Carisbamate has powerful disease-modifying effects in the lithium-pilocarpine model of temporal lobe epilepsy

François, Jennifer; Germé, Katuschia; Ferrandon, Arielle; Koning, Estelle; Nehlig, Astrid

doi:10.1016/j.neuropharm.2011.04.018

Cited by 27 publications

(72 citation statements)

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“…However, one study (Feindel and Rasmussen, 1991) found no difference in seizure reduction after removal of the amygdala with substantial sparing of hippocampus, as compared to larger resections that included the hippocampus. Additionally, while not as well studied as the hippocampus or even the amygdala, several anatomical and physiological studies have demonstrated perturbations in mid-thalamic nuclei and extrahippocampal regions that influence excitability and/or the expression of TLE (Andre et al, 2003; Bertram et al, 2001; Bertram and Scott, 2000; Bertram et al, 1998; Du et al, 1993; Francois et al, 2011; Spencer and Spencer, 1994). The inability of lesional or physiological alterations in the hippocampal formation to account for all cases of TLE, along with documented cases of isolated damage to other regions that result in the clinical features of TLE indistinguishable from those with clear damage in the hippocampus, suggest that while the hippocampus may be important in a subset of TLE patients, other regions and mechanisms may also be involved.…”

Section: Discussionmentioning

confidence: 99%

Neuronal degeneration is observed in multiple regions outside the hippocampus after lithium pilocarpine-induced status epilepticus in the immature rat

2013

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Although hippocampal sclerosis is frequently identified as a possible epileptic focus in patients with temporal lobe epilepsy, neuronal loss has also been observed in additional structures, including areas outside the temporal lobe. The claim from several researchers using animal models of acquired epilepsy that the immature brain can develop epilepsy without evidence of hippocampal neuronal death raises the possibility that neuronal death in some of these other regions may also be important for epileptogenesis. The present study used the lithium pilocarpine model of acquired epilepsy in immature animals to assess which structures outside the hippocampus are injured acutely after status epilepticus. Sprague Dawley rat pups were implanted with surface EEG electrodes, and status epilepticus was induced at 20 days of age with lithium pilocarpine. After 72 h, brain tissue from 12 animals was examined with Fluoro-Jade B, a histochemical marker for degenerating neurons. All animals that had confirmed status epilepticus demonstrated Fluoro-Jade B staining in areas outside the hippocampus. The most prominent staining was seen in thalamus (mediodorsal, paratenial, reuniens, and ventral lateral geniculate nuclei), amygdala (ventral lateral, posteromedial, and basomedial nuclei), ventral premammillary nuclei of hypothalamus, and paralimbic cortices (perirhinal, entorhinal, and piriform) as well as parasubiculum and dorsal endopiriform nuclei. These results demonstrate that lithium pilocarpine-induced status epilepticus in the immature rat brain consistently results in neuronal injury in several distinct areas outside of the hippocampus. Many of these regions are similar to areas damaged in patients with temporal lobe epilepsy, thus suggesting a possible role in epileptogenesis.

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Section: Discussionmentioning

confidence: 99%

Neuronal degeneration is observed in multiple regions outside the hippocampus after lithium pilocarpine-induced status epilepticus in the immature rat

2013

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“…Partly this is due to power analysis issues and partly to the lack of uniform system of classifying and diagnosing seizures in experimental animals. Of note, when carisbamate was tested in the lithium‐pilocarpine model, it prevented motor seizures but increased the incidence of spike‐wave discharges in rats 62. As in humans, animal models of epilepsy do not necessarily have one type of seizures.…”

Section: Opportunities To Narrow the Preclinical‐clinical Trial Gap Amentioning

confidence: 99%

Not all that glitters is gold: A guide to critical appraisal of animal drug trials in epilepsy

Galanopoulou

Mowrey

2016

Epilepsia Open

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SummaryPreclinical studies have produced numerous drugs with antiseizure properties that currently are the standard of care. One third of the human population with epilepsy still continues to have seizures despite the ongoing discoveries. The recognized clinical gaps of care that need to be addressed are the identification of antiepileptogenic and disease‐modifying treatments, and treatments for refractory seizures or for seizures and epilepsies with limited or unsatisfactory treatments, such as early life epileptic encephalopathies. In this invited review, we provide a historical summary of the international efforts to reevaluate the strategies adopted in preclinical epilepsy therapy discovery studies. We discuss issues that may affect the quality, interpretation, and validation of preclinical studies and their translation to successful therapies for humans affected with epilepsy. These include the selection of animal models and the study design; research practices that affect rigor (such as appropriate use of statistics and reporting of study methods and results, their validation across models, labs, and preclinical‐clinical studies); the need to harmonize research methods and outcome assessment; and the importance of improving translation to clinically appropriate situations. The epilepsy research community is incrementally adopting collaborative research, including consortia or multicenter studies to meet these needs. Improving the infrastructure that can support these efforts will be instrumental in future success.

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“…Its mechanism of action in epilepsy is related to an antiglutamatergic effect, as reductions in glutamate transmission have been observed in the granule cell of the dentate gyrus (Lee et al, 2011). Indeed, it has been shown to display neuroprotective properties by dose dependently reducing neuronal loss in the hippocampus, amygdala, and thalamus after status epilepticus in rats (François et al, 2011). Another research group demonstrated that carisbamate had an antidepressant-like effect in the forced swim test (FST) model of depression in rodent models, with no significant affinity for 5-hydroxytryptamine (5-HT) or dopamine (DA) receptors.…”

Section: Introductionmentioning

confidence: 99%

Modulation of the Antidepressant-Like Effects of Sustained Administration of Carisbamate and Lamotrigine on Monoaminergic Systems: Electrophysiological Studies in the Rat Brain

Shim

Mansari

Blier

2013

J Pharmacol Exp Ther

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Carisbamate and lamotrigine are anticonvulsants that act on neuronal voltage-gated sodium channels. Carisbamate has shown antidepressant-like effects in animal models of depression, and lamotrigine is a mood stabilizer with a therapeutic effect in depressive episodes of patients with bipolar disorder. This study examined the effects of carisbamate and lamotrigine on monoaminergic transmission in rodents, which could contribute to their antidepressant action. In vivo electrophysiological recordings were carried out in rats after 2 and 14 days administration of vehicle, carisbamate (60 mg/kg daily), or lamotrigine (25 mg/kg daily). Overall firing activity of the dorsal raphe nucleus (DRN) serotonin (5-HT), locus coeruleus norepinephrine, and ventral tegmental area dopamine (DA) neurons was decreased with carisbamate. Lamotrigine also decreased 5-HT neuronal firing, and this effect was abolished by lesion of the prefrontal cortex. Despite these decreases in firing activity after their prolonged administration, both anticonvulsants exhibited a significant increase in tonic activation of hippocampus 5-HT 1A receptors, as shown by a disinhibition of the firing activity of pyramidal neurons in response to the selective antagonist WAY-100635 (N-{2-[4(2-methoxyphenyl)-1-piperazinyl] ethyl}-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride). This finding reveals an increase in the 5-HT level that may be attributed to a desensitization of the terminal 5-HT 1B autoreceptors. This study demonstrates that sustained carisbamate and lamotrigine administration decreases 5-HT firing in the DRN but nevertheless enhances 5-HT transmission in the forebrain. This serotonergic effect may be associated with an antiglutamatergic action and may contribute to the antidepressant-like effect of carisbamate in the forced swim test and the antidepressant properties of lamotrigine.

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Carisbamate has powerful disease-modifying effects in the lithium-pilocarpine model of temporal lobe epilepsy

Cited by 27 publications

References 50 publications

Neuronal degeneration is observed in multiple regions outside the hippocampus after lithium pilocarpine-induced status epilepticus in the immature rat

Neuronal degeneration is observed in multiple regions outside the hippocampus after lithium pilocarpine-induced status epilepticus in the immature rat

Not all that glitters is gold: A guide to critical appraisal of animal drug trials in epilepsy

Modulation of the Antidepressant-Like Effects of Sustained Administration of Carisbamate and Lamotrigine on Monoaminergic Systems: Electrophysiological Studies in the Rat Brain

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