Number Of Spike-wave Discharges Research Articles

Spindles in WAG/Rij Rats with Absence Epilepsy and Comorbid Depression

WAG/Rij rats are a valid model of absence epilepsy and comorbid depression. We have previously shown that WAG/Rij rats have disturbances in the sleep-wake cycle and changes in the characteristics of sleep spindles. A negative correlation was also found between the number of spike-wave discharges (SWD) and the duration of rapid eye movement (REM) sleep. Clinical evidence suggests that the traditional antidepressants imipramine and fluoxetine are effective in suppressing symptoms of depression, but may have a negative impact on the sleep-wake cycle and comorbid epilepsy in patients. Our previous studies in WAG/Rij rats showed that imipramine, when administered chronically, increases the number of SWDs, while fluoxetine at the same dose reduces their number, although both antidepressants have a pronounced antidepressant effect. Comparison of the effects of the antidepressants imipramine and fluoxetine on the sleep-wake cycle and sleep spindles in WAG/Rij rats remains unstudied. The purpose of this work is to find out: 1) what effects do imipramine and fluoxetine have on the sleep-wake cycle and the characteristics of sleep spindles in WAG/Rij rats and 2) whether there are differences in their effects. To achieve this goal, the characteristics of the sleep-wake cycle and sleep spindles were compared in WAG/Rij rats after chronic administration of antidepressants and saline and in non-epileptic Wistar rats. Administration of imipramine led to a significant decrease in the duration of REM sleep. The administration of imipramine, compared with fluoxetine, also increased the latency of the transition to sleep and the transition to REM sleep. Sleep spindle amplitude was significantly increased by both antidepressants. However, the spectral power density of “slow” and “medium” spindles, which predominate in WAG/Rij rats compared to Wistar rats, was significantly higher after administration of imipramine than fluoxetine. The results suggest that imipramine causes greater negative changes in the sleep-wake cycle and sleep spindles than fluoxetine. Studies in the WAG/Rij rat model indicate that fluoxetine is more preferable antidepressant for the treatment of depressive disorders comorbid with absence epilepsy, since it does not cause a significant deterioration in sleep quality. These results are consistent with clinical data.

BAER-101, a selective potentiator of α2- and α3-containing GABAA receptors, fully suppresses spontaneous cortical spike-wave discharges in Genetic Absence Epilepsy Rats from Strasbourg (GAERS).

BAER-101 (formerly AZD7325) is a selective partial potentiator of α2/3-containing γ-amino-butyric acid A receptors (GABAARs) and produces minimal sedation and dizziness. Antiseizure effects in models of Dravet and Fragile X Syndromes have been published. BAER-101 has been administered to over 700 healthy human volunteers and patients where it was found to be safe and well tolerated. To test the extent of the antiseizure activity of BAER-1010, we tested BAER-101 in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model, a widely used and translationally relevant model. GAERS rats with recording electrodes bilaterally located over the frontal and parietal cortices were used. Electroencepholographic (EEG) signals in freely moving awake rats were analyzed for spike-wave discharges (SWDs). BAER-101 was administered orally at doses of 0.3-100 mg/kg and diazepam was used as a positive control using a cross-over protocol with a wash-out period between treatments. The number of SWDs was dose-dependently reduced by BAER-101 with 0.3 mg/kg being the minimally effective dose (MED). The duration of and total time in SWDs were also reduced by BAER-101. Concentrations of drug in plasma achieved an MED of 10.1 nM, exceeding the Ki for α2 or α3, but 23 times lower than the Ki for α5-GABAARs. No adverse events were observed up to a dose 300×MED. The data support the possibility of antiseizure efficacy without the side effects associated with other GABAAR subtypes. This is the first report of an α2/3-selective GABA PAM suppressing seizures in the GAERS model. The data encourage proceeding to test BAER-101 in patients with epilepsy.

Parallel changes in the promoter methylation of voltage-gated T-type calcium channel alpha 1 subunit G and histone deacetylase activity in the WAG/Rij model of absence epilepsy

Objective: In the last two decades, research on epigenetic mechanisms has expanded dramatically. Recent studies demonstrated that epigenetic mechanisms regulate epilepsy and epileptogenic pathologies. In this study, we aimed to investigate changes in the promoter methylation status of the voltage-gated T-type calcium channel alpha 1 subunit G (CACNA1G) gene and total histone deacetylase activity in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats which is one of the commonly used genetic absence rat models of epilepsy in the three different age groups (3, 6, and 9 months old) on both sexes. 
 Material and Method: Evaluation of changes in the spike-wave discharges (SWDs) was performed with electrocorticography (ECoG). The promoter methylation status of the CACNA1G gene was determined by methylation-specific PCR (MSP), and histone deacetylase (HDAC) activity was determined spectrophotometrically. 
 Results: Our results demonstrated that the number of SWDs increased time-dependent in WAG/Rij. Additionally, it was observed that CACNA1G promoter methylation decreased, and total HDAC activity increased with age in both sexes. 
 Conclusion: Our results provide further support for epigenetic regulation in the absence epilepsy phenotype and suggest that the underlying mechanism behind the increase in the number of SWDs with age in the WAG/Rij animals might be regulated by CACNA1G promoter methylation or HDAC activity.

Investigating the mechanism of action of ginkgolides and bilobalide on absence seizures in male WAG/Rij rats.

The effects of a single and multiple doses of ginkgolide A, B, C, and bilobalide, active components of Ginkgo biloba extract (EGb 761), on absence seizures were investigated in male WAG/Rij rats, a genetic animal model of absence epilepsy. Furthermore, the interactions of ginkgolide A together with NMDA receptor antagonist MK-801, AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), or L-type calcium channel blocker nicardipine were studied to figure out how ginkgolide A affects spike-wave discharges (SWDs) in the brain. The experiments were done using 6-8-month-old male WAG/Rij rats with infusion cannula and EEG electrode implanted. Ginkgolide A, B, C, and bilobalide were administered intraperitoneally for 7 days at a dose of 6mg/kg. In interaction groups, 6μg ginkgolide A was injected intracerebroventricularly in combination with MK-801 (10μg), CNQX (1μg), and nicardipine (50 μg) for 7 days. EEG was recorded from animals at the baseline, first dose, and seventh dose periods for 4 h. Ginkgolide A (p=.028), C (p=.046), and bilobalide (p=.043) significantly increased the frequency of SWDs in WAG/Rij rats. Ginkgolide A injected into the lateral ventricle with MK-801 (p=.046), CNQX (p=.043), and nicardipine (p=.046) significantly increased the number of SWDs after seventh dose. Finally, the EGb 761-related increase in absence epilepsy was determined to be caused by ginkgolide A, C, and bilobalide. All three receptor antagonists/channel blockers do not inhibit the pro-absence effect of ginkgolide A. The findings revealed that ginkgolide A's pro-absence effect is mediated by brain circuits other than ionotropic glutamate receptors or L-type calcium channels.

Maternal Methyl-Enriched Diet Normalizes Characteristics of the Sleep–Wake Cycle and Sleep Spindles in Adult Offspring of WAG/Rij Rats with Genetic Absence Epilepsy

It has been previously shown that the perinatal maternal methyl-enriched diet (MED) reduces the number of spike-wave discharges (SWDs) and behavioral symptoms of depression in the adult offspring of WAG/Rij rats. Epilepsy and depression are usually accompanied by disturbances in the sleep-wake cycle. SWDs and sleep spindles are different manifestations of thalamocortical activity It is assumed that pathological alterations in the thalamocortical system that lead to SWD also change the sleep spindles. It is possible that the maternal MED has a positive effect not only on the SWD, but also on the sleep spindles. The purpose of this work is to find out whether maternal MED affects the sleep-wake cycle and whether it changes the characteristics of sleep spindles in adult offspring of WAG/Rij rats. It has been shown that in the offspring of WAG/Rij rats born to mothers who consumed MED during the perinatal period compared to the offspring whose mothers consumed control diet (CD), the relative duration of REM sleep significantly increases. In the offspring of WAG/Rij rats whose mothers consumed MED, the relative duration of REM sleep and the number of its episodes become indistinguishable from those in non-epileptic Wistar rats. Maternal MED also increases the number of transitions from slow-wave to REM sleep. There is a significant negative correlation between the number of SWDs and the duration of REM sleep. Maternal MED compare to CD decreased the amplitude and spectral power density of sleep spindles. They became much closer to the amplitude and spectral power of density of sleep spindles in Wistar rats. Thus, maternal MED normalizes characteristics of the sleep-wake cycle and sleep spindles in adult offspring of WAG/Rij rats. We hypothesize that this positive effect is associated with a reduction in the symptoms of absence epilepsy and comorbid depression, as well as with the correction of the activity of the thalamocortical system.

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.

Probiotic supplementation alleviates absence seizures and anxiety- and depression-like behavior in WAG/Rij rat by increasing neurotrophic factors and decreasing proinflammatory cytokines

AimEpilepsy is one of the most common chronic brain disorders that affect millions of people worldwide. In the present study, we investigated the effects of probiotic supplementation on absence epilepsy and anxiety-and depression-like behavior in WAG/Rij rats. Material and methodFourteen male WAG/Rij rats (absence-epileptic) and seven male Wistar rats (nonepileptic) were used. The effects of probiotic VSL#3 (12.86 bn living bacteria/kg/day for 30 day/gavage) on absence seizures, and related psychiatric comorbidities were evaluated in WAG/Rij rats. Anxiety-like behavior was evaluated by the open-field test and depression-like behavior by the forced swimming test. In addition, the brain tissues of rats were evaluated histopathologically for nerve growth factor [NGF], brain-derived neurotrophic factor [BDNF], SRY sex-determining region Y-box 2 [SOX2] and biochemically for nitric oxide [NO], tumor necrosis factor-alpha [TNF-α] ,and Interleukin-6 [IL-6]. ResultsCompared to Wistar rats, WAG/Rij rats exhibited anxiety- and depression-like behavior, and had lower BDNF, NGF and SOX2 immunoreactivity, and higher TNF-α, IL-6 levels in brain tissue. VSL#3 supplementation reduced the duration and number of spike-wave discharges (SWDs) and exhibited anxiolytic or anti-depressive effect. VSL#3 supplement also increased the NGF immunoreactivity while decreasing IL-6, TNF-α and NO levels in WAG/Rij rat brain. ConclusionThe findings of the present study showed that neurotrophins, SOX2 deficiency, and pro-inflammatory cytokines may play a role in the pathogenesis of absence epilepsy. Our data support the hypothesis that the probiotics have anti-inflammatory effect. The present study is the first to show the positive effects of probiotic bacteria on absence seizures and anxiety- and depression-like behavior.

Vasoactive intestinal peptide (VIP) conducts the neuronal activity during absence seizures: GABA seems to be the main mediator of VIP

Absence epilepsy is classified as a childhood generalized epilepsy syndrome with distinctive electroencephalographic patterns. The Wistar Albino Glaxo originating from Rijswijk (WAG/Rij) strain is a very well validated animal model of absence epilepsy that also shows behavioral deficits. In addition to the gastrointestinal system, VIP is highly expressed throughout numerous brain regions, and it plays crucial roles as a neurotransmitter and as a neuromodulatory, neurotrophic and neuroprotective factor in both the central and peripheral nervous systems.In this study, adult WAG/Rij rats were divided into two groups (n = 10): a group that was administered VIP (25 ng/kg i.p.) every 2 days for 15 days and an age-matched control group that was administered physiological saline. Electrical brain activity and behavior (depressive- like behavior, learning and memory and anxiety) were investigated in both groups. In addition, the extracellular concentrations of GABA and glutamate and the GABA/glutamate ratio were measured by high-performance liquid chromatography in microdialysate samples collected from the somatosensorial cortex of WAG/Rij rats.Our results demonstrated that VIP treatment significantly suppressed the total duration and number of spike wave discharges in WAG/Rij rats. However, VIP had no significant effect on behavior. VIP increased the extracellular concentration of GABA and the GABA/glutamate ratio in the somatosensory cortex. In conclusion, VIP has suppressive effects on absence seizures, possibly by increasing the GABA concentration and inducing the transformation of glutamate to GABA in the somatosensory cortex of WAG/Rij rats.

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.

Enhancement of Ketone Supplements-Evoked Effect on Absence Epileptic Activity by Co-Administration of Uridine in Wistar Albino Glaxo Rijswijk Rats.

Both uridine and exogenous ketone supplements decreased the number of spike-wave discharges (SWDs) in a rat model of human absence epilepsy Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. It has been suggested that alleviating influence of both uridine and ketone supplements on absence epileptic activity may be modulated by A1 type adenosine receptors (A1Rs). The first aim was to determine whether intraperitoneal (i.p.) administration of a specific A1R antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 0.2 mg/kg) and a selective adenosine A2A receptor antagonist (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo [1,5-c]pyrimidine) (SCH 58261; 0.5 mg/kg) have a modulatory influence on i.p. 1000 mg/kg uridine-evoked effects on SWD number in WAG/Rij rats. The second aim was to assess efficacy of a sub-effective dose of uridine (i.p. 250 mg/kg) combined with beta-hydroxybutyrate salt + medium chain triglyceride (KSMCT; 2.5 g/kg, gavage) on absence epilepsy. DPCPX completely abolished the i.p. 1000 mg/kg uridine-evoked alleviating effect on SWD number whereas SCH 58261 was ineffective, confirming the A1R mechanism. Moreover, the sub-effective dose of uridine markedly enhanced the effect of KSMCT (2.5 g/kg, gavage) on absence epileptic activity. These results demonstrate the anti-epilepsy benefits of co-administrating uridine and exogenous ketone supplements as a means to treat absence epilepsy.

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.

Response of spike-wave discharges in aged APP/PS1 Alzheimer model mice to antiepileptic, metabolic and cholinergic drugs

Epileptic nonconvulsive spike-wave discharges (SWDs) are commonly seen in amyloid plaque bearing transgenic mice but only rarely in their wild-type littermates. To shed light on their possible treatment options, we assessed the effect of drugs with variable and known mechanisms of action on the occurrence of SWDs in aged APPswe/PS1dE9 mice. The treatments included prototypic antiepileptic drugs (ethosuximide and levetiracetam), donepezil as the typical Alzheimer drug and atropine as an antagonistic effect, GABAB antagonist CGP-35348, and alternate energy substrates beta-hydroxybutyrate (BHB), pyruvate and lactate on the occurrence of SWDs in aged APPswe/PS1dE9 mice. All agents were administered by single intraperitoneal injections at doses earlier documented to be effective and response was assessed by recording 3 h of video-EEG. Atropine at 25 mg/kg significantly decreased SWD occurrence in all behavioral states, and also resulted in altered frequency composition of SWDs and general EEG slowing during sleep. Ethosuximide at 200 mg/kg and levetiracetam at 75 mg/kg effectively suppressed SWDs only during a period of mixed behavioral states, but levetiracetam also increased SWDs in sleep. BHB at 1 g/kg decreased SWDs in sleep, while both pyruvate and lactate at the same dose tended to increase SWD number and total duration. Unexpectantly, donepezil at 0.3 mg/kg CGP-35348 at 100 mg/kg had no effect on SWDs. These findings call for re-evaluation of some prevailing theories on neural circuit alternations that underlie SWD generation and show the utility of APP/PS1 mice for testing potential new treatments for nonconvulsive epileptic activity related to Alzheimer pathology.

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.

Swimming exercise decreases the absence-like epileptic activity in WAG/Rij rats

AimThe aim of the present study was to evaluate the effects of long (60 min/day), moderate (30 min/day) and short (15 min/day) term daily swimming exercise programs for 90 days on durations and the spike-wave discharges (SWDs) seen in the electrocorticographic (ECoG) recordings of WAG/Rij rats with absence epilepsy. Materials and methodsThirty-five adult male rats were divided into 5 groups as; Group 1: Control, Group 2: Sham (daily exposed to shallow water), Group 3: 15 min/day swimming exercise, Group 4: 30 min/day swimming exercise, Group 5: 60 min/day swimming exercise. After 90 days of swimming exercise program; ECoG recordings were taken for 2 h. Total number and cumulative length of SWDs in the recordings were used for evaluation of the seizures. ResultsBoth of the SWD parameters were significantly decreased in all swimming exercise groups compared to control and sham groups. The moderate swimming group (30 min/day) was found the most effective exercise program considering both of the SWD parameters of absence epilepsy. ConclusionThe results of the present study provide electrophysiologic evidence for the role of swimming exercise on the modulation of genetic absence epilepsy seizures in WAG/Rij rats.

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.

Adenosine A1 Receptor Antagonism Abolished the Anti-seizure Effects of Exogenous Ketone Supplementation in Wistar Albino Glaxo Rijswijk Rats.

The state of therapeutic ketosis can be achieved by using the ketogenic diet (KD) or exogenous ketone supplementation. It was suggested previously that the adenosinergic system may be involved in the mediating effect of KD on suppressing seizure activity in different types of epilepsies, likely by means of adenosine A1 receptors (A1Rs). Thus, we tested in the present study whether exogenous ketone supplements (ketone ester: KE, 2.5 g/kg/day; ketone salt/KS + medium chain triglyceride/MCT: KSMCT, 2.5 g/kg/day) applied sub-chronically (for 7 days) by intragastric gavage can modulate absence epileptic activity in genetically absence epileptic Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. The number of spike-wave discharges (SWDs) significantly and similarly decreased after both KE and KSMCT treatment between 3rd and 7th days of gavage. Moreover, blood beta-hydroxybutyrate (βHB) levels were significantly increased alike after KE and KSMCT gavage, compared to control levels. The SWD number and βHB levels returned to the baseline levels on the first day without ketone supplementation. To determine whether A1Rs can modify ketone supplement-evoked changes in absence epileptic activity, we applied a non-pro-epileptic dose of a specific A1R antagonist DPCPX (1,3-dipropyl-8-cyclopentylxanthine) (intraperitoneal/i.p. 0.2 mg/kg) in combination with KSMCT (2.5 g/kg/day, gavage). As expected, DPCPX abolished the KSMCT-evoked decrease in SWD number. Thus, we concluded that application of exogenous ketone supplements may decrease absence epileptic activity in WAG/Rij rats. Moreover, our results suggest that among others the adenosinergic system, likely via A1Rs, may modulate the exogenous ketone supplements-evoked anti-seizure effects.