Duration Of Spike-wave Discharges Research Articles

The role of HCN channels on the effects of T-type calcium channels and GABAA receptors in the absence epilepsy model of WAG/Rij rats.

In this study we used ivabradine (IVA), a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker, to identify its effect on spike-wave discharges (SWDs); and aimed to determine the role of IVA on the effects of T-type calcium channel blocker NNC 55-0396, GABAA receptor agonist muscimol and antagonist bicuculline in male WAG/Rij rats. After tripolar electrodes for electrocorticogram (ECoG) recordings were placed on the WAG/Rij rats' skulls, 5, 10, and 20 mg/kg IVA were intraperitoneally administered for 7 consecutive days and ECoG recordings were obtained on days 0th, 3rd, 6th, and 7th for threehours before and after injections. While acute injection of 5, 10, and 20 mg/kg IVA did not affect the total number and the mean duration of SWDs, subacute administration (7 days) of IVA decreased the SWDs parameters 24 hours after the 7th injection. Interestingly, when IVA was administered again 24 hours after the 6th IVA injection, it increased the SWDs parameters. Western-blot analyses showed that HCN1 and HCN2 expressions decreased and HCN4 increased in the 5-month-old WAG/Rij rats compared to the 1-month-old WAG/Rij and 5-month-old native Wistar rats, while subacute IVA administration increased the levels of HCN1 and HCN2 channels, except HCN4. Subacute administration of IVA reduced the antiepileptic activity of NNC, while the proepileptic activity of muscimol and the antiepileptic activity of bicuculline were abolished. It might be suggested that subacute IVA administration reduces absence seizures by changing the HCN channel expressions in WAG/Rij rats, and this affects the T-type calcium channels and GABAA receptors.

The effect of quercetin on absence epilepsy in WAG/Rij rats

ABSTRACT Aim In the present study, the effect of quercetin, a powerful antioxidant flavonoid, on genetic absence epilepsy was studied in WAG/Rij rats. Material and Method Tripolar electrodes were implanted into WAG/Rij rats. Basal electrocorticography (ECoG) was recorded following a recovery period. After basal ECoG recording, different doses of quercetin (QRC) (25, 50 and 100 mg/kg) were injected intraperitoneally (i.p.) for 30 days. ECoG recording was continued for 31 days, three hours a day. After recording, the rats were anesthetized and euthanized through cervical dislocation and their brains were excised. Biochemically, TNF-alpha, IL-6 and NO were studied in whole rat brains. Results In WAG/Rij rats, low-dose quercetin (25 mg/kg) reduced the number and duration of spike-wave discharges (SWDs) compared to the control group. However, 50 and 100 mg/kg quercetin doses increased SWDs. Duration of SWDs was prolonged only with 100 mg/kg dose. None of the quercetin doses had any effect on average amplitude of SWDs. In addition, it was observed in biochemical analyses that 25 mg/kg quercetin reduced TNF-alpha, IL-6 and NO levels compared to the control group. While TNF-alpha and IL-6 levels in rat brains were not affected by 50 or 100 mg/kg doses, both doses were found to increase NO levels in rat brains. Conclusion Based on the results of the present study, 25 mg/kg low-dose quercetin may have reduced absence seizures by reducing proinflammatory cytokines and NO, but high-dose quercetin may have increased absence seizures through increasing the NO level. This contrasting effect of quercetin on absence seizures needs to be investigated by advanced mechanisms.

MGlu3 Metabotropic Glutamate Receptors as a Target for the Treatment of Absence Epilepsy: Preclinical and Human Genetics Data.

Previous studies suggest that different metabotropic glutamate (mGlu) receptor subtypes are potential drug targets for treating absence epilepsy. However, no information is available on mGlu3 receptors. To examine whether (i) changes of mGlu3 receptor expression/signaling are found in the somatosensory cortex and thalamus of WAG/Rij rats developing spontaneous absence seizures; (ii) selective activation of mGlu3 receptors with LY2794193 affects the number and duration of spikewave discharges (SWDs) in WAG/Rij rats; and (iii) a genetic variant of GRM3 (encoding the mGlu3 receptor) is associated with absence epilepsy. Animals: immunoblot analysis of mGlu3 receptors, GAT-1, GLAST, and GLT-1; realtime PCR analysis of mGlu3 mRNA levels; assessment of mGlu3 receptor signaling; EEG analysis of SWDs; assessment of depressive-like behavior. Humans: search for GRM3 and GRM5 missense variants in 196 patients with absence epilepsy or other Idiopathic Generalized Epilepsy (IGE)/ Genetic Generalized Epilepsy (GGE) and 125,748 controls. mGlu3 protein levels and mGlu3-mediated inhibition of cAMP formation were reduced in the thalamus and somatosensory cortex of pre-symptomatic (25-27 days old) and symptomatic (6-7 months old) WAG/Rij rats compared to age-matched controls. Treatment with LY2794193 (1 or 10 mg/kg, i.p.) reduced absence seizures and depressive-like behavior in WAG/Rij rats. LY2794193 also enhanced GAT1, GLAST, and GLT-1 protein levels in the thalamus and somatosensory cortex. GRM3 and GRM5 gene variants did not differ between epileptic patients and controls. We suggest that mGlu3 receptors modulate the activity of the cortico-thalamo-cortical circuit underlying SWDs and that selective mGlu3 receptor agonists are promising candidate drugs for absence epilepsy treatment.

0134 Circadian variation of absence seizures in an animal model of human leukodystrophy (H-ABC)

Abstract Introduction Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a human leukodystrophy is due to a mutation in the tubulin b 4a (TUBB4A) and the taiep rats is the only available model of this human disease with similar signs in the magnetic resonance imaging and a mutation in the TUBB4 that induced an accumulation of microtubules in the cytoplasm and its processes in the oligodendrocytes. Taiep rats had spike-wave discharges (SWD) that are similar to absence epilepsy with a progressive increase with the age of the subjects. The aim of this study is to analyze the circadian distribution of SWD on male taiep. Methods We used 16 male taiep rats at 6 and 9 months of age. All rats were kept in standard conditions with a 12/12 light-dark cycle (lights on at 0700) and free access to rodent food pellets and purified water and were implanted for EEG, EMG and EOG recordings to characterize the frequency and duration of SWD. All procedures followed the NIH rules, and the protocol was approved by BUAP-IACUC. Results The number of SWD are higher in male rats at 9 with respect to 6 months of age (P≤0.05), and also had higher incidence during the light phase with respect to the dark phase (P≤0.05). The duration of SWD had also a greater duration during the light period than the dark phase (P≤0.05). Conclusion Our results showed that SWD has higher incidence of SWD and of longer duration during the light period when the rats had more sleep suggesting that the neurotransmitters that are released during sleep facilitate the discharge in the thalamo-cortical circuit that support SWD. Support (If Any) Partially supported by PRONACES-CONACYT grant 194171, and VIEP-BUAP 2021 to CA in Neuroendocrinología. JMI is fellowship from CONACYT No. 735813.

440 Modulating decreases in Superior Colliculus activity through optogenetic activation attenuates seizures in the WAG/Rij genetic model of Absence Epilepsy

OBJECTIVES/GOALS: While anti-seizure medications are effective, nearly one third of patients have seizures that go untreated. Prior studies using evoked seizure models have shown that activation of the Superior Colliculus (SC) display anti-seizure effects. Here we monitored and modulated the DLSC to suppress spontaneous seizures in a genetic model of epilepsy. METHODS/STUDY POPULATION: WAG/Rij rats (4 months old) were employed as study subjects. Animals were surgically prepared for virus injection (ChR2 excitatory opsin, or control vector), fiber optic implantation and cortical EEG for optogenetic studies. For In vivo electrophysiology, animals were implanted with a 16 wire multi-electrode array into the DLSC. In optogenetic experiments, we compared the efficacy of continuous neuromodulation to that of on-demand neuromodulation (real time detection of seizures) paradigms on a within-subject basis. We compared three stimulation frequencies on a within-subject basis (5, 20, 100 Hz). We quantified the number and duration of each spike wave discharge (SWD) during each two-hour-long trial. Electrode array single units were sorted and analyzed for activity before, during and after seizures. RESULTS/ANTICIPATED RESULTS: In vivo electrophysiology found there to be a significant decrease in single unit activity leading up to the start of SWDs. Interestingly, on-demand neuromodulation was effective in both females and males – where the greatest reduction in seizure duration was under 100 Hz light delivery. As expected, male and female animals injected with a control vector did not show a reduction in seizures in response to light delivery. In the open-loop (continuous) stimulation paradigm, optogenetic activation of the DLSC was without effect on the number or duration of SWDs at any of the frequencies examined. DISCUSSION/SIGNIFICANCE: SC activity is significantly decreased prior to the start of seizures. Furthermore, activation of the SC displays anti-seizure effects in a model of spontaneous seizures. A striking difference between open and closed-loop neuromodulation approaches underscores the importance of stimulation paradigm in determining therapeutic effect.

The effect of Madopar on absence-like seizures in WAG/Rij rats

The aim of this study was to investigate the effect of Madopar on the absence seizures and the anxiety‑like behavior (assessed using the open field test) in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. Twenty‑eight male WAG/Rij rats were randomly divided into four groups: group I: control; group II: Madopar 5 mg/kg; group III: Madopar 50 mg/kg; group IV: Madopar 100 mg/kg. A tripolar electrode was attached to all WAG/Rij rats. Electrocorticography (ECoG) recordings were made before and after Madopar (5, 50, and 100 mg/kg) injection for three hours. Anxiety‑related behavior was studied using the open field test for 5 min after the ECoG recordings. Madopar significantly reduced the number and duration of spike‑wave discharges (SWDs) when compared to the control group. The highest dose of Madopar (100 mg/kg) significantly reduced the duration of SWDs when compared to Madopar (5 mg/kg). All Madopar doses did not alter the duration of grooming, but the highest doses of Madopar significantly increased the number of squares crossed in the open field test when compared to the control and Madopar (5 mg/kg) groups. These results revealed that Madopar reduced the absence‑like seizures and the anxiety‑related behavior in WAG/Rij rats. This may emphasize the therapeutic properties of the Madopar/L‑dopa in absence epilepsy.

Exendin-4 increases absence-like seizures and anxiety–depression-like behaviors in WAG/Rij rats

AimEpilepsy is a neurological condition affecting millions of people worldwide. Glucagon-like peptide-1 (GLP-1) is a gut hormone, and its neuroprotective effect was investigated in previous studies. In this study, the effects of exendin-4, a GLP-1 receptor agonist, were studied in genetic absence epileptic Wistar Albino Glaxo/Rijswijk rats (WAG/Rij). WAG/Rij rat is a genetic model of the absence epilepsy and depression-like comorbidity. MethodWe examined the effects of exendin-4 (10, 50 and 100 µg/kg) on the absence seizures (Electrocorticography [ECoG] recordings), anxiety level (open-field test [OF]), and depression-like levels (forced swimming test [FST]) in the WAG/Rij rats. Basal ECoG recording was performed for all rats. Then, exendin-4 (10, 50 or 100 µg/kg) was administered intraperitoneally and ECoG recording was made for 180 min. After ECoG recording, forced swimming test and open-field test were applied. ResultsAdministration of 10, 50, or 100 µg/kg exendin-4 increased the duration and number of spike-wave discharges (SWDs) considerably without changing the amplitude. The 100 µg/kg dose of exendin-4 was the most effective in increasing the total duration of SWDs. Additionally, all exendin-4 doses increased anxiety level in OF and depression-like level in FST. ConclusionOur results showed that exendin-4 increased SWD incidence and anxiety- and depression-like behaviors in the WAG/Rij rats. Besides, it was also found that high doses caused the most proabsence effect.

Electroencephalographic investigation of the effects of Ginkgo biloba on spike-wave discharges in rats with genetic absence epilepsy

ObjectiveEGb 761, a plant extract obtained from the leaves of the Ginkgo biloba tree, is widely used in modern medicine and traditional medicine applications in the treatment of many diseases. However, in some clinical case reports, it has been suggested that G. biloba causes epileptic seizures. A limited number of experimental animal studies related to the effects of G. biloba on epileptic seizures do not provide sufficient information on the solution of a serious clinical problem with contrasting findings. We aimed to investigate the effects of EGb 761 administered in different doses to adult male Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats which is the genetic animal model of absence epilepsy, on absence seizures using in vivo electrophysiological method. In addition, the effects of EGb 761 doses on locomotor behavior of WAG/Rij rats were evaluated with open-field and rotarod behavioral tests. Methods50, 100, 200, and 400 mg/kg doses of EGb 761 were administered to male WAG/Rij rats with implanted EEG electrodes by oral gavage for 28 days. Evaluation of absence seizures was performed on spike-wave discharges (SWDs) in EEG recorded for 4 h each week. The number of SWDs, the total duration of SWDs, and the mean duration of SWD were determined for the analysis. ResultsIn the group treated with 400 mg/kg EGb 761, the number of SWDs and the mean duration of SWD at the 1st and 7th doses and the total duration of SWDs at the 1st, 7th and 14th doses were significantly increased (p < 0.05). In all experimental groups treated with EGb 761 doses, there was no significant change in locomotor activity in the open-field and the rotarod tests. ConclusionGinkgo biloba extract EGb 761 increased the epileptic SWD parameters of WAG/Rij rats at high doses (400 mg/kg), causing a pro-epileptic effect on absence seizures. It should be noted that in patients with epilepsy and in high-dose applications, G. biloba extract EGb 761 may lead to an increase in neuronal excitability.

Spike-wave seizures, slow-wave sleep EEG and morphology of substantia nigra pars compacta in WAG/Rij rats with genetic predisposition to absence epilepsy

Spike-wave discharges (SWDs) are EEG hallmarks of absence epilepsy, and they spontaneously appear in adult WAG/Rij rats. SWDs are known to be vigilance-dependent and are modulated by monoaminergic mechanisms. It is also known that loss of neurons in the center of the nigrostriatal dopamine system, substantia nigra pars compacta (SNc), is associated with a variety of sleep disorders. We hypothesized that a disorder of the nigrostriatal dopamine system described for WAG/Rij rats might facilitate generation of SWDs through changes in vigilance state and the quality of sleep. Our study was conducted in ‘epileptic’ and ‘non-epileptic’ phenotype (less than 1 SWDs per h). Analysis included (1) EEG examination, i.e., analysis of SWDs, rudimentary SWDs and slow wave sleep EEG and (2) microstructural examination of SNc, i.e., measuring its size and the number of neurons and glial cells. No differences in size and cellular content of SNc were found between ‘epileptic’ and ‘non-epileptic’ phenotypes. Meanwhile in ‘epileptic’ subjects, the number of SWDs correlated with the number of neurons in SNc (SWDs more frequently occurred in subjects with fewer neurons in SNc). Rudimentary SWDs were found in both phenotypes. No differences in number and duration of rudimentary SWDs were found between ‘epileptic’ and ‘non-epileptic’ phenotypes. Spike-wave EEG activity showed strong association with the number of neurons in SNc: subjects with fewer neurons in SNc were characterized by higher number of SWDs and longer rudimentary SWDs. In sum, our data suggested that intense epileptic EEG activity (in the form of SWDs and rudimentary SWDs) might lead to sleep disruption. However, the lack of direct correlations between sleep parameters and SWDs number indicated that the link between sleep features, SNc cellularity and spike-wave EEG activity could be more complex than we had expected.

The effect of GABAergic neurotransmission on the seizure-related activity of the laterodorsal thalamic nuclei and the somatosensory cortex in a genetic model of absence epilepsy

The present study aimed to investigate the alterations of the GABAergic system in the laterodorsal nucleus (LDN) of the thalamus and the somatosensory cortex (SC) in an experimental model of absence seizure. The effects of pharmacological manipulation of both GABAA and GABAB receptor subunits in the LDN on the generation of spike-wave discharges (SWD) were evaluated. The experiments were carried out in four groups of both WAG/Rij and Wistar rats with 2 and 6 months of age. The expressions of various GABA receptor subunits were studied in the LDN and SC. Furthermore, recordings of unit activity from the LDN and electrocorticography were simultaneously monitored before, during, and after the application of GABAA and GABAB antagonists in the LDN. The generation of SWD in the older WAG/Rij rats was associated with significant alterations in the expression of GABAARα1, GABAARβ3, and GABABR2 subunits in the LDN as well as GABAARα1, GABAARβ3, GABAARγ2, and GABABR2 subunits in the SC. Furthermore, the occurrence of SWD was associated with a significant reduction of gene expression of GABAARα1 and increase of GABAARβ3 in the LDN as well as reduction of GABAARα1, GABAARβ3, GABAARγ2, and GABABR2 in the SC. The microionthophoretic application of the GABAA antagonist bicuculline resulted in a significant increase in the population firing rate of LDN neurons as well as the mean number and duration of SWD. The application of the GABAB antagonist CGP35348 significantly increased the population firing rate of LDN neurons but decreased the mean number of SWD. Our data indicate the regulatory effect of the GABAergic system of the LDN and SC in absence seizures.

Cardiovascular changes in genetic absence epileptic WAG/Rij rats: Effects of chronic ethosuximide treatment

Purpose: The aim of this study was to investigate the effects of chronic ethosuximide (ETX) treatment on absence seizures and cardiovascular parameters in WAG/Rij rats with genetic absence epilepsy.Materials and Methods: Eight-weeks old, male Wistar and WAG/Rij rats were divided into four groups (n=20): Wistar control, Wistar ETX, WAG/Rij control and WAG/Rij ETX. ETX groups received chronic ETX treatment (oral, 300 mg/kg/day) for 3 months. At the end of the 3-month-treatment period; the total and mean duration, also number of spike wave discharges (SWDs) were evaluated using EEG recordings. Mean arterial blood pressure (MAP) and heart rate (HR) measurements were performed. Results: ETX treatment significantly decreased the duration and frequency of SWDs in WAG/Rij rats. MAP in WAG/Rij control group was markedly higher than Wistar control group. In Wistar ETX group, HR was significantly slower than Wistar control group. KCl-induced contraction response enhanced in Wistar ETX group and diminished in WAG/Rij control group compared to Wistar control group. Conclusion: Increased MAP and vascular reactivity in WAG/Rij rats. ETX treatment did not alter cardiovascular parameters in WAG/Rij rats whereas the treatment decreased the HR and vascular reactivity without affecting MAP in Wistar rats. T-type Ca++ channels may play a role in these changes.

Neonatal Tactile Stimulations Affect Genetic Generalized Epilepsy and Comorbid Depression-Like Behaviors.

Recent studies suggest that development of absence epilepsy and comorbid depression might be prevented by increased maternal care of the offspring, in which tactile stimulation induced by licking/grooming and non-nutritive contact seem to be crucial. In this study, we aimed to evaluate the effect of neonatal tactile stimulations (NTS) on absence epilepsy and depression-like behaviors in adulthood. Wistar Albino Glaxo from Rijswijk (WAG/Rij) rat pups with a genetic predisposition to absence epilepsy were divided into tactile stimulation (TS) group, deep touch pressure (DTP) group, maternal separation (MS) group or control group. Between postnatal day 3 and 21, manipulations (TS, DTP, and MS) were carried out for 15 min and three times a day. Animals were submitted to locomotor activity, sucrose consumption test (SCT) and forced swimming test (FST) at five months of age. At the age of six months, the electroencephalogram (EEG) recordings were conducted in order to quantify the spike-wave discharges (SWDs), which is the hallmark of absence epilepsy. The TS and DTP groups showed less and shorter SWDs in later life in comparison to maternally separated and control rats. SWDs’ number and total duration were significantly reduced in TS and DTP groups whereas mean duration of SWDs was reduced only in DTP group (p < 0.05). TS and DTP also decreased depression-like behaviors measured by SCT and FST in adult animals. In the SCT, number of approaches was significantly higher in TS and DTP groups than the maternally separated and control rats. In the FST, while the immobility latency of TS and DTP groups was significantly higher, only TS group showed significantly decreased immobility and increased swimming time. The results showed that NTS decreases both the number and length of SWDs and the depression-like behaviors in WAG/Rij rats probably by increasing arousal level and causing alterations in the level of some neurotrophic factors as well as in functions of the neural plasticity in the developing rat’s brain.

Effects of vitamin D and paricalcitol on epileptogenesis and behavioral properties of WAG/Rij rats with absence epilepsy

AimVitamin D (Vit D) has been considered as a neurosteroid and has a pivotal role in neuroprotection including epilepsy. Vit D regulator acts via a Vit D receptor (VDR). WAG/Rij rats have a genetically epileptic model of absence epilepsy with comorbidity of depression. The aim of the present study was to investigate the effect of Vit D and paricalcitol (PRC) on WAG/Rij rats. Material and methodsSixty-three male WAG/Rij rats and seven male Wistar rats were used. The effects of acute and chronic treatment with Vit D (5.000 and 60.000 IU/kg, i.p) and PRC (0.5, 5 and 10 μg/kg, i.p) on absence seizures, and related psychiatric comorbidity were investigated in WAG/Rij rats. Depression-like behavior was assayed by using the forced swimming test (FST) and; anxiety-like behavior by using the open field test (OFT). ResultsAcute Vit D treatments (5.000 and 60.000 IU/kg) similarly reduced the number and duration of spike-wave discharges (SWDs) and showed anxiolytic-antidepressive effect whereas there were no significant changes in other measured parameters between the daily and the bolus dose of Vit D. Acute administration of PRC (0.5, 5 and 10 μg/kg) showed anti-convulsive and anxiolytic-antidepressive effect. The dose (0.5 μg/kg) of PRC was the most effective dose. Chronic treatment was more effective than acute therapy in all parameters. ConclusionThe results of the present study demonstrate that Vit D and PRC have antiepileptic and anxiolytic-antidepressive effects on the absence epilepsy in WAG/Rij rats.

Coenzyme Q10 increases absence seizures in WAG/Rij rats: The role of the nitric oxide pathway

Several results have suggested that coenzyme Q10 has protective effects in different models of epilepsy. This study was designed to investigate the acute effect of coenzyme Q10 in genetic absence epileptic WAG/Rij rats. We also determined the role of l-arginine (l-Arg), a biological precursor of nitric oxide (NO), and 7-nitroindazole (7-NI), an inhibitor of neuronal NO synthase (nNOS), on the effects of coenzyme Q10. Electrocorticography (ECoG) recordings were obtained during the 180 min after the administration of the different doses of coenzyme Q10 (25, 50, 100 and 200 mg/kg), l-Arg (500 and 1000 mg/kg), 7-NI (25 and 50 mg/kg) or the combinations of coenzyme Q10 (100 mg/kg) with l-Arg (1000 mg/kg) or 7-NI (50 mg/kg). The total number of spike wave discharges (SWDs) and the mean duration of SWDs were calculated and compared. Coenzyme Q10, at the doses of 50 mg/kg, increased the total number of SWDs but did not changed the mean duration of SWDs. Coenzyme Q10 (100 and 200 mg/kg) or l-Arg (500 and 1000 mg/kg) increased both the total number and the mean duration of SWDs. In contrast, the administration of 7-NI (25 and 50 mg/kg) decreased the total number of SWDs and the mean duration of SWDs. Coadministration of l-Arg enhanced the effect of coenzyme Q10 on the total number of SWDs but not on the mean duration of SWDs. Moreover, the coadministration of 7-NI abolished the effect of coenzyme Q10 on both SWD parameters. The electrophysiological evidences from this study suggest that administration of coenzyme Q10 increases absence seizures by stimulating the synthesis of neuronal NO.

Quercetin ameliorates cadmium chloride-induced hepatotoxicity in Wistar rats

Several results have suggested that coenzyme Q10 has protective effects in different models of epilepsy. This study was designed to investigate the acute effect of coenzyme Q10 in genetic absence epileptic WAG/Rij rats. We also determined the role of l-arginine (l-Arg), a biological precursor of nitric oxide (NO), and 7-nitroindazole (7-NI), an inhibitor of neuronal NO synthase (nNOS), on the effects of coenzyme Q10. Electrocorticography (ECoG) recordings were obtained during the 180 min after the administration of the different doses of coenzyme Q10 (25, 50, 100 and 200 mg/kg), l-Arg (500 and 1000 mg/kg), 7-NI (25 and 50 mg/kg) or the combinations of coenzyme Q10 (100 mg/kg) with l-Arg (1000 mg/kg) or 7-NI (50 mg/kg). The total number of spike wave discharges (SWDs) and the mean duration of SWDs were calculated and compared. Coenzyme Q10, at the doses of 50 mg/kg, increased the total number of SWDs but did not changed the mean duration of SWDs. Coenzyme Q10 (100 and 200 mg/kg) or l-Arg (500 and 1000 mg/kg) increased both the total number and the mean duration of SWDs. In contrast, the administration of 7-NI (25 and 50 mg/kg) decreased the total number of SWDs and the mean duration of SWDs. Coadministration of l-Arg enhanced the effect of coenzyme Q10 on the total number of SWDs but not on the mean duration of SWDs. Moreover, the coadministration of 7-NI abolished the effect of coenzyme Q10 on both SWD parameters. The electrophysiological evidences from this study suggest that administration of coenzyme Q10 increases absence seizures by stimulating the synthesis of neuronal NO.

Voluntary Control of Epileptiform Spike-Wave Discharges in Awake Rats.

Genetically inherited absence epilepsy in humans is typically characterized by brief (seconds) spontaneous seizures, which involve spike-wave discharges (SWDs) in the EEG and interruption of consciousness and ongoing behavior. Genetic (inbred) models of this disorder in rats have been used to examine mechanisms, comorbidities, and antiabsence drugs. SWDs have also been proposed as models of complex partial seizures (CPSs) following traumatic brain injury (post-traumatic epilepsy). However, the ictal characteristics of these rat models, including SWDs and associated immobility, are also prevalent in healthy outbred laboratory rats. We therefore hypothesized that SWDs are not always associated with classically defined absence seizures or CPSs. To test this hypothesis, we used operant conditioning in male rats to determine whether outbred strains, Sprague Dawley and Long-Evans, and/or the inbred WAG/Rij strain (a rat model of heritable human absence epilepsy) could exercise voluntary control over these epileptiform events. We discovered that both inbred and outbred rats could shorten the duration of SWDs to obtain a reward. These results indicate that SWD and associated immobility in rats may not reflect the obvious cognitive/behavioral interruption classically associated with absence seizures or CPSs in humans. One interpretation of these results is that human absence seizures and perhaps CPSs could permit a far greater degree of cognitive capacity than often assumed and might be brought under voluntary control in some cases. However, these results also suggest that SWDs and associated immobility may be nonepileptic in healthy outbred rats and reflect instead voluntary rodent behavior unrelated to genetic manipulation or to brain trauma.SIGNIFICANCE STATEMENT Our evidence that inbred and outbred rats learn to control the duration of spike-wave discharges (SWDs) suggests a voluntary behavior with maintenance of consciousness. If SWDs model mild absence seizures and/or complex partial seizures in humans, then an opportunity may exist for operant control complementing or in some cases replacing medication. Their equal occurrence in outbred rats also implies a major potential confound for behavioral neuroscience experiments, at least in adult rats where SWDs are prevalent. Alternatively, the presence and voluntary control of SWDs in healthy outbred rats could indicate that these phenomena do not always model heritable absence epilepsy or post-traumatic epilepsy in humans, and may instead reflect typical rodent behavior.

Timing of high-frequency cortical stimulation in a genetic absence model

Introduction: Seizure control is one of the ultimate aims of epileptology: here acute and prolonged effects of closed loop high-frequency stimulation of the somatosensory cortex on the expression of spontaneously occurring spike-wave discharges (SWD) were investigated in a genetic absence model. Effects of closed loop stimulation in the experimental group were compared with a yoked control group allowing to investigate the effect of timing related to SWD occurrence, while controlling for amount and intensity of stimulation.Methods: WAG/Rij rats were implanted with stimulation electrodes in the deep layers of the somatosensory cortex, and recording electrodes in the cortex and thalamus. Closed-loop and yoked stimulation (1sec trains, biphasic 0.4msec pulses, 130Hz) sessions lasted 24h. The stimulation sessions were preceded and followed by baseline and post stimulation 24-h recordings.Results: Closed-loop stimulation interrupted SWD and duration of SWD was shortened. Both types of stimulation resulted in a reduction in SWD number during stimulation sessions. Closed-loop stimulation also resulted in less SWD during the last eight hours of the post-stimulation recording session. Sometimes yoked stimulation induced low-frequency afterdischarges.Discussion: SWD can be aborted by closed-loop stimulation of the somatosensory cortex, and at the same time the number of SWD was reduced. It can be regarded as a relatively safe neuromodulatory technique without habituation. The reduction of SWD during yoked stimulation session might be caused by 3Hz afterdischarges. The reduction of SWD on the stimulation and post-stimulation sessions demonstrates the critical relevance of timing for the induction of longer lasting neuromodulatory effects: it suggests that absence seizures themselves might be involved in their reoccurrence.

The Modulatory Effect of Metabotropic Glutamate Receptor Type-1α on Spike-Wave Discharges in WAG/Rij Rats.

Modulatory function of metabotropic glutamate type 1 (mGlu1) receptors plays a crucial role in the pathophysiology of some neurological disorders, including schizophrenia and epilepsy. In this study, the expression of mGlu1α receptors in the thalamic nuclei was assessed during development of absence seizures in the WAG/Rij rats, a valid genetic animal model of absence epilepsy. In addition, the effect of pharmacological modulation of mGlu1α receptors in the laterodorsal (LD) nucleus of the thalamus on the characteristic features of bioelectrical brain activities in the WAG/Rij rats was assessed. The expression of mGlu1α receptors in the LD was assessed in four experimental groups of both WAG/Rij and Wistar rats with 2 and 6months of age. Agonist and antagonist of mGlu1α receptors were infused in LD in the six months old WAG/Rij (epileptic) rats. The protein level of mGlu1α receptors in the thalamus of the 6-month-old WAG/Rij rats was lower than non-epileptic animals. In addition, the distribution of mGlu1α receptors in different thalamic nuclei was lower in the 6-month-old WAG/Rij compared to age-matched Wistar rats. The gene expression of mGlu1α receptor was also significantly lower in 6-month-old WAG/Rij rats in the LD compared to other animal groups. The microinjection of mGlu1α receptors agonist and antagonist in the LD reduced the duration of spike-wave discharges (SWDs) and increased the amplitude and duration of SWDs, respectively, in 6-month-old WAG/Rij rats. The alterations of mGlu1α receptors expression in the thalamus of epileptic WAG/Rij rats as well as its modulatory effects in the generation of SWDs suggest the potential of mGlu1 receptors as a therapeutic target in absence epilepsy.

Evaluation of effects of T and N type calcium channel blockers on the electroencephalogram recordings in Wistar Albino Glaxo/Rij rats, an absence epilepsy model.

Objectives:It is suggested that excessive calcium entry into neurons is the main triggering event in the initiation of epileptic discharges. We aimed to investigate the role of T and N type calcium channels in absence epilepsy experimental model.Materials and Methods:Wistar Albino Glaxo/Rij (WAG/Rij) rats (12–16 weeks old) were randomly allocated into four groups; sham, mibefradil (T type calcium channel blocker), w-Conotoxin MVIIA (N type calcium channel blocker), and mibefradil + w-Conotoxin MVIIA. Beta, alpha, theta, and delta wave ratios of EEG recordings and frequency and duration of spike wave discharges (SWDs) were analyzed and compared between groups.Results:Beta and delta recording ratios in 1 μM/5 μl mibefradil group was significantly different from basal and other dose-injected groups. Beta, alpha, and theta recordings in 0.2 μM/5 μl w-Conotoxin MVIIA group was significantly different from basal and other dose-injected groups. In w-Conotoxin MVIIA after mibefradil group, beta, alpha, and theta recording ratios were significantly different from basal and mibefradil group. Mibefradil and w-Conotoxin MVIIA significantly decreased the frequency and duration of SWDs. The decrease of frequency and duration of SWDs in mibefradil group was significantly different from w-Conotoxin MVIIA group. The frequency and duration of SWDs significantly decreased in w-Conotoxin MVIIA after mibefradil group compared with basal, mibefradil, and w-Conotoxin MVIIA groups.Conclusions:We concluded that both T and L type calcium channels play activator roles in SWDs and have positive effects on frequency and duration of these discharges. These results are related with their central effects more than peripheral effects.

The effects of agomelatine and melatonin on ECoG activity of absenceepilepsy model in WAG/Rij rats

The aim of this study was to evaluate the effect of the melatonergic M1 and M2 receptor agonist and serotonergic 5-HT2C receptor antagonist agomelatine on the spike wave discharges (SWDs) seen in electrocorticographic (ECoG) recordings of WAG/Rij rats with absence epilepsy. Twenty-one WAG/Rij male rats were used in this study. Tripolar electrodes were placed on skulls and control ECoG activities were recorded. Experimental groups received normal saline (Group I: 1 mL, intraperitoneally (i.p)), agomelatine (Group II: 40 mg/kg, i.p), and melatonin (Group III: 40 mg/kg, i.p) injections for 7 days. Following this period, 2-h ECoG recordings were repeated. The number of SWDs and their durations were calculated. The total number and duration of SWDs decreased in both the agomelatine and melatonin groups. The systemic administration of agomelatine and melatonin attenuated the genetic absence epilepsy seizures in WAG/Rij rats. The repressive effect of agomelatine on the absence seizures was similar to that of the melatonin used in this study.