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Objective: Sudden unexpected death in epilepsy (SUDEP) results in more years of potential life lost than any neurological condition with the exception of stroke. It is generally agreed that SUDEP happens due to some form of respiratory, cardiac, and electrocerebral dysfunction following a seizure; however, the mechanistic cause of these perturbations is unclear. One possible explanation lies with adenosinergic signaling. Extracellular levels of the inhibitory neuromodulator adenosine rapidly rise during seizures, a countermeasure that is necessary for seizure termination. Previous evidence has suggested that excessive adenosinergic inhibition could increase the risk of SUDEP by silencing brain areas necessary for life, such as the respiratory nuclei of the brainstem. The goal of this investigation was to further clarify the role of adenosine in seizure‐induced respiratory and electrocerebral dysfunction. Methods: To determine the role of adenosine in postictal physiological dysregulation, we pharmacologically manipulated adenosine signaling prior to amygdala‐kindled seizures in mice while recording electroencephalogram (EEG), electromyogram, and breathing using whole body plethysmography. The adenosinergic drugs used in this study included selective and nonselective adenosine receptor antagonists and inhibitors of adenosine metabolism. Results: We found that high doses of adenosine receptor antagonists caused some seizures to result in seizure‐induced death; however, counterintuitively, animals in these conditions that did not experience seizure‐induced death had little or no postictal generalized EEG suppression. Inhibitors of adenosine metabolism had no effect on postictal breathing but did worsen some postictal electrocerebral outcomes. Significance: The unexpected effect of high doses of adenosine antagonists on seizure‐induced death observed in this study may be due to the increase in seizure severity, vasoconstriction, or phosphodiesterase inhibition caused by these drugs at high doses. These findings further clarify the role of adenosine in seizure‐induced death and may have implications for the consumption of caffeine in epilepsy patients and the prevention of SUDEP. [ABSTRACT FROM AUTHOR]

Objective: Alcohol‐related seizures (ARS) are one of the most important consequences of alcohol withdrawal syndrome (AWS). However, demographic and clinical characteristics, and furthermore, the relationship of ARS with delirium tremens (DT), have not yet been evaluated in detail. Therefore, the aim of the present study was to reveal the correlates of ARS and examine the interaction of ARS with the occurrence of DT and with the severity of AWS. Methods: In the retrospective study (Study 1) 2851 medical charts of inpatient admissions characterized by AWS and DT were listed. Demographic and clinical variables of ARS were assessed. In the follow‐up study (Study 2), patients admitted with AWS without (N = 28) and with (N = 18) ARS were enrolled. Study 1 was performed between 2008 and 2023, and Study 2 was performed in 2019 in Hungary. To determine the severity of AWS, the Clinical Institute Withdrawal Assessment Scale for Alcohol, Revised (CIWA‐Ar) was used. ARS is a provoked, occasional seizure; therefore, patients with epilepsy syndrome were excluded from the two studies. Statistical analyses were performed by the means of chi‐square tests, multinomial logistic regressions, mixed ANOVA, and derivation. Results: The occurrence of DT, the history of ARS, and somatic co‐morbidities were found to be risk factors for the appearance of ARS. ARS was proved to be a risk factor for the development of DT. In the follow‐up study, there was no difference in the decrease of CIWA‐Ar scores between the groups. Significance: Our present findings support the likelihood of kindling, which is one of the most important mechanisms underlying the development of ARS, but do not directly prove its presence. Additionally, our results revealed that the severity of AWS is not influenced by the presence of ARS. Plain Language Summary: Provoked, occasional seizures during AWS are defined as ARS. In the present study, predictors and interactions of these seizures with DT—the most severe form of withdrawal—and with the severity of withdrawal were examined in retrospective and follow‐up studies. The present study shows that a history of withdrawal seizures, the occurrence of DT, and somatic comorbidities are predictors of the development of seizures. Furthermore, our findings suggest that the presence of seizures does not influence the severity of withdrawal. [ABSTRACT FROM AUTHOR]

Seizures beget seizures is a longstanding theory that proposed that seizure activity can impact the structural and functional properties of the brain circuits in ways that contribute to epilepsy progression and the future occurrence of seizures. Originally proposed by Gowers, this theory continues to be quoted in the pathophysiology of epilepsy. We critically review the existing data and observations on the consequences of recurrent seizures on brain networks and highlight a range of factors that speak for and against the theory. The existing literature demonstrates clearly that ictal activity, especially if recurrent, induces molecular, structural, and functional changes including cell loss, connectivity reorganization, changes in neuronal behavior, and metabolic alterations. These changes have the potential to modify the seizure threshold, contribute to disease progression, and recruit wider areas of the epileptic network into epileptic activity. Repeated seizure activity may, thus, act as a pathological positive‐feedback mechanism that increases seizure likelihood. On the other hand, the time course of self‐limited epilepsies and the presence of seizure remission in two thirds of epilepsy cases and various chronic epilepsy models oppose the theory. Experimental work showed that seizures could induce neural changes that increase the seizure threshold and decrease the risk of a subsequent seizure. Due to the complex nature of epilepsies, it is wrong to consider only seizures as the key factor responsible for disease progression. Epilepsy worsening can be attributed to the various forms of interictal epileptiform activity or underlying disease mechanisms. Although seizure activity can negatively impact brain structure and function, the "seizures beget seizures" theory should not be used dogmatically but with extreme caution. [ABSTRACT FROM AUTHOR]

Aims: Deep brain electrical stimulation (DBS), as a potential therapy for drug resistive epileptic patients, has inhibitory action on epileptogenesis. In the present investigation, the role of dopamine D2‐like receptors in the antiepileptogenic action of DBS was studied. Methods: Seizures were induced in adult rats by stimulating the perforant path in a semi‐rapid kindling method. Five minutes after the last kindling stimulation, daily DBS was applied to the perforant path at the pattern of low frequency stimulation (LFS; 1 Hz; pulse duration: 0.1 ms; intensity: 50–150 μA; 4 trains of 200 pulses at 5 min intervals). Sulpiride (10 μg/1 μl, i.c.v.), a selective dopamine D2‐like receptor antagonist, was administered prior to the daily LFS application. Results: Kindling stimulations increased cumulative daily behavioral seizure stages, daily afterdischarge duration (dADD), and population spike amplitude (PS) in dentate gyrus following perforant path stimulation, while applying LFS decreased the kindled seizures' parameters. In addition, kindling potentiated the early (at 10–50 ms inter‐pulse interval) and late (at 150–1000 ms inter‐pulse interval) paired‐pulse inhibition and decreased the paired‐pulse facilitation (at 70–100 ms inter‐pulse interval). These effects were also inhibited by applying LFS. All inhibitory effects of LFS on kindling procedure were prevented by sulpiride administration. Conclusion: These data may suggest that LFS exerts its preventive effect on kindling development, at least partly, through the receptors on which sulpiride acts which are mainly dopamine D2‐like (including D2, D3, and D4) receptors. [ABSTRACT FROM AUTHOR]

Photothermal therapy (PTT) has been approved clinically to ablate epileptogenic focus, while the clinical application of this approach is still hindered due to its limited selectivity and potential safety concerns related to extreme hyperthermia. Hypothermal PPT (HPTT) is a novel treatment modality employing mild hyperthermia to ablate abnormal cells, which has a distinctive advantage of minimal side effects on healthy tissues. The significantly elevated hydrogen peroxide (H2O2) concentration in the epileptogenic zone provides a suitable microenvironment for selective chemodynamic therapy (CDT), which utilizes the Fenton reaction of H2O2 and iron‐based nanomaterials to generate cytotoxic free radicals. Herein, the authors report proof‐of‐concept evidence that HPTT and CDT can be successfully integrated to ablate epileptogenic focus. A photothermal nanocatalyst ferrous disulfide nanoplatform is prepared for CDT of epilepsy. More importantly, the CDT efficacy is augmented by the second near‐infrared irradiation‐induced hyperthermia, leading to synergistic HPTT and CDT therapy. In vivo studies on pentylenetetrazole kindling epileptic rats show that the frequency and severity of epileptic attacks are remarkably suppressed after ablation of the epileptogenic focus. It is envisioned that this HPTT augmented CDT strategy may serve as a novel strategy for the treatment of focal epilepsy. [ABSTRACT FROM AUTHOR]

Objective: Patients with temporal lobe epilepsy (TLE) frequently report debilitating comorbidities such as memory impairments, anxiety, and depression. An extensive neuronal network generates epileptic seizures and associated comorbidities, but a detailed description of this network is unavailable, which requires the generation of neuronal activation maps in experimental animals. Methods: We recorded electrographic seizures from the hippocampi during a kindling‐evoked focal impaired awareness seizure with observed freezing, facial twitching, and involuntary head bobbing. We mapped seizure circuits activated during these seizures by permanently tagging neurons through activity‐induced immediate early genes, combined with immunohistochemical approaches. Results: There was bilateral activation of circuits necessary for memory consolidation, including the hippocampal complex, entorhinal cortex, cingulate gyrus, retrosplenial cortex, piriform cortex, and septohippocampal complex in kindled animals compared with unstimulated awake behaving mice. Neuronal circuits in the ventral hippocampus, amygdala, and anterior cingulate cortex, which regulate the stress response of hypothalamic‐pituitary‐adrenal axis, were also markedly activated during a focal impaired awareness seizure. Significance: This study highlights neuronal circuits preferentially activated during a focal awareness impaired seizure in a rodent model. Many of the seizure‐activated neuronal circuits are critical modulators of memory consolidation and long‐term stress/depression response. The hijack of these memory and depression regulatory systems by a focal seizure could account for the frequent reports of comorbidities such as memory impairment and depression in many TLE patients. [ABSTRACT FROM AUTHOR]

In this study, it was aimed to investigate possible ameliorating effects of thymoquinone on testicular damage in an epilepsy model. Adult male Wistar rats were divided into 4 groups. The animals in sham‐operated groups were given saline or thymoquinone (s.c.); and the animals in pentylenetetrazole (PTZ) group were applied PTZ. The animals in PTZ+thymoquinone group were given thymoquinone (i.p) for 6 days after applying PTZ. Hematoxylin‐eosin, periodic acid–Schiff and TUNEL staining and PCNA, StAR, inhibin β‐B immunohistochemistry and ZO‐1 immunofluorescence methods were applied. Staining intensity and cell numbers were determined. Degeneration of seminiferous tubules was observed in PTZ group. Most of the tubules showed normal morphology in the PTZ+thymoquinone group. Apoptotic cell index was found to be increased and proliferative index decreased in PTZ group. Thymoquinone administration decreased apoptotic index and increased proliferation index. In PTZ group, ZO‐1, StAR and inhibin β‐B immunohistochemical staining intensity was observed to be decreased and after thymoquinone application, ZO‐1 was increased. StAR and inhibin β‐B‐positive cell numbers were decreased in PTZ group and increased in the PTZ +thymoquinone group. In this study, it was observed that PTZ‐induced epileptic seizures caused testicular damage in the rat and thymoquinone ameliorated these effects. [ABSTRACT FROM AUTHOR]

This study evaluated the effect of lacosamide (LCM) on biochemical and mitochondrial parameters after PTZ kindling in mice. Male mice were treated on alternative days for a period of 11 days with LCM (20, 30, or 40 mg/kg), saline, or diazepam (2 mg/kg), before PTZ administration (50 mg/kg). The hippocampi were collected to evaluate free radicals, the activities of superoxide dismutase (SOD), catalase (CAT), and the mitochondrial complexes I‐III, II, and II‐III, as well as Bcl‐2 and cyclo‐oxygenase‐2 (COX‐2) expressions. Hippocampi, blood, and bone marrow were collected for genotoxic and mutagenic evaluations. LCM 40 mg/kg increased latency and decreased percentage of seizures, only on the 3rd day of observation. The dose of 30 mg/kg only showed positive effects on the percentage of seizures on the 2nd day of observation. LCM decreased free radicals and SOD activity and the dose of 40 mg/kg were able to increase CAT activity. LCM 30 and 40 mg/kg improved the enzymatic mitochondrial activity of the complex I‐III and LCM 30 mg/kg improved the activity of the complex II. In the comet assay, the damage induced by PTZ administration was reduced by LCM 20 and 30 mg/kg. The dose of 20 mg/kg increased COX‐2 expression while the highest dose used, 40 mg/kg, was able to reduce this expression when compared to the group treated with LCM 20 mg/kg. Although LCM did not produce the antiepileptogenic effect in vivo, it showed the neuroprotective effect against oxidative stress, bioenergetic dysfunction, and DNA damage induced by the repeated PTZ administration. [ABSTRACT FROM AUTHOR]

Chrysin is the major bioactive compound of blue passionflower, an important medicinal plant used in traditional herbal formulations since ancient times. In the present study, we report that chrysin nanoparticles (chrysin NPs) protect Wistar rats against kindling‐induced epilepsy. Nanoparticles of sizes less than 150 nm with a spherical shape were prepared using poly(d,l‐lactic‐co‐glycolic acid) and polyvinyl alcohol, respectively, as polymer and stabilizer. Rats were injected with subconvulsive doses of pentylenetetrazole (PTZ) (35 mg/kg, intraperitoneal) every second day, with 22 injections in total, and on the same days, they received protective doses of the chrysin NPs (5 and 10 µg/mL, PO), respectively, 45 min before each PTZ injection. After the last PTZ injection, an average of thirteen seizure scores was recorded. Animals were killed by decapitation 24 h after a seizure. The cortex and hippocampus were removed and stored in liquid nitrogen for determining oxidative stress terminal deoxynucleotidyl transferase dUTP nick‐end labeling assay, histopathology, and reverse transcription‐polymerase chain reaction for messenger RNA expression. The result showed chrysin NPs treatment has counteracted oxidative stress, reduced neuronal apoptosis, and upregulated nuclear factor erythroid 2‐related factor 2 (Nrf2), heme oxygenase‐1 (HO‐1), and NAD(P)H quinone oxidoreductase 1. In conclusion, our findings demonstrate that the neuroprotective effect of chrysin NPs against kindling‐induced epilepsy might be escorted by the alleviation of oxidative stress through the Nrf2/antioxidant response element/HO‐1 pathway signal pathway. [ABSTRACT FROM AUTHOR]

Epileptogenesis is a dynamical process that involves synaptic plasticity changes such as synaptic reorganization of excitatory and inhibitory systems and axonal sprouting in the hippocampus, which is one of the most studied epileptogenic regions in the brain. However, the early events that trigger these changes are not understood well. We investigated short‐term and long‐term synaptic plasticity parameters and T‐type Ca2+ channel activity changes in the early phase of a rat kindling model. Chronic pentylenetetrazole (PTZ) application was used in order to induce the kindling process in rats. The recordings were obtained from hippocampal slices in the CA1 region at 25th day of PTZ application. Tetraethylammonium was used in order to induce long‐term potentiation and T‐type Ca2+ channel activity was assessed in the presence of mibefradil. We found that tetraethylammonium‐induced long‐term potentiation was not prevented by mibefradil in the kindling group in contrast to control group. We also found an increase in paired‐pulse ratios in the PTZ‐applied group. Our findings indicate an increase in the "T‐type Ca2+ channel component of LTP" in the kindling group, which may be an early mechanism in epileptogenesis. [ABSTRACT FROM AUTHOR]

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 (ED50) 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 Ca2+ 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. [ABSTRACT FROM AUTHOR]

Objective: The cystine/glutamate antiporter system xc− could represent a new target for antiepileptogenic treatments due to its crucial roles in glutamate homeostasis and neuroinflammation. To demonstrate this, we compared epilepsy development and seizure susceptibility in xCT knockout mice (xCT−/−) and in littermate controls (xCT+/+) in different chronic models of epilepsy. Methods: Mice were surgically implanted with electrodes in the basolateral amygdala and chronically stimulated to develop self‐sustained status epilepticus (SSSE); continuous video‐electroencephalography monitoring was performed for 28 days after SE and hippocampal histopathology was assessed. Corneal kindling was induced by twice daily electrical stimulation at 6 Hz and maintenance of the fully kindled state was evaluated. Next, messenger RNA (mRNA) and protein levels of xCT and of the proteins involved in the phosphoinositide 3‐kinase (PI3K)/Akt/glycogen synthase kinase 3β (GSK‐3β)/eukaryotic initiation factor 2α (eIF2α)/activating transcription factor 4 (ATF4) signaling pathway were measured at different time points during epileptogenesis in NMRI mice treated with pilocarpine. Finally, the anticonvulsant effect of sulfasalazine (SAS), a nonselective system xc− inhibitor, was assessed against 6 Hz‐evoked seizures in pilocarpine‐treated mice. Results: In the SSSE model, xCT−/− mice displayed a significant delayed epileptogenesis, a reduced number of spontaneous recurrent seizures, and less pronounced astrocytic and microglial activation. Moreover, xCT−/− mice showed reduced seizure severity during 6 Hz kindling development and a lower incidence of generalized seizures during the maintenance of the fully kindled state. In pilocarpine‐treated mice, protein levels of the PI3K/Akt/GSK‐3β/eIF2α/ATF4 pathway were increased during the chronic phase of the model, consistent with previous findings in the hippocampus of patients with epilepsy. Finally, repeated administration of SAS protected pilocarpine‐treated mice against acute 6 Hz seizure induction, in contrast to sham controls, in which system xc− is not activated. Significance: Inhibition of system xc− could be an attractive target for the development of new therapies with a potential for disease modification in epilepsy. [ABSTRACT FROM AUTHOR]

Summary: Objective: Sex differences are evident in the antiseizure activity of neurosteroids; however, the potential mechanisms remain unclear. In this study, we sought to determine whether differences in target extrasynaptic δ‐subunit γ‐aminobutyric acid type A (GABA‐A) receptor expression and function underlie the sex differences in seizure susceptibility and the antiseizure activity of neurosteroids. Methods: Sex differences in seizure susceptibility and protective activity of three distinct neurosteroids—allopregnanolone (AP), androstanediol (AD), and ganaxolone—were evaluated in the pilocarpine model of status epilepticus (SE) and kindling seizure test in mice. Immunocytochemistry was used for δGABA‐A receptor expression analysis, and patch‐clamp recordings in brain slices evaluated its functional currents. Results: Sex differences were apparent in kindling epileptogenic seizures, with males exhibiting a faster progression to a fully kindled state. Neurosteroids AP, AD, or ganaxolone produced dose‐dependent protection against SE and acute partial seizures. However, female mice exhibited strikingly enhanced sensitivity to the antiseizure activity of neurosteroids compared to males. Sex differences in neurosteroid protection were unrelated to pharmacokinetic factors, as plasma levels of neurosteroids associated with seizure protection were similar between sexes. Mice lacking extrasynaptic δGABA‐A receptors did not exhibit sex differences in neurosteroid protection. Consistent with a greater abundance of extrasynaptic δGABA‐A receptors, AP produced a significantly greater potentiation of tonic currents in dentate gyrus granule cells in females than males; however, such enhanced AP sensitivity was diminished in δGABA‐A receptor knockout female mice. Significance: Neurosteroids exhibit greater antiseizure potency in females than males, likely due to a greater abundance of extrasynaptic δGABA‐A receptors that mediate neurosteroid‐sensitive tonic currents and seizure protection. These findings indicate the potential to develop personalized gender‐specific neurosteroid treatments for SE and epilepsy in men and women, including catamenial epilepsy. [ABSTRACT FROM AUTHOR]

Summary: Objective: Although the cystine/glutamate antiporter System xc− (Sxc−) plays a permissive role in glioma‐associated seizures, its contribution to other acquired epilepsies has not been determined. As such, the present study investigates whether and how Sxc− contributes to the pentylenetetrazole (PTZ) chemical kindling model of epileptogenesis. Methods: Male Sxc− null (sut/sut) mice and their wild‐type littermates were administered PTZ (i.p.) daily for up to 21 days (kindling paradigm). Seizure severity was scored on a 5‐point behavioral scale. Mossy fiber sprouting, cellular degeneration, and Sxc− light chain (xCT) messenger RNA (mRNA) were explored using Timm staining, thionin staining, and real‐time quantitative polymerase chain reaction (qPCR), respectively. Levels of reduced and oxidized glutathione and cysteine were determined via high‐performance liquid chromatography (HPLC). Plasma membrane protein levels of glutamate and γ‐aminobutyric acid (GABA) receptor subunits as well as the K+/Cl− co‐transporter KCC2 were quantified via western blot analysis. Results: Repeated administration of PTZ produced chemical kindling in only 50% of Sxc− null mice as compared to 82% of wild‐type littermate control mice. Kindling did not result in any changes in xCT mRNA levels assessed in wild‐type mice. No cellular degeneration or mossy fiber sprouting was discernible in either genotype. Except for a small, but significant, decrease in oxidized cysteine in the hippocampus, no other change in measured redox couples was determined in Sxc− null mice. Cortical levels of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor subunit GluA1 were decreased in Sxc− null mice as compared to wild‐type littermates, whereas all other proteins tested showed no difference between genotypes. Significance: This study provides the first evidence that Sxc− signaling contributes to epileptogenesis in the PTZ kindling model of acquired epilepsy. Further data indicate that a reduction in AMPA receptor signaling could underlie the resistance to PTZ kindling uncovered in Sxc− null mice. [ABSTRACT FROM AUTHOR]

Summary: We describe a patient with new‐onset temporal lobe epilepsy during prolonged maintenance electroconvulsive therapy. We suggest a possible causal relationship with maintenance electroconvulsive therapy through electrical kindling of the temporal lobe. [ABSTRACT FROM AUTHOR]

Abstract: Epoxy‐carvone (EC) has chiral centers that allow generation of stereoisomers, including (+)‐cis‐EC and (−)‐cis‐EC, whose effects in the kindling tests have never been studied. Accordingly, this study aims to comparatively investigate the effect of stereoisomers (+)‐cis‐epoxy‐carvone and (−)‐cis‐epoxy‐carvone on behavioral changes measured in scores, in the levels of cytokines (IL‐1β, IL‐6, and TNFα) and neuronal protection in the face of continuous treatment with pentylenetetrazol. Swiss mice were divided into five groups (n = 10), receiving vehicle, (+) – cis‐EC, (−) – cis‐EC (both at the dose of 30 mg/kg), and diazepam (4 mg/kg). Thirty minutes after the respective treatment was administered to the animals one subconvulsive dose of PTZ (35 mg/kg). Seven subconvulsives treatments were made on alternate days, in which each treatment several parameters were recorded. In the eighth treatment, the animals receiving the highest dose of PTZ (75 mg/kg) and were sacrificed for quantification of cytokines and histopathologic analysis. All drugs were administered by intraperitoneal route. In the kindling test, (+)‐cis‐EC and (−)‐cis‐EC reduced the average scores. The stereoisomer (+)‐cis‐EC decreased levels of proinflammatory cytokines IL‐1β, IL‐6, and TNFα, whereas comparatively (−)‐cis‐EC did not reduce IL‐1β levels. Histopathological analysis of the mice hippocampi undergoing this methodology showed neural protection for treated with (+)‐cis‐EC. The results suggest that the anticonvulsant effect of (+)‐cis‐EC possibly takes place due to reduction of proinflammatory cytokines involved in the epileptogenic process, besides neuronal protection, yet further investigation of the mechanisms involved is required. [ABSTRACT FROM AUTHOR]

Summary: Objective: Studies have addressed the potential involvement of L‐12/15‐lipoxygenases (LOs), a polyunsaturated fatty acid metabolizing enzyme, in experimental models of acute stroke and chronic neurodegeneration; however, none to our knowledge has explored its role in epilepsy development. Thus, this study characterizes the cell‐specific expression of L‐12/15 ‐LO in the brain and examines its contribution to epileptogenesis. Methods: L‐12/15‐LO messenger RNA (mRNA) and protein expression and activity were characterized via polymerase chain reaction (PCR), immunocytochemistry and enzyme‐linked immunosorbent assay (ELISA), respectively. To assess its role in epileptogenesis, L‐12/15 ‐LO‐deficient mice and their wild‐type littermates were treated with pentylenetetrazole (PTZ, ip) every other day for up to 43 days (kindling paradigm). The innate seizure threshold was assessed by the acute PTZ‐induced seizure response of naive mice. Results: L‐12/15 ‐LO mRNA is expressed in hippocampal and cortical tissue from wild‐type C57BL/6 mice. In addition, it is physically and functionally expressed by microglia, neurons, and brain microvessel endothelial cells, but not by astrocytes. Mice deficient in L‐12/15 ‐LO were resistant to PTZ‐induced kindling and demonstrated an elevated innate seizure threshold. Despite this, a significant increase in seizure‐related mortality was observed during the kindling paradigm in L‐12/15 ‐LO nulls relative to their wild‐type littermates. Significance: The present study is the first to detail the role of L‐12/15‐LO in the epileptogenic process. The results suggest that constitutive L‐12/15‐LO expression contributes to a lower innate set point for PTZ acute seizure generation, translating to higher rates of kindling acquisition. Nevertheless, increased seizure‐related deaths in mice lacking activity of L‐12/15‐LO suggests that its products may influence endogenous mechanisms involved in termination of seizure activity. [ABSTRACT FROM AUTHOR]

Objective Perampanel ( PER) is a selective noncompetitive antagonist at α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, the first of its class approved for the adjunctive treatment of partial onset seizures and generalized seizures. This study explored anti-ictogenic and antiepileptogenic effects of PER in rats at different stages of development. Methods Using a rapid kindling model in postnatal day 14 (P14), P21, P28, and P60 rats, we studied two doses of PER: 1 and 2 mg/kg injected intraperitoneally 30 min before afterdischarge assessment. We also assessed blood and brain concentrations of PER 30 min after the injection. Results PER 2 mg/kg significantly increased the afterdischarge threshold ( ADT) at all ages, whereas PER at 1 mg/kg increased ADT only in P21 rats. PER 2 mg/kg also shortened the afterdischarge duration in P14 and P28 rats. PER increased the number of stimulations required to achieve a stage 4-5 seizure in a dose-dependent manner in P14 and P21 rats, with almost complete elimination of stage 4-5 seizures. At P28, only PER 2 mg/kg increased the number of stimulations required to develop a stage 4-5 seizure. In contrast, PER had no effect on the number of stage 4-5 seizures at P60. We did not observed any age-dependent significant difference in the serum and brain levels of PER 30 min after the injection. Significance PER exerted anti-ictogenic effects from P14 to P60 independent of brain maturation. PER also exhibited antiepileptogenic effects with a stronger effect in the younger animals. [ABSTRACT FROM AUTHOR]

THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) is a GABAA receptor agonist with varying potencies and efficacies at γ-subunit-containing receptors. More importantly, THIP acts as a selective superagonist at δ-subunit-containing receptors (δ-GABAARs) at clinically relevant concentrations. Evaluation of THIP as a potential anticonvulsant has given contradictory results in different animal models and for this reason, we reevaluated the anticonvulsive properties of THIP in the murine pentylenetetrazole (PTZ) kindling model. As loss of δ-GABAAR in the dentate gyrus has been associated with several animal models of epilepsy, we first investigated the presence of functional δ-GABAA receptors. Both immunohistochemistry and Western blot data demonstrated that δ-GABAAR expression is not only present in the dentate gyrus, but also the expression level was enhanced in the early phase after PTZ kindling. Whole-cell patch-clamp studies in acute hippocampal brain slices revealed that THIP was indeed able to induce a tonic inhibition in dentate gyrus granule cells. However, THIP induced a tonic current of similar magnitude in the PTZ-kindled mice compared to saline-treated animals despite the observed upregulation of δ-GABAARs. Even in the demonstrated presence of functional δ-GABAARs, THIP (0.5-4 mg/kg) showed no anticonvulsive effect in the PTZ kindling model using a comprehensive in vivo evaluation of the anticonvulsive properties. [ABSTRACT FROM AUTHOR]

Introduction Epileptogenesis is a process of seizure development. Lamotrigine is a novel antiepileptic drug which is also used for antiepileptogenic research. Kindling models are recommended as potentially useful tools for antiepileptogenic treatment discovery. However, previous studies demonstrated that the antiepileptogenic effect of lamotrigine is controversial in the electrical kindling model. Chemical kindling such as with pentylenetetrazole is another kindling model. The aims of this study were to examine whether lamotrigine could prevent the development of seizure in pentylenetetrazole kindling rats. Methods Female rats were kindled by subconvulsive doses of pentylenetetrazole (35 mg/kg) once every other day for 15 times. Thereafter, the kindled rats received different doses of lamotrigine (5, 10 and 20 mg/kg) before pentylenetetrazole to observe the anticonvulsant effect. For the antiepileptogenic experiment, rats were kindled as the same way while pretreated (1 h) with different doses of lamotrigine (5, 10 and 20 mg/kg) before each injection of pentylenetetrazole. After a washout period for 1 week, the rats were administrated with pentylenetetrazole again for 3 times. The seizures were recorded each time. Later it was in vivo electrophysiological experiments followed with histologic analysis. Results For the anticonvulsant experiment lamotrigine dose-dependently suppressed pentylenetetrazole-induced seizures. Here, 20 mg/kg of lamotrigine pretreatment significantly blocked the seizure development in rats for their seizure stages remained longer in 1-3 during the kindling phase. Mean seizure stages or generalized seizure durations in the 10 and 20 mg/kg lamotrigine pretreated groups were significantly lower or shorter when received 3 times of pentylenetetrazole after the washout period. Electrophysiological study also demonstrated 20 mg/kg of lamotrigine pretreatment obviously eliminated increased population spike amplitude in hippocampus. However, different doses of lamotrigine pretreatment could not alleviate severity of hippocampal neuronal damage. Conclusions The results suggest that adequate doses of lamotrigine can prevent seizure development in the pentylenetetrazole kindling rat model. [ABSTRACT FROM AUTHOR]

Convulsive seizures are due to abnormal synchronous and repetitive neuronal discharges in the central nervous system ( CNS). Finding new therapeutics to overcome the side effects of the current drug therapies and to increase their effectiveness is ongoing. Orexin-A and orexin-B are brain neuropeptides originating from postero-lateral hypothalamic neurons. Studies show that orexins, through activation of OX1 and OX2 receptors, have excitatory effects in the CNS. Accordingly, this study was designed to evaluate the effect of OX1 receptor antagonist ( SB-334867) on seizure- and anxiety-related behaviors of pentylenetetrazol ( PTZ)-kindled rats. Kindling was induced by repeated intraperitoneal ( IP) injections of PTZ (32 mg/kg) with two-day intervals for 24 days in male Wistar rats. Three groups received intracerebroventricular ( ICV) injections of SB-334867 (2.5, 5, and 10 μg/rat) before PTZ injections. Two control groups received vehicle (2 μL/rat, ICV) and valproate (26 μg/rat, ICV) before PTZ injections. An extra group of control animals received saline both ICV and IP. Seizure-related behaviors were monitored for 30 min following PTZ administration. The anxiety-like behaviors were also assessed using elevated plus-maze in the first and last days of the study. The results revealed that ICV injection of SB-334867, mainly at the dose of 10 μg/rat, decreased the median of seizure stages, prolonged the latency and reduced the duration of different seizure stages, and reversed the PTZ-induced anxiety-like behaviors. Based on the presented results, it is suggested that pharmacological blockade of the OX1 receptor is a potential target in the treatment of seizure and concomitant anxiety disorders. [ABSTRACT FROM AUTHOR]

The vulnerability and plasticity of hippocampal GABAergic interneurons is a topic of broad interest and debate in the field of epilepsy. In this experiment, we used the electrical kindling model of epilepsy to determine whether seizures that originate in different brain regions have differential effects on hippocampal interneuron subpopulations. Long-Evans rats received 99 electrical stimulations of the hippocampus, amygdala, or caudate nucleus, followed by sacrifice and immunohistochemical or western blot analyses. We analyzed markers of dendritic (somatostatin), perisomatic (parvalbumin), and interneuron-selective (calretinin) inhibition, as well as an overall indicator (GAD67) of interneuron distribution across all major hippocampal subfields. Our results indicate that kindling produces selective effects on the number and morphology of different functional classes of GABAergic interneurons. In particular, limbic kindling appears to enhance dendritic inhibition, indicated by a greater number of somatostatin-immunoreactive (-ir) cells in the CA1 pyramidal layer and robust morphological sprouting in the dentate gyrus. We also found a reduction in the number of interneuron-selective calretinin-ir cells in the dentate gyrus of hippocampal-kindled rats, which suggests a possible reduction of synchronized dendritic inhibition. In contrast, perisomatic inhibition indicated by parvalbumin immunoreactivity appears to be largely resilient to the effects of kindling. Finally, we found a significant induction in the number of GAD67-cells in caudate-kindled rats in the dentate gyrus and CA3 hippocampal subfields. Taken together, our results demonstrate that kindling has subfield-selective effects on the different functional classes of hippocampal GABAergic interneurons. J. Comp. Neurol. 525:389-406, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Maintenance electroconvulsive therapy ( ECT) is sometimes prescribed for refractory psychiatric conditions. We describe five patients who received maintenance ECT and developed florid temporal epileptiform abnormalities on electroencephalography ( EEG) despite no history of epilepsy and normal neuroimaging. All patients had received regular ECT for at least 8 months. Three patients had clinical events consistent with epileptic seizures, and video- EEG monitoring captured electrographic seizures in two patients. After cessation of ECT the EEGs normalized in all patients, and no further clinical seizures occurred. Maintenance ECT may predispose to epilepsy with a seizure focus in the temporal lobe. [ABSTRACT FROM AUTHOR]

Objectives The process of sensitization (increased responsivity) to the recurrence of stressors, affective episodes, and bouts of substance abuse that can drive illness progression in the recurrent affective disorders requires a memory of and increased reactivity to the prior exposures. A wealth of studies now supports the postulate that epigenetic mechanisms underlie both normal and pathological memory processes. Methods We selectively reviewed the literature pertinent to the role of epigenetics in behavioral sensitization phenomena and discuss its clinical implications. Results Epigenetics means above genetics and refers to environmental effects on the chemistry of DNA, histones (around which DNA is wound), and micro RNA that change how easily genes are turned on and off. The evidence supports that sensitization to repeated stressor, affective episodes, and substance is likely based on epigenetic mechanisms and that these environmentally based processes can then become targets for prevention, early intervention, and ongoing treatment. Sensitization processes are remediable or preventable risk factors for a poor illness outcome and deserve increased clinical, public health, and research attention in the hopes of making the recurrent unipolar and bipolar affective disorders less impairing, disabling, and lethal by suicide and increased medical mortality. Conclusions The findings that epigenetic chemical marks, which change in the most fundamental way how genes are regulated, mediate the long-term increased responsivity to recurrent stressors, mood episodes, and bouts of substance abuse should help change how the affective disorders are conceptualized and move treatment toward earlier, more comprehensive, and sustained pharmacoprophylaxis. [ABSTRACT FROM AUTHOR]

Objective Environmental exposures impart powerful effects on vulnerability to many brain diseases, including epilepsy. Mesial temporal lobe epilepsy ( MTLE) is a common form of epilepsy, and it is often accompanied by neuropsychiatric comorbidities. This study tests the hypothesis that environmental enrichment ( EE) confers antiepileptogenic, psychoprotective, and neuroprotective effects in the amygdala kindling model of MTLE, and explores potential neurobiologic mechanisms. Methods At weaning, male Wistar rats were allocated into either EE (large cages containing running wheels and toys; n = 43) or standard housing ( SH; standard laboratory cages; n = 39) conditions. At P56, a bipolar electrode was implanted into the left amygdala, and rats underwent rapid amygdala kindling until experiencing five class V seizures (Racine scale, fully kindled). The elevated plus maze was used to assess anxiety. Postmortem histologic and molecular analyses investigated potential biologic mediators of effects. Results EE significantly delayed kindling epileptogenesis, with EE rats requiring a significantly greater number of kindling stimulations to reach a fully kindled state compared to SH rats (p < 0.05). EE and kindling both reduced anxiety (p < 0.05). Timm's staining revealed significant reductions in aberrant mossy fiber sprouting in EE rats (p < 0.05), and these effects of EE were accompanied by reduced expression of TrkB and CRH genes. Significance We identify beneficial effects of EE on vulnerability to limbic epileptogenesis and anxiety, and identify reduced pathologic neuroplasticity and plasticity-related gene expression as potential underlying mechanisms. Enhanced environmental stimulation represents a potential antiepileptogenic strategy that might also mitigate the common psychiatric comorbidities of MTLE. [ABSTRACT FROM AUTHOR]

Aims: Deep brain electrical stimulation (DBS), as a potential therapy for drug resistive epileptic patients, has inhibitory action on epileptogenesis. In the present investigation, the role of dopamine D 2 -like receptors in the antiepileptogenic action of DBS was studied., Methods: Seizures were induced in adult rats by stimulating the perforant path in a semi-rapid kindling method. Five minutes after the last kindling stimulation, daily DBS was applied to the perforant path at the pattern of low frequency stimulation (LFS; 1 Hz; pulse duration: 0.1 ms; intensity: 50-150 μA; 4 trains of 200 pulses at 5 min intervals). Sulpiride (10 μg/1 μl, i.c.v.), a selective dopamine D 2 -like receptor antagonist, was administered prior to the daily LFS application., Results: Kindling stimulations increased cumulative daily behavioral seizure stages, daily afterdischarge duration (dADD), and population spike amplitude (PS) in dentate gyrus following perforant path stimulation, while applying LFS decreased the kindled seizures' parameters. In addition, kindling potentiated the early (at 10-50 ms inter-pulse interval) and late (at 150-1000 ms inter-pulse interval) paired-pulse inhibition and decreased the paired-pulse facilitation (at 70-100 ms inter-pulse interval). These effects were also inhibited by applying LFS. All inhibitory effects of LFS on kindling procedure were prevented by sulpiride administration., Conclusion: These data may suggest that LFS exerts its preventive effect on kindling development, at least partly, through the receptors on which sulpiride acts which are mainly dopamine D 2 -like (including D 2 , D 3 , and D 4 ) receptors., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

This study compares 20 subjects, in each of three different settings, with serious psychotic disorder (they meet inclusion criteria for schizophrenia) who hear voices, and compares their voice-hearing experience. We find that while there is much that is similar, there are notable differences in the kinds of voices that people seem to experience. In a California sample, people were more likely to describe their voices as intrusive unreal thoughts; in the South Indian sample, they were more likely to describe them as providing useful guidance; and in our West African sample, they were more likely to describe them as morally good and causally powerful. What we think we may be observing is that people who fall ill with serious psychotic disorder pay selective attention to a constant stream of many different auditory and quasi-auditory events because of different 'cultural invitations'-variations in ways of thinking about minds, persons, spirits and so forth. Such a process is consistent with processes described in the cognitive psychology and psychiatric anthropology literature, but not yet described or understood with respect to cultural variations in auditory hallucinations. We call this process 'social kindling.' [ABSTRACT FROM AUTHOR]

Objective Brivaracetam ( BRV) is a new antiepileptic drug candidate rationally designed for high affinity and selectivity for the synaptic vesicle protein 2A. This study explored anti-ictogenic and antiepileptogenic effects of BRV in rats at different stages of development. Methods Using a rapid kindling model in P14, P21, P28, and P60 rats, we studied two doses of BRV: 10 and 100 mg/kg injected intraperitoneally 30 min before afterdischarge assessment. We also assessed blood and brain concentrations of BRV 30 min after the injection. Results BRV 100 mg/kg significantly increased the afterdischarge threshold ( ADT) at all ages, whereas BRV at 10 mg/kg increased ADT in P60, P28, and P21 rats. BRV also shortens the afterdischarge duration ( ADD), achieving statistical significance with 10 and 100 mg/kg at P60 and with 100 mg/kg at P21. At P60, BRV increases the number of stimulations required to achieve a stage 4-5 seizure in a dose-dependent manner. At P28 and P21, BRV increased the number of stimulations required to develop a stage 4-5 seizure in a dose-dependent manner with almost complete elimination of stage 4-5 seizures. In contrast, at P14, BRV had no effect on the number of stage 4-5 seizures. An age-related decrease in blood and brain concentrations of BRV was observed 30 min after injection of BRV 10 mg/kg, whereas with 100 mg/kg there were no significant age-correlated differences in brain and serum BRV concentrations. Significance BRV exerted dose-dependent anti-ictogenic effects from P60 to P14 independent of brain maturation. BRV also exhibited antiepileptogenic effects at P60, whereas this effect need to be further evaluated at P28 and P21. We did not observe any effect on epileptogenesis at P14 at either dose. [ABSTRACT FROM AUTHOR]

Objective The principal molecular targets of conventional antiseizure drugs consist of ligand-gated and voltage-gated ion channels and proteins subserving synaptic function. Inhibition of the receptor tyrosine kinase TrkB limits epileptogenesis, but its effect on individual seizures is unknown. We sought to determine whether inhibition of TrkB kinase exerts an antiseizure effect. Methods We utilized the kindling model in combination with an inducible conditional knockout of the TrkB gene ( Act-Cre ER TrkB flox/flox mice treated with tamoxifen), and also with a chemical-genetic approach in which mice carry a TrkB kinase with a phenylalanine to alanine substitution of residue 616 ( Trk B F 616A), which allows inhibition of the kinase by a blood-brain barrier permeable small molecule, 1′-naphthylmethyl-4-amino-1- tert-butyl-3-( p-methylphenyl)pyrazolo[3,4- d]pyrimidine (1 NMPP1). Results Following induction of kindling, reduction of TrkB protein levels in Act-Cre ER TrkB flox/flox mice treated with tamoxifen was associated with reduced severity of behavioral seizures evoked by stimulation. Treatment with 1 NMPP1 for 2 weeks following induction of kindling reversibly elevated both focal electrographic and generalized seizure thresholds in Trk B F 616A , but not wild-type ( WT), mice. In contrast to kindled animals, treatment of naive Trk B F 616A mice for 2 weeks had no detectable effect on electrographic seizure threshold ( EST). Significance This study provides proof of concept of a novel molecular target for antiseizure drugs, namely the receptor tyrosine kinase TrkB. A PowerPoint slide summarizing this article is available for download in the Supporting Information section . [ABSTRACT FROM AUTHOR]

Disturbances of GABAergic inhibition are a major cause of epileptic seizures. GABA exerts its actions via ionotropic GABAA receptors and metabotropic G protein-coupled GABAB receptors. Malfunction of GABAA inhibition has long been recognized in seizure genesis but the role of GABAB receptors in controlling seizure activity is still not well understood. Here, we examined the anticonvulsive, or inhibitory effects, of GABAB receptors in a mouse model of hippocampal kindling as well as mouse hippocampal slices through the use of GS 39783, a positive allosteric GABAB receptor modulator, and CGP 55845, a selective GABAB receptor antagonist. When administered via intraperitoneal injections in kindled mice, GS 39783 (5 mg/kg) did not attenuate hippocampal EEG discharges, but did reduce aberrant hippocampal spikes, whereas CGP 55845 (10 mg/kg) prolonged hippocampal discharges and increased spike incidences. When examined in hippocampal slices, neither GS 39783 at 5 μmol/L nor the GABAB receptor agonist baclofen at 0.1 μmol/L alone significantly altered repetitive excitatory field potentials, but GS 39783 and baclofen together reversibly abolished these field potentials. In contrast, CGP 55845 at 1 μmol/L facilitated induction and incidence of these field potentials. In addition, CGP 55845 attenuated the paired pulse depression of CA3 population spikes and increased the frequency of EPSCs in individual CA3 pyramidal neurons. Collectively, these data suggest that GABABB receptors regulate hippocampal hyperexcitability by inhibiting CA3 glutamatergic synapses. We postulate that positive allosteric modulation of GABAB receptors may be effective in reducing seizure-related hyperexcitability. [ABSTRACT FROM AUTHOR]

The diuretic bumetanide, which acts by blocking the Na- K- Cl cotransporter ( NKCC), is widely used to inhibit neuronal NKCC1, particularly when NKCC1 expression is abnormally increased in brain diseases such as epilepsy. However, bumetanide poorly penetrates into the brain and, in rodents, is rapidly eliminated because of extensive oxidation of its N-butyl sidechain, reducing the translational value of rodent experiments. Inhibition of oxidation by piperonyl butoxide ( PBO) has previously been reported to increase the half-life and diuretic activity of bumetanide in rats. Here we studied whether inhibition of bumetanide metabolism by PBO also increases brain levels of bumetanide in rats, and whether this alters pharmacodynamic effects in the kindling model of epilepsy. Furthermore, we studied the effects of PBO in mice. Mice eliminated bumetanide less rapidly than rats (elimination half-life 47 min vs. 13 min). Pretreatment with PBO increased the half-life in mice to average values (70 min) previously determined in humans, and markedly elevated brain levels of bumetanide. In rats, the increase in plasma and brain levels of bumetanide by PBO was less marked than in mice. PBO significantly increased the diuretic activity of bumetanide in rats and, less effectively, in mice. In epileptic mice, bumetanide (with PBO) did not suppress spontaneous seizures. In the rat kindling model, bumetanide (with or without PBO) did not exert anticonvulsant effects on fully kindled seizures, but dose-dependently altered kindling development. These data indicate that PBO offers a simple means to enhance the translational properties of rodent experiments with bumetanide, particularly when using mice. [ABSTRACT FROM AUTHOR]

Purpose Encapsulated cell biodelivery ( ECB) is a relatively safe approach, since the devices can be removed in the event of adverse effects. The main objectives of the present study were to evaluate whether ECB could be a viable alternative of cell therapy for epilepsy. We therefore developed a human cell line producing galanin, a neuropeptide that has been shown to exert inhibitory effects on seizures, most likely acting via decreasing glutamate release from excitatory synapses. To explore whether ECB of genetically modified galanin-producing human cell line could provide seizure-suppressant effects, and test possible translational prospect for clinical application, we implanted ECB devices bilaterally into the hippocampus of rats subjected to rapid kindling, a model for recurrent temporal lobe seizures. Methods Two clones from a genetically modified human cell line secreting different levels of galanin were tested. Electroencephalography ( EEG) recordings and stimulations were performed by electrodes implanted into the hippocampus at the same surgical session as ECB devices. One week after the surgery, rapid kindling stimulations were initiated. Key Findings Enzyme-linked immunosorbent assay ( ELISA) measurements prior to device implantation showed a release of galanin on average of 8.3 ng/mL/24 h per device for the low-releasing clone and 12.6 ng/mL/24 h per device for the high-releasing clone. High-releasing galanin-producing ECB devices moderately decreased stimulation-induced focal afterdischarge duration, whereas low-releasing ECB devices had no significant effect. Significance Our study shows that galanin-releasing ECB devices moderately suppress focal stimulation-induced recurrent seizures. Despite this moderate effect, the study provides conceptual proof that ECB could be a viable alternative approach to cell therapy in humans, with the advantage that the treatment could be terminated by removing these devices from the brain. Thereby, this strategy provides a higher level of safety for future therapeutic applications, in which genetically modified human cell lines that are optimized to produce and release antiepileptic compounds could be clinically evaluated for their seizure-suppressant effects. A PowerPoint slide summarizing this article is available for download in the Supporting Information section . [ABSTRACT FROM AUTHOR]

ABSTRACT Temporal lobe epilepsy is associated with changes in the morphology of hippocampal dentate granule cells. These changes are evident in numerous models that are associated with substantial neuron loss and spontaneous recurrent seizures. By contrast, previous studies have shown that in the kindling model, it is possible to administer a limited number of stimulations sufficient to produce a lifelong enhanced sensitivity to stimulus evoked seizures without associated spontaneous seizures and minimal neuronal loss. Here we examined whether stimulation of the amygdala sufficient to evoke five convulsive seizures (class IV or greater on Racine's scale) produce morphological changes similar to those observed in models of epilepsy associated with substantial cell loss. The morphology of GFP-expressing granule cells from Thy-1 GFP mice was examined either 1 day or 1 month after the last evoked seizure. Interestingly, significant reductions in dendritic spine density were evident 1 day after the last seizure, the magnitude of which had diminished by 1 month. Further, there was an increase in the thickness of the granule cell layer 1 day after the last evoked seizure, which was absent a month later. We also observed an increase in the area of the proximal axon, which again returned to control levels a month later. No differences in the number of basal dendrites were detected at either time point. These findings demonstrate that the early stages of kindling epileptogenesis produce transient changes in the granule cell body layer thickness, molecular layer spine density, and axon proximal area, but do not produce striking rearrangements of granule cell structure. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Relevant to the definition of epileptic encephalopathy ( EE) is the concept that the epileptic activity itself may contribute to bad outcomes, both in terms of epilepsy and cognition, above and beyond what might be expected from the underlying pathology alone, and that these can worsen over time. The review of the clinical and experimental evidence that seizures or interictal electroencephalography ( EEG) discharges themselves can induce a progression toward more severe epilepsy and a regression of brain function leads to the following conclusions: The possibility of seizure-dependent worsening is by no means a general one but is limited to some types of epilepsy, namely mesial temporal lobe epilepsy ( MTLE) and EEs., Clinical and experimental data concur in indicating that prolonged seizures/status epilepticus ( SE) are a risky initial event that can set in motion an epileptogenic process leading to persistent, possibly drug-refractory epilepsies., The mechanisms for SE-related epileptogenic process are incompletely known; they seem to involve inflammation and/or glutamatergic transmission., The evidence of the role of recurrent individual seizures in sustaining epilepsy progression is ambiguous. The correlation between high seizure frequency and bad outcome does not necessarily demonstrate a cause-effect relationship, rather high seizure frequency and bad outcome can both depend on a particularly aggressive epileptogenic process., The results of EE studies challenge the idea of a common seizure-dependent mechanism for epilepsy progression/intellectual deterioration. [ABSTRACT FROM AUTHOR]

Purpose There is a gap in our knowledge of the factors that modulate the predisposition to seizures following perinatal hypoxia. Herein, we investigate in a mouse model the effects of two distinct factors: developmental stage after the occurrence of the perinatal insult, and the presence of a seizure predisposing mutation. Methods Effects of age: P6 (postnatal day 6) mouse pups were subjected to acute hypoxia down to 4% O2 over the course of 45 min. Seizure susceptibilities to flurothyl-induced seizures (single exposures) and to flurothyl kindling were determined at specific subsequent ages. Effects of mutation: Heterozygote mice, with deletion of one copy of the Kcn1a gene, subjected to P6 hypoxia were compared as adults to wild-type mice with respect to susceptibility to a single exposure to flurothyl and to the occurrence of spontaneous seizures as detected by hippocampal electroencephalography ( EEG) and video recordings. Key Findings Effects of age: As compared to controls, wild-type mice exposed to P6 hypoxia had a shortened seizure latency in response to a single flurothyl exposure at P50, but not at P7 or P28 (p < 0.04). In addition, perinatal hypoxia at P6 enhanced the rate of development of flurothyl kindling performed at P28-38 (p < 0.03), but not at P7-17 . Effects of mutation: Kcn1a heterozygous mice subjected to P6 hypoxia exhibited increased susceptibility to flurothyl-induced seizures at P50 as compared to Normoxia heterozygote littermates, and to wild-type Hypoxia and Normoxia mice. In addition, heterozygotes exposed to P6 hypoxia were the only group in which spontaneous seizures were detected during the period of long-term monitoring (p < 0.027 in all comparisons). Significance Our data establish a mouse model of mild perinatal hypoxia in which we document the following: (1) the emergence, after a latent period, of increased susceptibility to flurothyl-induced seizures, and to flurothyl induced kindling; and (2) an additive effect of a gene mutation to the seizure predisposing consequences of perinatal hypoxia, thereby demonstrating that a modifier (or susceptibility) gene can exacerbate the long-term consequences of hypoxic injury. [ABSTRACT FROM AUTHOR]

Purpose Kindling is a well-established model of secondarily generalized partial seizures that is widely employed in the search for novel antiseizure drugs. During the kindling and postkindling acquisition phase, an active process of neuronal remodeling occurs. We tested the hypothesis that exposure to the voltage-gated sodium channel blockers lamotrigine ( LTG) and carbamazepine ( CBZ) during the period of active remodeling will lead to a diminished therapeutic effect. Methods Two days after the last kindling stimulation, fully kindled rats were randomized to receive either 0.5% methyl cellulose ( MC), LTG (30 mg/kg), or CBZ (40 mg/kg). The effect of LTG and CBZ on behavioral seizure severity and electrographic afterdischarge duration ( ADD) was recorded. One week after this treatment, rats in both groups were rechallenged with LTG 30 or CBZ 40 mg/kg and their seizure score and ADD recorded. In vitro efficacy of LTG on neuronal action potentials was also evaluated using whole cell current clamp recording in hippocampal brain slices obtained from kindled control rats, LTG-sensitive kindled rats, and LTG-resistant kindled rats. Key Findings When acutely administered 48 h after the last kindling stimulation, LTG and CBZ blocked the expression of behavioral seizures and reduced the ADD. In contrast, a second challenge dose of LTG or CBZ administered after a 7-day 'no drug, no stimulation' period did not result in reduction of either the seizure score or the ADD. Interestingly, the potassium channel opener, ezogabine, also known as retigabine ( EZG; 40 mg/kg), blocked the expression of behavioral seizures at both time points evaluated (i.e., 2 days and 9 days after last stimulation). In vivo resistance to LTG was associated with a similar reduction in the ability of LTG to limit action potential firing in CA1 neurons. LTG (50 μ m) significantly decreased the number of action potentials generated by a depolarizing current pulse in neurons recorded from slices obtained from kindled control and LTG-sensitive rats, but not in slices obtained from LTG-resistant rats. Significance Collectively, results obtained from both in vivo and in vitro studies demonstrate that even a single exposure to the sodium channel blockers LTG, or CBZ, during the postkindling remodeling phase leads to an altered pharmacologic response to these two ASDs, but not to EZG. The LTG- and CBZ-resistant amygdala kindled rats may serve as a useful model of therapy-resistant epilepsy. [ABSTRACT FROM AUTHOR]

Summary Purpose: The ketogenic diet (KD) has been used as an effective antiepileptic treatment for nearly a century. Inhibition of glycolysis and increased levels of ketone bodies are both known to contribute to the antiepileptic effects of the KD. Neuron-restrictive silencer factor (NRSF), also known as RE-1 silencing transcription factor (REST), is implicated in the antiepileptic effects of the glycolytic inhibitor 2-deoxy- d-glucose (2DG). Glycolytic inhibition is a common feature of the KD and 2DG treatment, leading to the hypothesis that NRSF might also be involved in the antiepileptic effect of the KD. To test this hypothesis, the present study was designed to investigate the role of NRSF in the antiepileptic effect of 2DG, the KD, and acetone in vivo. Methods: Kindling was used as a model to test the antiepileptic effects of 2DG, the KD, and acetone on control and NRSF conditional knockout mice (NRSF-cKO; from the intercross of CamKIIα-iCre and NRSF exon 2 floxed mice). After recovery from electrode implantation, adult mice were stimulated twice a day at afterdischarge threshold (ADT) current intensity. In the 2DG- (500 mg/kg) and acetone- (10 mmol/kg) treated groups, drugs were injected intraperitoneally 20 min before each stimulus. In the 2DG group, mice were pretreated with intraperitoneal injections for 3 days in addition to the injections administered before the regular kindling stimulation. In the KD group, mice were fed the KD instead of a control diet until the end of stimulations. Key Findings: Compared with control mice, the antiepileptic effect of 2DG was abolished in NRSF-cKO mice, indicating that NRSF is required for the antiepileptic effect of 2DG. In the KD-fed group, kindling development was retarded in both control and NRSF-cKO mice. In the acetone-treated group, inhibition of kindling-induced epileptogenesis was observed in both control and NRSF-cKO mice, similar to the action of the KD. Significance: These findings imply that NRSF repression complex is not essential for the antiepileptic effect of the ketogenic diet. [ABSTRACT FROM AUTHOR]

Summary Purpose: Temporal lobe epilepsy, one of the most common epilepsy syndromes, is characterized by hippocampal hyperexcitability and progressive seizure susceptibility. Omega-3 fatty acids are involved in neuronal excitability and have anticonvulsant properties. We studied the effect of docosahexaenoic acid (DHA) or its derived lipid mediator, neuroprotectin D1 (NPD1, 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid), in evoked seizures using a rapid kindling model of temporal lobe epilepsy. Methods: DHA or NPD1 was administered in rodents with or without kindling acquisition. Locomotor seizures and evoked epileptiform hippocampal activity immediately after hippocampal stimulations were analyzed. Key Findings: DHA or NPD1 limits hippocampal electrically induced hyperexcitability. Seizures induced by kindling triggered NPD1 synthesis in the hippocampus. Supplying its precursor, DHA, or direct injection of NPD1 into the third ventricle resulted in attenuation of kindling progression and hippocampal hyperexcitability. Significance: The significance of NPD1 in temporal lobe epilepsy could open new pathways for understanding the initiation and propagation of seizures and the role this lipid mediator plays in the neuronal network. [ABSTRACT FROM AUTHOR]

We have previously shown that after kindling (a model of temporal lobe epilepsy), the neuroactive steroid tetrahydrodeoxycorticosterone (THDOC) was unable to augment GABA type A receptor (GABAA)-mediated synaptic currents occurring on pyramidal cells of the piriform cortex. Phosphorylation of GABAA receptors has been shown previously to alter the activity of THDOC, so we tested the hypothesis that kindling induces changes in the phosphorylation of GABAA receptors and this accounts for the loss in efficacy. To assay whether GABAA receptors are more phosphorylated after kindling, we examined the phosphorylation state of the b3 subunit and found that it was increased. Incubation of brain slices with the protein kinase C activator phorbol 12-myristate 13-acetate (PMA) (100 nM) also increased phosphorylation in the same assay. In patch clamp, recordings from non-kindled rat brain slices PMA also reduced the activity of THDOC in a manner that was identical to what is observed after kindling. We also found that the tonic current was no longer augmented by THODC after kindling and PMA treatment. The protein kinase C (PKC) antagonist bisindolylmaleimide I blocked the effects PMA on the synaptic but not the tonic currents. However, the broad spectrum PKC antagonist staurosporine blocked the effects of PMA on the tonic currents, implying that different PKC isoforms phosphorylate GABAA receptors responsible for phasic and tonic currents. The phosphatase activator Li+palmitate restored the 'normal' activity of THDOC on synaptic currents in kindled brain slices but not the tonic currents. These data demonstrate that kindling enhances the phosphorylation state of GABAA receptors expressed in pyramidal neurons reducing THDOC efficacy. [ABSTRACT FROM AUTHOR]

Temporal lobe epilepsy is associated with the inflammatory process related to the basic mechanisms that lead to seizure susceptibility and brain damage. Platelet-activating factor (PAF), a potent, short-lived phospholipid mediator of inflammation, participates in physiologic signaling in the brain. However, after seizures, PAF accumulates in the brain and activates intracellular signaling related with inflammation-mediated excitotoxicity and hippocampal hyperexcitability. The objective of this study is to evaluate the effect of PAF antagonism on hippocampal hyperexcitability, seizure susceptibility, and neuroprotection using the kindling paradigm and pilocarpine-induced seizure damage models. The PAF antagonist, LAU-0901 (60 mg/kg, i.p.), or vehicle, was administrated each day of kindling or daily during the 4 weeks after status epilepticus (SE). We analyzed seizure severity, electrical activity, cellular damage, and inflammation in the hippocampi of both treated groups. LAU-0901 limits the progression of kindling and attenuates seizure susceptibility 1 week after the kindling procedure. In addition, under the seizure-damage conditions studied here, we observed that LAU-0901 induces hippocampal neuroprotection and limits somatostatin interneuronal cell loss and inflammation. Our results indicate that modulation of PAF overactivity attenuates seizure susceptibility, hippocampal hyperexcitability, and neuroinflammation. [ABSTRACT FROM AUTHOR]

The goal of this study was to determine whether prophylactic prandial administration of rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, could alter seizure generation, kindling acquisition, and/or kindling maintenance in the mouse pentylenetetrazole (PTZ) epilepsy model. Male CD-1 mice were fed ad libitum with control chow or chow formulated to deliver 30 mg/kg/day rofecoxib. After 5 days, mice were treated with a single dose of 40 or 55 mg/kg PTZ (acute paradigm) or 40 mg/kg PTZ delivered daily (kindling paradigm). Seizure severity was scored on a four-point behavioral scale and COX-2 expression was assessed in brain slices from a subset of mice 3 h or 72 h after acute PTZ or following establishment of kindling. Hippocampal COX-2 expression was transiently upregulated 3 h after an acute PTZ-induced convulsion and returned to baseline levels within 72 h, whereas it remained elevated for at least 72 h after the final seizure in the kindling paradigm. Despite this increase, chronic rofecoxib treatment did not attenuate the severity of acute PTZ-induced seizures and failed to alter kindling development or maintenance. The present study demonstrates that prophylactic, prandial rofecoxib treatment lacks efficacy against acute PTZ-induced seizure generation and kindling acquisition, and does not reverse the kindled state once established. [ABSTRACT FROM AUTHOR]

The present study was undertaken to clarify the effects of (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA), a metabotropic glutamate receptor (mGluR) 1 antagonist, (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate ((2R,4R)-APDC), a mGluR2/3 agonist, and L-(+)-2-amino-4-phosphonobutyric acid (L-AP4), a mGluR4/8 agonist, on pentetrazol-induced kindled seizures. Mice were anesthetized with pentobarbital; the electrodes and guide cannula were chronically implanted into the cortex and lateral ventricle. To induce kindling, pentetrazol at a dose of 40 mg/kg was injected once every 48 h. Behavioral and electroencephalographic seizures were monitored for 20 min following pentetrazol administration. Fully kindled mice were used for pharmacologic studies. Intracerebroventricular injection of AIDA and L-AP4 showed significant inhibitory effects on pentetrazol-induced kindled seizures. In addition, simultaneous use of AIDA and (2R,4R)-APDC or L-AP4 caused more potent inhibition of seizure activities. The inhibitory effect of AIDA on pentetrazol-induced kindled seizures was antagonized by (RS)-3,5-dihydroxyphenylglycine ((RS)-3,5-DHPG), a group I mGluR agonist; (2S)-a-ethylglutamic acid (EGLU), a group II mGluR antagonist; and (RS)-α-methyl-4-phosphonophenylglycine (MPPG), a group III mGluR antagonist. On the other hand, the inhibitory effect of L-AP4 was antagonized only by MPPG. It is proposed that mGluR1 antagonists and mGluR4/8 agonists show anticonvulsive effects on pentetrazol-induced kindled seizures. Furthermore, it is also proposed that the simultaneous use of an mGluR1 antagonist and an mGluR2/3 or mGluR4/8 agonist is a potential novel therapeutic strategy in epileptic disorders. [ABSTRACT FROM AUTHOR]

Purpose: Racine’s classic study suggested that after discharge thresholds were reduced in the primary stimulation site (amygdala) of kindled rats, but that that they were not reduced in secondary (nonstimulated) sites. However, recent reports of neurochemical changes related to excitation and inhibition in nonstimulated sites in kindled brains would be expected to cause reductions in afterdischarge thresholds in these sites. More recently Sanei et al. have reported a significant threshold reduction in the piriform cortex of amygdala- and hippocampus-kindled cats, but not in the entorhinal cortex. The present study was designed to determine whether the results of Sanei et al. in cats could be replicated in rats kindled in the amygdala—a model commonly used in studies of seizure mechanisms and anticonvulsant drug development. Methods: Adult, male Long-Evans rats were kindled in the amygdala or given matched handling. Beginning 48 h following the last stimulation, afterdischarge thresholds were determined in the ipsilateral piriform and entorhinal cortices. Amygdala thresholds were determined 24 h later. Results: Afterdischarge thresholds were significantly reduced in both the amygdala and the ipsilateral entorhinal cortex of amygdala-kindled rats. Afterdischarge thresholds in the piriform cortex did not differ significantly between kindled and control subjects. Discussion: These data suggest that threshold reduction occurs outside the primary kindling site in rats as well as in cats. Extrafocal changes in afterdischarge threshold may be functionally important, and might possibly relate to extrafocal neurochemical changes and progressive generalization of seizure discharge from discrete focal sites. [ABSTRACT FROM AUTHOR]

The present study was designed to determine whether low-frequency stimulation (LFS) of the entorhinal cortex (EC) has an anticonvulsive effect, and whether LFS delivered at different times plays different roles. We found that LFS of the EC immediately or 4 s after kindling stimulation had an anticonvulsive effect, and that the latter had a better effect on both kindling and kindled seizures. However, LFS delivered after the cessation of afterdischarge or 10 s after the kindling stimulation, augmented the epileptic activity. So the EC is a potential target for LFS to interfere with epilepsy. Our findings suggest that even in the duration of afterdischarge, there exists a “time window” for LFS treatment, indicating that the time delay of closed-loop stimulation is crucial for LFS treatment. [ABSTRACT FROM AUTHOR]

Persistent down-regulation in the expression of the hyperpolarization-activated HCN1 cation channel, a key determinant of intrinsic neuronal excitability, has been observed in febrile seizure, temporal lobe epilepsy, and generalized epilepsy animal models, as well as in patients with epilepsy. However, the role and importance of HCN1 down-regulation for seizure activity is unclear. To address this question we determined the susceptibility of mice with either a general or forebrain-restricted deletion of HCN1 to limbic seizure induction by amygdala kindling or pilocarpine administration. Loss of HCN1 expression in both mouse lines is associated with higher seizure severity and higher seizure-related mortality, independent of the seizure-induction method used. Therefore, down-regulation of HCN1 associated with human epilepsy and rodent models may be a contributing factor in seizure behavior. [ABSTRACT FROM AUTHOR]

Purpose: 2-Deoxy-d-glucose (2-DG), a glucose analog that accumulates in cells and interferes with carbohydrate metabolism by inhibiting glycolytic enzymes, has anticonvulsant actions. Recognizing that severe glucose deprivation can induce seizures, we sought to determine whether acute treatment with 2-DG can promote seizure susceptibility by assessing its effects on seizure threshold. For comparison, we studied 3-methyl-glucose (3-MG), which like 2-DG accumulates in cells and reduces glucose uptake, but does not inhibit glycolysis. Methods: Mice were treated with 2-DG or 3-MG and the seizure threshold determined in the 6-Hz test, the mouse electroshock seizure threshold (MEST) test, and the intravenous pentylenetetrazol (i.v. PTZ) or kainic acid (i.v. KA) seizure threshold tests. 2-DG was also tested in fully amygdala-kindled rats. Results: 2-DG (125–500 mg/kg, i.p., 30 min before testing) significantly elevated the seizure threshold in the 6-Hz seizure test. 2-DG (250–500 mg/kg) decreased the threshold in the MEST and i.v. PTZ and i.v. KA tests. 3-MG had no effect on seizure threshold in the 6-Hz test but, like 2-DG, decreased seizure threshold in the i.v. PTZ test. 2-DG (250 and 500 mg/kg, i.p., 30 min before testing) had no effect on amygdala-kindled seizures. Conclusions: Although 2-DG protects against seizures in the 6-Hz seizure test, it promotes seizures in some other models. The proconvulsant action may relate to reduced glucose uptake, whereas the anticonvulsant action may require inhibition of glycolysis and shunting of glucose metabolism through the pentose phosphate pathway. [ABSTRACT FROM AUTHOR]

Inflammatory signaling in the central nervous system (CNS) has been shown to exacerbate both seizure activity and seizure-induced neuronal injury. However, it has not been firmly established whether neurodegeneration is a prerequisite of proconvulsant effect of neuroinflammation, or whether the latter may facilitate seizures without involving neuronal injury. We examined effects of inflammation in the rapid kindling model, where seizure progression occurs in the absence of neurodegeneration. P14 male Wistar rats were subjected to a rapid kindling procedure: 60 electrical stimulations of the hippocampus delivered every 5 min at the current that had been established to induce afterdischarge. Lipopolysaccharide (LPS) was injected (50 μg/kg, i.p., 2 h prior to the rapid kindling protocol [RKP]); IL-1Ra was injected (25 mg/kg, i.p., 2 h prior to the RKP). The effects of treatments were examined on baseline hippocampal excitability, on the progression of rapid kindling, and on the retention of rapid kindling. LPS increased baseline hippocampal excitability, evident as the decrease of hippocampal ADT. LPS also increased kindling progression. Twenty-four hours after the completion of kindling procedure, LPS-treated animals exhibited increased excitability as compared with saline-treated kindling controls. The kindling progression was blocked by IL1RA when given in combination with LPS. IL1RA was able to reverse the effect of LPS on afterdischarge duration (ADD) while IL1RA alone decreased ADT. We showed that inflammation provoked by LPS enhanced rapid kindling epileptogenesis in immature rat brains. IL1RA was also able to mitigate this augmentation of epileptogenesis enhanced by LPS. [ABSTRACT FROM AUTHOR]

Purpose: Kindling of audiogenic seizure (AGS) involves ≥14 AGS over 1-2 weeks in genetically epilepsy-prone rats (GEPR-9s) and induces gradual seizure duration increases, epileptiform electroencephalography (EEG), and emergence of post tonic clonus (PTC), which are long-lasting. N-methyl-D-aspartate (NMDA)-receptor activation in lateral amygdala (LA) is implicated in AGS kindling initiation. However, the persistence of AGS kindling appears to be dependent on molecular mechanisms initiated by NMDA-receptor activation, which may involve adenylyl cyclase (AC). This study attempted to mimic AGS kindling persistently in nonkindled GEPR-9s by one-time activation of AC in LA. Methods: The effects of a single focal bilateral microinjection into LA of an AC activator, MPB forskolin {7-Deacetyl-7-[O-(N-methylpiperazino)-γ-butyryl]-forskolin dihydrochloride} (25-100 pmol/side), on seizure behavior in GEPR-9s were evaluated. Results: One-time bilateral microinjection of MPB forskolin in GEPR-9s precipitously induced an AGS kindling–like effect, which involved significant increases in seizure duration and long-lasting susceptibility to AGS that culminates in PTC. This effect occurred at 24 h after MPB forskolin microinjection and lasted ≥5 weeks. The effect was seen when AGS was initiated at 1 and 12 h after microinjection, but not if AGS was induced only at 24 h, indicating the importance of the temporal proximity of AGS induction to the MPB forskolin microinjection. Discussion: These findings indicate that one-time activation of AC within the NMDA receptor–mediated molecular cascade results in precipitous induction of AGS kindling. These data further suggest that AC activation in the LA may be an important epileptogenic mechanism that subserves the long-lasting persistence of AGS kindling. [ABSTRACT FROM AUTHOR]

Purpose: The present study was undertaken to clarify the behavioral and electroencephalographic characteristics of olfactory bulb (OB) kindling in rats, in comparison with those of amygdala (AMG) kindling. In addition, the usefulness of OB kindling as a model to evaluate antiepileptics was studied. Methods: Bipolar electrical stimulation was applied to the OB or AMG every day until generalized seizure was achieved. Antiepileptics (carbamazepine, sodium valproate, zonisamide, clobazam, and topiramate), which are used for complex partial epilepsy or secondary generalized epilepsy in clinical practice, were orally administrated to kindled rats. Results: The afterdischarge (AD) threshold of OB kindling is not different from that of AMG kindling. OB-kindled rats showed more rapid development of the seizure stage and AD duration than AMG-kindled rats; however, fully kindled AD duration did not differ between groups. In AMG kindled rats, AD on day 1 was localized only at the stimulation site, whereas in OB-kindled rats, AD on day 1 was observed at not only the stimulation site (OB) but also in the frontal cortex, hippocampus, and AMG. All five antiepileptics significantly inhibited both the seizure stage and AD duration in OB-kindled rats. In addition, carbamazepine, zonisamide, and topiramate were more effective in suppressing OB-kindled seizures. Zonisamide was not effective at any dose tested in AMG-kindled rats. Discussion: OB kindling can be used as a new valuable model to evaluate antiepileptic drugs, with the advantage of its rapid development and the efficacy of antiepileptics. [ABSTRACT FROM AUTHOR]