism or may in GABAergic neurons be converted to [1,[2][3][4][5][6][7][8][9][10][11][12][13] C]GABA. It should be noted that the largest pool of glutamate is situated in the glutamatergic neurons and the [4,[5][6][7][8][9][10]…”

Section: Nuclear Magnetic Resonance Spectroscopymentioning

confidence: 99%

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A Subconvulsive Dose of Kainate Selectively Compromises Astrocytic Metabolism in the Mouse Brain In Vivo

Walls

Eyjolfsson

Schousboe

et al. 2014

J Cereb Blood Flow Metab

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Despite the well-established use of kainate as a model for seizure activity and temporal lobe epilepsy, most studies have been performed at doses giving rise to general limbic seizures and have mainly focused on neuronal function. Little is known about the effect of lower doses of kainate on cerebral metabolism and particularly that associated with astrocytes. We investigated astrocytic and neuronal metabolism in the cerebral cortex of adult mice after treatment with saline (controls), a subconvulsive or a mildly convulsive dose of kainate. A combination of [1,2-13 C]acetate and [1-13 C]glucose was injected and subsequent nuclear magnetic resonance spectroscopy of cortical extracts was employed to distinctively map astrocytic and neuronal metabolism. The subconvulsive dose of kainate led to an instantaneous increase in the cortical lactate content, a subsequent reduction in the amount of [4,[5][6][7][8][9][10][11][12][13] C]glutamine and an increase in the calculated astrocytic TCA cycle activity. In contrast, the convulsive dose led to decrements in the cortical content and 13 C labeling of glutamate, glutamine, GABA, and aspartate. Evidence is provided that astrocytic metabolism is affected by a subconvulsive dose of kainate, whereas a higher dose is required to affect neuronal metabolism. The cerebral glycogen content was dose-dependently reduced by kainate supporting a role for glycogen during seizure activity.

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“…The mechanisms underlying AED pharmacoresistance might be distinct from each other according to different etiologies of epilepsy, as suggested by Semah et al; 35 acquired epilepsies, such as those following stroke or due to the development of a vascular malformation or tumor, seem to be much more treatment-responsive than those associated with cortical dysgenesis, hippocampal sclerosis or dual pathologies. In the present study, subdivision of samples according to lesion etiologies was not attempted in an effort to avoid decreasing statistical power due to the small sample size.…”

Section: Discussionmentioning

confidence: 97%

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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Is the underlying cause of epilepsy a major prognostic factor for recurrence?

Cited by 971 publications

References 23 publications

Inhibition of endocannabinoid metabolism attenuates enhanced hippocampal neuronal activity induced by kainic acid

Inhibition of endocannabinoid metabolism attenuates enhanced hippocampal neuronal activity induced by kainic acid

A Subconvulsive Dose of Kainate Selectively Compromises Astrocytic Metabolism in the Mouse Brain In Vivo

Association of a synonymous GAT3 polymorphism with antiepileptic drug pharmacoresistance

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