The usefulness of olfactory bulb kindling as a model for evaluation of antiepileptics

Fujiwara, Akinori; Watanabe, Yusuke; Takechi, Kenshi; Ishikawa, Takashi; Kaida, Yuko; Akagi, Masaaki; Kamei, Chiaki

doi:10.1111/j.1528-1167.2009.02378.x

Cited by 7 publications

(4 citation statements)

References 32 publications

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“…Of note, however, this estimation does not effectively encapsulate the bladder retention and skin discoloration that have limited ezogabine's clinical utility. 34,36,43 Topiramate was not highly effective in this model and poorly tolerated in a majority of animals at the dose tested. 19 Further, valproate has previously demonstrated efficacy against the amygdala-kindled seizure model.…”

Section: Discussionmentioning

confidence: 81%

“…[34][35][36][37] Similarly, tiagabine reduces seizures in amygdala kindling 38 and hippocampal kindling at comparable doses. Conversely, carbamazepine, lacosamide, and phenytoin were better tolerated in lamotrigine-resistant fully kindled rats, as their estimated TD 50 values in these animals are 1.5-to 3-fold higher than those obtained in young adult rats.…”

Section: Discussionmentioning

confidence: 96%

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Evaluation of antiseizure drug efficacy and tolerability in the rat lamotrigine‐resistant amygdala kindling model

et al. 2019

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Objective The lamotrigine‐resistant amygdala kindling model uses repeated administration of a low dose of lamotrigine during the kindling process to produce resistance to lamotrigine, which also extends to some other antiseizure drugs (ASDs). This model of pharmacoresistant epilepsy has been incorporated into the testing scheme utilized by the Epilepsy Therapy Screening Program (ETSP). Although some ASDs have been evaluated in this model, a comprehensive evaluation of ASD prototypes has not been reported. Methods Following depth electrode implantation and recovery, rats were exposed to lamotrigine (5 mg/kg, i.p.) prior to each stimulation during the kindling development process (~3 weeks). A test dose of lamotrigine was used to confirm that fully kindled rats were lamotrigine‐resistant. Efficacy (unambiguous protection against electrically elicited convulsive seizures) was defined as a Racine score < 3 in the absence of overt compound‐induced side effects. Various ASDs, comprising several mechanistic classes, were administered to fully kindled, lamotrigine‐resistant rats. Where possible, multiple doses of each drug were administered in order to obtain median effective dose (ED 50 ) values. Results Five sodium channel blockers tested (eslicarbazepine, lacosamide, lamotrigine, phenytoin, and rufinamide) were either not efficacious or effective only at doses that were not well‐tolerated in this model. In contrast, compounds targeting either GABA receptors (clobazam, clonazepam, phenobarbital) or GABA‐uptake proteins (tiagabine) produced dose‐dependent efficacy against convulsive seizures. Compounds acting to modulate Ca 2+ channels show differential activity: Ethosuximide was not effective, whereas gabapentin was moderately efficacious. Ezogabine and valproate were also highly effective, whereas topiramate and levetiracetam were not effective at the doses tested. Significance These results strengthen the conclusion that the lamotrigine‐resistant amygdala kindling model demonstrates pharmacoresistance to certain ASDs, including, but not limited to, sodium channel blockers, and supports the utility of the model for helping to identify compounds with potential efficacy against pharmacoresistant seizures.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 96%

Evaluation of antiseizure drug efficacy and tolerability in the rat lamotrigine‐resistant amygdala kindling model

et al. 2019

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“…The OB has long been known to generate various types of oscillations in vivo (Adrian 1942;Macrides and Chorover 1972), ranging from respiratory delta/theta frequencies (ϳ1-12 Hz), through the beta range (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), to gamma oscillations (40 -100 Hz) (Kay et al 2009). Like other cortical structures with a capacity for oscillations, the OB is very seizure prone (Araki et al 1995;Cain 1977;Fujiwara et al 2010;McEvoy et al 2002). The rodent OB slice ( Fig.…”

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confidence: 94%

Low-magnesium medium induces epileptiform activity in mouse olfactory bulb slices

Igelström

Shirley

Heyward

2011

Journal of Neurophysiology

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Magnesium-free medium can be used in brain slice studies to enhance glutamate receptor function, but this manipulation causes seizure-like activity in many cortical areas. The rodent olfactory bulb (OB) slice is a popular preparation, and potentially ictogenic ionic conditions have often been used to study odor processing. We studied low Mg(2+)-induced epileptiform discharges in mouse OB slices using extracellular and whole cell electrophysiological recordings. Low-Mg(2+) medium induced two distinct types of epileptiform activity: an intraglomerular delta-frequency oscillation resembling slow sniff-induced activity and minute-long seizure-like events (SLEs) consisting of large negative-going field potentials accompanied by sustained depolarization of output neurons. SLEs were dependent on N-methyl-D-aspartate receptors and sodium currents and were facilitated by α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors. The events were initiated in the glomerular layer and propagated laterally through the external plexiform layer at a slow time scale. Our findings confirm that low-Mg(2+) medium should be used with caution in OB slices. Furthermore, the SLEs resembled the so-called slow direct current (DC) shift of clinical and experimental seizures, which has recently been recognized as being of great clinical importance. The OB slice may therefore provide a robust and unique in vitro model of acute seizures in which mechanisms of epileptiform DC shifts can be studied in isolation from fast oscillations.

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“…Intense olfactory input induced by octanol elicits seizures in the transgenic mice engineered to express an octanal receptor in almost all olfactory sensory neurons [20]. In addition, olfactory kindling can cause epilepsy in normal rats [21].…”

Section: Th-positive Interneuron Did Not Show Any Increasing Tendency In Their Number In Nermentioning

confidence: 99%

PHF24 is expressed in the inhibitory interneurons in rats

et al. 2021

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Noda epileptic rat (NER) is a mutant model for epilepsy that exhibits spontaneous generalized tonic-clonic seizure. Epileptogenesis of NER remains to be elucidated; but it is detected an insertion of an endogenous retrovirus sequence in intron 2 of the PHD finger protein 24 (Phf24) gene, encoding Gαi-interacting protein (GINIP). Phf24 is a strong candidate gene for epileptogenesis in NER. PHF24 modulates GABA B signaling through interacting with Gαi protein. To clarify the epileptogenesis of NER, we investigated a distribution of PHF24-expressing cells in the central nerve system (CNS). While broad expression of PHF24 was observed in the CNS, characteristic expression was noted in the periglomerular layer of the olfactory bulb and the lamina II of the spinal cord in the control rats. These cells showed co-expression with calbindin or calretinin, inhibitory interneuron markers. In the olfactory bulb, 15.6% and 41.2 % of PHF24-positive neurons co-expressed calbindin and calretinin, respectively. Immunoelectron microscopy revealed that PHF24 was located in the presynaptic terminals, synaptic membranes and cytoplasmic matrix of neuronal soma. Our data suggested PHF24 is expressed in the inhibitory interneurons and may play important roles in modulation of the GABA B signaling.

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The usefulness of olfactory bulb kindling as a model for evaluation of antiepileptics

Cited by 7 publications

References 32 publications

Evaluation of antiseizure drug efficacy and tolerability in the rat lamotrigine‐resistant amygdala kindling model

Evaluation of antiseizure drug efficacy and tolerability in the rat lamotrigine‐resistant amygdala kindling model

Low-magnesium medium induces epileptiform activity in mouse olfactory bulb slices

PHF24 is expressed in the inhibitory interneurons in rats

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