Seizures In Adult Rats Research Articles

Pentylenetetrazol-induced seizures in adult rats are associated with plastic changes to the dendritic spines on hippocampal CA1 pyramidal neurons

Epilepsy is a chronic neurobehavioral disorder whereby an imbalance between neurochemical excitation and inhibition at the synaptic level provokes seizures. Various experimental models have been used to study epilepsy, including that based on acute or chronic administration of Pentylenetetrazol (PTZ). In this study, a single PTZ dose (60 mg/kg) was administered to adult male rats and 30 min later, various neurobiological parameters were studied related to the transmission and modulation of excitatory impulses in pyramidal neurons of the hippocampal CA1 field. Rats experienced generalized seizures 1−3 min after PTZ administration, accompanied by elevated levels of Synaptophysin and Glutaminase. This response suggests presynaptic glutamate release is exacerbated to toxic levels, which eventually provokes neuronal death as witnessed by the higher levels of Caspase-3, TUNEL and GFAP. Similarly, the increase in PSD-95 suggests that viable dendritic spines are functional. Indeed, the increase in stubby and wide spines is likely related to de novo spinogenesis, and the regulation of neuronal excitability, which could represent a plastic response to the synaptic over-excitation. Furthermore, the increase in mushroom spines could be associated with the storage of cognitive information and the potentiation of thin spines until they are transformed into mushroom spines. However, the reduction in BDNF suggests that the activity of these spines would be down-regulated, may in part be responsible for the cognitive decline related to hippocampal function in patients with epilepsy.

Divergent effects of levetiracetam and tiagabine against spontaneous seizures in adult rats following neonatal hypoxia

Animal models are valuable tools for screening novel therapies for patients who suffer from epilepsy. However, a wide array of models are necessary to cover the diversity of human epilepsies. In humans, neonatal hypoxia (or hypoxia-ischemia) is one of the most common causes of epilepsy early in life. Hypoxia-induced seizures (HS) during the neonatal period can also lead to spontaneous seizures in adulthood. This phenomenon, i.e., early-life hypoxia leading to adult epilepsy − is also seen in experimental models, including rats. However, it is not known which anti-seizure medications are most effective at managing adult epilepsy resulting from neonatal HS. Here, we examined the efficacy of three anti-seizure medications against spontaneous seizures in adult rats with a history of neonatal HS: (1) phenobarbital (PHB), the oldest epilepsy medicine still in use today; (2) levetiracetam (LEV); and (3) tiagabine (TGB). Both LEV and TGB are relatively new anticonvulsant drugs that are ineffective in traditional seizure models, but strikingly effective in other models. We found that PHB and LEV decreased seizures in adult rats with a history of HS, whereas TGB exacerbated seizures. These divergent drug effects indicate that the HS model may be useful for differentiating the clinical efficacy of putative epilepsy therapies.

The effect of subchronic supplementation with folic acid and l-arginine on homocysteine-induced seizures.

The aim of the present study was to examine the effect of subchronic co-administration of folic acid (F) and l-arginine (A) on behavioural and electroencephalographic (EEG) characteristics of dl homocysteine thiolactone (H) induced seizures in adult rats. The activity of membrane ATPases in different brain regions were also investigated. Rats were treated with F, A, or vehicle for 15 days (regimen: F 5 mg/kg + A 500 mg/kg (F5A500); F 10 mg/kg + A 300 mg/kg (F10A300)). Seizures were elicited by convulsive dose of H (H, F5A500H, F10A300H) Subchronic supplementation with F and A did not affect seizure incidence, number of seizure episodes, and severity in F5A500H and F10A300H groups vs. H group. However, a tendency to increase latency and decrease the number of seizure episodes was noticed in the F10A300H group. EEG mean spectral power densities during ictal periods were significantly lower in F10A300H vs. H group. The activity of Na+/K+-ATPase and Mg2+-ATPase was significantly increased in almost all examined structures in rats treated with F and A. We can conclude that subchronic supplementation with folic acid and l-arginine has an antiepileptic effect in dl homocysteine thiolactone induced epilepsy.

Efficacy of Retigabine on Acute Limbic Seizures in Adult Rats.

Background and Purpose:The efficacy of retigabine (RGB), a positive allosteric modulator of K+ channels indicated for adjunct treatment of partial seizures, was studied in two adult models of kainic acid (KA)-induced status epilepticus to determine it’s toleratbility.Methods:Retigabine was administered systemiclly at high (5 mg/kg) and low (1–2 mg/kg) doses either 30 min prior to or 2 hr after KA-induced status epilepticus. High (1 µg/µL) and low (0.25 µg/µL) concentrations of RGB were also delivered by intrahippocampal microinjection in the presence of KA.Results:Dose-dependent effects of RGB were observed with both models. Lower doses increased seizure behavior latency and reduced the number of single spikes and synchronized burst events in the electroencephalogram (EEG). Higher doses worsened seizure behavior, produced severe ataxia, and increased spiking activity. Animals treated with RGB that were resistant to seizures did not exhibit significant injury or loss in GluR1 expression; however if stage 5–6 seizures were reached, typical hippocampal injury and depletion of GluR1 subunit protein in vulernable pyramidal fields occurred.Conclusions:RGB was neuroprotective only if seizures were significantly attenuated. GluR1 was simultaneously suppressed in the resistant granule cell layer in presence of RGB which may weaken excitatory transmission. Biphasic effects observed herein suggest that the human dosage must be carefully scrutinized to produce the optimal clinical response.

The effect of subchronic supplementation with folic acid on homocysteine induced seizures.

Influence of folic acid on the CNS is still unclear. Folate has a neuroprotective effect, while on the other hand excess folate can exacerbate seizures in epileptics. The aim of the present study was to examine the effect of subchronic administration of folic acid on behavioural and electroencephalographic (EEG) characteristics of DL homocysteine thiolactone induced seizures in adult rats. The activity of Na⁺/K⁺-ATPase and Mg²⁺-ATPase in different brain regions was investigated. Adult male Wistar rats were divided into groups: 1. Controls (C, 0.9% NaCl); 2. DL homocysteine-thiolactone 8.0 mmol/kg (H); 3. Subchronic supplementation with folic acid 5 mg/kg for 7 days (F) and 4. Subchronic supplementation with F + single dose of H (FH). Seizure behaviour was assessed by incidence, latency, number and intensity of seizure episodes. Seizure severity was described by a descriptive scale with grades 0-4. For EEG recordings, three gold-plated recording electrodes were implanted into the skull. Subchronic supplementation with folic acid did not affect seizure incidence, median number of seizure episodes and severity in FH, comparison with H (p > 0.05). The majority of seizure episodes in all groups were of grade 2. There were no significant differences in lethal outcomes at 24 h upon H injection in the FH vs. H group. The activity of Na⁺/K⁺-ATPase and Mg²⁺-ATPase was significantly increased in almost all examined structures in the FH vs. H group. Subchronic folic acid administration did not exacerbate H induced seizures and completely recovered the activity of ATPases.

Inflammation induced at different developmental stages affects differently the range of microglial reactivity and the course of seizures evoked in the adult rat.

In the brain, inflammation occurs following a variety of types of brain damage, including epileptic seizures. Proinflammatory cytokines, like IL-1β or TNFα, can increase neuronal excitability and initiate spontaneous seizures or epileptogenesis. Recent studies indicate that the effects can be attenuated or even abolished in animals subjected to inflammation-inducing treatments at earlier developmental stages, termed "preconditioning". Immunocompetent microglial cells display particular sensitivity to subtle brain pathologies showing a morphological continuum from resting to reactive forms. Following inflammation, multiple ramified processes of resting microglia become gradually shorter, and the cells transform into macrophages. Parameters of the morphological variations were used here as indicators of the nervous tissue reactivity to seizures in adult rats experiencing inflammation at earlier stages of postnatal development. Systemic inflammation was induced with lipopolysaccharide (LPS) in 6-day-old or 30-day-old rats. In two-month-old survivors of the inflammatory status, seizures were evoked with pilocarpine injection. The seizure intensity was scored during a six-hour continuous observation period following the injection. Brain sections were immunostained for Iba1 to visualize microglia. Thereafter, morphology of microglial cells located in the hippocampal formation was analyzed using parameters such as solidity, circularity, ramification index, and area. In naïve rats, seizure-induced transformations of microglial cells were reflected by strong changes in the parameters of their morphology. However, in the adult rats pretreated with LPS on their 6th or 30th postnatal days, the seizure-induced changes were significantly reduced, and microglial morphology remained significantly closer to normal. Significant amelioration of the acute phase of seizures was observed only when inflammation was induced in 30-day-old, but not in 6-day-old, rats. The results confirm previous reports that moderate inflammation protects the nervous tissue from subsequent damage by reducing influences of proinflammatory factors on reactive glial cells. The young-age inflammation may have age-dependent effects on susceptibility to seizures induced in adulthood. This article is part of a Special Issue entitled "Status Epilepticus".

Proconvulsant effects of tramadol and morphine on pentylenetetrazol-induced seizures in adult rats using different routes of administration

Tramadol is frequently used as a pain reliever. However, it has been sometimes noted to have the potential to cause seizures. Because of its dual mechanism of action (both opioid and nonopioid), the adverse effect profile of tramadol can be different in comparison with single-mechanism opioid analgesics, such as morphine. In the present study, the facilitatory effects of tramadol and morphine on pentylenetetrazol-induced seizures using different routes of administration were compared in rats. Adult female rats were divided into six groups and continuously received saline, morphine, or tramadol on a daily basis for 15days [gavage (PO) or intraperitoneal (IP)]. An increasing dose of morphine and tramadol was used to prevent resistance to repetitive dose (20–125mg/kg). Following one week of withdrawal period and 30min before the seizure induction (PTZ=80mg/kg, IP), each group of rats was further divided into subgroups that received saline, morphine, or tramadol for the second time on the 22nd day of the experiment. Results showed that, while morphine, tramadol, and their administration had different effects on seizure behaviors, both acute and chronic administrations of morphine and tramadol potentiated PTZ-induced seizures. However, there was no significant difference between morphine and tramadol in terms of seizure severity. Effects of morphine and tramadol on PTZ-induced seizures were also stable following one week of withdrawal. In conclusion, this study indicated similar severity in the proconvulsant effect of morphine and tramadol on PTZ-induced seizures, which might depend on their similar effects on GABAergic pathways.

21. The effect of folic acid on lindane induced seizures in adult rats

Purpose: The aim of our study was to investigate the effects of folic acid on lindane induced seizures in rats. Methods: Adult male Wistar rats were divided into groups: 1. Saline-treated (C); 2. Lindane i.p. in doses: 4 mM/kg (L 4 ), 6 mM/kg (L 6 ) and 8 mM/kg (L 8 ); 3. Folic acid 15 mg/kg, i.p. (F); and 6. Folic acid 30 min prior to L4, L6 and L8 (L 4 F; L 6 F; L 8 F). Seizure behaviour was assessed by incidence, latency, number and intensity of seizure episodes. Seizure severity was determined by a descriptive scale with grades from 0 to 4. Results: There were no behavioural signs of seizure activity in groups C and F. Acute treatment with folic acid did not affect incidence and latency of seizure episodes in experimental groups. Folic acid treatment significantly reduced severity of seizure episodes in L 8 F group, compared to the L 8 group ([2 (0–3)] vs. [4(0–4)] p Conclusions: Our findings suggest that acute administration of folic acid has anticonvulsive effect on seizures induced by the highest dose of lindane.

Homocysteine thiolactone-induced seizures in adult rats are aggravated by inhibition of inducible nitric oxide synthase

Homocysteine and its metabolites (homocysteine thiolactone (HT)) induce seizures via different but still not well-known mechanisms. The role of nitric oxide (NO) in epileptogenesis is highly contradictory and depends on, among other factors, the source of NO production. The aim of the present study was to examine the effects of aminoguanidine, selective inhibitor of inducible NO synthase (iNOS), on HT-induced seizures. Aminoguanidine (50, 75, and 100mg/kg, intraperitoneally (i.p.)) was injected to rats 30min prior to inducing HT (5.5mmol/kg, i.p.). Seizure behavior was assessed by seizure incidence, latency time to first seizure onset, number of seizure episodes, and their severity during observational period of 90min. Number and duration of spike and wave discharges (SWDs) were determined in electroencephalogram (EEG). Seizure latency time was significantly shortened, while seizure incidence, number, and duration of HT-induced SWD in EEG significantly increased in rats receiving aminoguanidine 100mg/kg before subconvulsive dose of HT. Aminoguanidine in a dose-dependent manner also significantly increased the number of seizure episodes induced by HT and their severity. It could be concluded that iNOS inhibitor (aminoguanidine) markedly aggravates behavioral and EEG manifestations of HT-induced seizures in rats, showing functional involvement of iNOS in homocysteine convulsive mechanisms.

Paradoxical sleep deprivation potentiates epilepsy induced by homocysteine thiolactone in adult rats

There is an intriguing and still poorly understood relationship between sleep deprivation and epilepsy. It has recently been shown that paradoxical sleep deprivation decreases levels of homocysteine, an amino acid involved together with its thiolactone metabolite in epileptogenesis. The aim of the present study was to investigate the effects of paradoxical sleep deprivation on homocysteine thiolactone (H)-induced seizures in rats, a model of generalized seizures. Selective deprivation of paradoxical sleep in adult male Wistar rats was achieved by the platform method. Animals with implanted electrodes for electroencephalogram (EEG) registration were assigned to appropriate experimental conditions (dry cage for control, large platform for stress control and small platform for paradoxical sleep deprivation) and 72 h later were intraperitoneally treated with either H (5.5 mmol/kg) or saline (0.9% NaCl). This study showed that paradoxical sleep deprivation increased the incidence and number of H-induced seizure episodes, shortened latency time to seizures and led to significant rates of lethality after H administration, but without effect on the seizure severity. Paradoxical sleep deprivation increased the number and duration of spikes-and-wave discharges, while decreased latency to its appearance in EEG. Judging by the behavioral and EEG findings, it could be concluded that paradoxical sleep deprivation can provoke the expression of factors that can potentiate H-induced seizures in adult rats.

Positive Allosteric Modulator of mGluR4 PHCCC Exhibits Proconvulsant Action in Three Models of Epileptic Seizures in Immature Rats

The activation of metabotropic glutamate receptors subtype 4 (mGluR4) potentiates models of absence seizures in adult rats. These seizures are age-dependent, but data concerning the role of mGluR4 in immature brain is insufficient. N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1acarboxamide (PHCCC), which is a positive allosteric modulator of these receptors, was used in three different models of seizures in immature rats: 1) convulsions induced by high doses of pentetrazol (PTZ; a model of generalised tonic-clonic seizures); 2) rhythmic electro-encephalographic (EEG) activity induced by low doses of PTZ (a model of absence seizures); and 3) electrically elicited cortical afterdischarges (ADs, a model of myoclonic seizures). We administered four doses of PHCCC (1, 3, 10 and 20 mg/kg) in PTZ-induced convulsions and two doses (3 and 10 mg/kg) in the two electrophysiological models of freely moving rats with implanted electrodes. Every dose and age group consisted from 8 to 10 rats. PTZ-elicited convulsions were not significantly influenced by PHCCC. In contrast, PHCCC potentiated the effect of a subconvulsant dose (60 mg/kg) of PTZ. The 10-mg/kg dose of PHCCC significantly prolonged the duration of PTZ-induced rhythmic activity episodes and shortened the intervals between individual episodes in 25-day-old rats (P25). In contrast, this potentiation was not seen in P18 rats. Cortical ADs were significantly prolonged with repeated stimulations by both doses of PHCCC in P12 and P18 animals. P25 rats exhibited only slightly longer AD durations. In conclusion, we did not find any anticonvulsant effect of PHCCC. On the contrary, proconvulsant action was demonstrated in all three models in immature rats.

Do Prenatally Methamphetamine-Exposed Adult Male Rats Display General Predisposition to Drug Abuse in the Conditioned Place Preference Test?

Drug abuse of pregnant women is a growing problem. The effect of prenatal drug exposure may have devastating effect on development of the offsprings that may be long-term or even permanent. One of the most common drug abused by pregnant women is methamphetamine (MA), which is also the most frequently abused illicit drug in the Czech Republic. Our previous studies demonstrated that prenatal MA exposure alters behavior, cognition, pain and seizures in adult rats in sex-specific manner. Our most recent studies demonstrate that prenatal MA exposure makes adult rats more sensitive to acute injection of the same or related drugs than their controls. The aim of the present study was to examine the effect of prenatal MA exposure on drug-seeking behavior of adult male rats tested in the Conditioned place preference (CPP). Adult male rats were divided to: prenatally MA-exposed (5 mg/kg daily for the entire prenatal period), prenatally saline-exposed (1 ml/kg of physiological saline) and controls (without maternal injections). The following drugs were used in the CPP test in adulthood: MA (5 mg/kg), amphetamine (5 mg/kg), cocaine (5 and 10 mg/kg), morphine (5 mg/kg), MDMA (5 mg/kg) and THC (2 mg/kg). Our data demonstrated that prenatally MA-exposed rats displayed higher amphetamine-seeking behavior than both controls. MA as well as morphine induced drug-seeking behavior of adult male rats, however this effect did not differ based on the prenatal MA exposure. In contrast, prenatal MA exposure induced rather tolerance to cocaine than sensitization after the conditioning in the CPP. MDMA and THC did not induce significant effects. Even though the present data did not fully confirmed our hypotheses, future studies are planned to test the drug-seeking behavior also in self-administration test.

Atypical Febrile Seizures, Mesial Temporal Lobe Epilepsy, and Dual Pathology

Febrile seizures occurring in the neonatal period, especially when prolonged, are thought to be involved in the later development of mesial temporal lobe epilepsy (mTLE) in children. The presence of an often undetected, underlying cortical malformation has also been reported to be implicated in the epileptogenesis process following febrile seizures. This paper highlights some of the various animal models of febrile seizures and of cortical malformation and portrays a two-hit model that efficiently mimics these two insults and leads to spontaneous recurrent seizures in adult rats. Potential mechanisms are further proposed to explain how these two insults may each, or together, contribute to network hyperexcitability and epileptogenesis. Finally the clinical relevance of the two-hit model is briefly discussed in light of a therapeutic and preventive approach to mTLE.

Inhibition of the Neuronal Nitric Oxide Synthase Potentiates Homocysteine Thiolactone- Induced Seizures in Adult Rats

Nitric oxide (NO), one of the gaseous neurotransmitters, is produced in reaction catalyzed by family of NO synthases (NOS). The involvement of neuronal NOS (nNOS) in seizures induced by homocysteine thiolactone has not been studied. Therefore, the aim of this study was to determine the effects of 7-nitroindazole, a selective nNOS inhibitor, on behavioral manifestations of homocysteine - induced seizures in adult rats. Adult male Wistar albino rats were treated with 7-nitroindazole (25, 50 and 75 mg/kg, i.p.) 30 min before injection of subconvulsive dose of homocysteine (D,L homocysteine thiolactone 5.5 mmol/kg, i.p.). Convulsive behavior was assessed during 90 min upon homocysteine administration by the following parameters: seizure incidence, duration of latency, number of seizure episodes per rat and their severity. Severity of seizures was evaluated using a descriptive scale graded from 0 to 4. It was shown that 7-nitroindazole increased seizure incidence, shortened latency time to first seizure, increased number of seizure episodes per rat and increased severity of seizures induced by homocysteine in rats. 7- nitroindazole in dose of 25 mg/kg led to a statistically significant increase in the seizure incidence and number of seizure episodes per rat, while doses of 50 and 75 mg/kg significantly increased severity of homocysteine-induced seizures. It could be concluded that inhibition of nNOS by 7-nitroindazole potentiates seizures induced by homocysteine in rats.

Anticonvulsive effect of folic acid in homocysteine thiolactone-induced seizures.

Numerous studies have linked folate deficiency and resultant elevated plasma homocysteine levels with an increased risk of neurodegenerative diseases and seizures. The aim of the present study was to examine the effect of acute folic acid administration on behavioural and electroencephalographic (EEG) characteristics of DL homocysteine thiolactone-induced seizures in adult rats. Adult male Wistar rats were divided into following groups: (1) saline-treated (C); (2) DL homocysteine thiolactone 8 mmol/kg, i.p. (H); (3) groups that received folic acid i.p. in doses: 5 mg/kg (F(5)), 10 mg/kg (F(10)) and 15 mg/kg (F(15)) and (4) F 30 min prior to H (F(5)H, F(10)H and F(15)H, respectively). Seizure behaviour was assessed by incidence, latency, number and intensity of seizure episodes. Seizure severity was described by a descriptive scale with grades 0-4. For EEG recordings, under pentobarbital anaesthesia three gold-plated recording electrodes were implanted into the skull. There were no behavioural and EEG signs of seizure activity in C, F(5), F(10) and F(15) groups. In F(15)H group, the incidence of seizures was significantly lower, and the latency significantly prolonged, comparing to the H. Pre-treatment with F did not affect median number and severity of seizure episodes in all FH groups. Administration of F decreased mean total spectral power density in all FH groups, in a dose-dependent manner, in comparison with H. Our findings suggest that folic acid has anticonvulsive and antiepileptic effect on H-induced seizures in adult rats.

Neuropharmacological effects of lipoic acid and ubiquinone on δ‐aminolevulinic dehydratase, Na+, K+‐ATPase, and Mg2+‐ATPase activities in rat hippocampus after pilocarpine‐induced seizures

In this study, we investigated the effects of lipoic acid (LA) in the hippocampus oxidative stress caused by pilocarpine-induced seizures in adult rats. Wistar rats were treated with 0.9% saline (i.p., control group), LA (10mg/kg, i.p., LA group), ubiquinone [20mg/kg, i.p., ubiquinone (UQ) group], pilocarpine (400mg/kg, i.p., P400 group), and the association of LA (10mg/kg, i.p.) plus pilocarpine (400mg/kg, i.p.) or UQ (20mg/kg, i.p.) plus pilocarpine (400mg/kg, i.p.), 30min before of administration of P400 (LA plus P400 group and UQ plus P400 group, respectively). After the treatments, all groups were observed for 1h. The enzyme activities (δ-aminolevulinic dehydratase (δ-ALA-D), Mg(2+) -ATPase, and Na(+) , K(+) -ATPase) were measured using spectrophotometric methods, and the results compared to values obtained from saline and pilocarpine-treated animals. Protective effects of LA and UQ were also evaluated on the same parameters. We reported here for the first time that Na(+) , K(+) -ATPase and δ-ALA-D activities inhibition and Mg(2+) -ATPase stimulation in the pilocarpine model are probably attributed to the oxidative stress caused by seizures in the rat hippocampus. The addition of the antioxidants LA and UQ may reverses the previously mentioned Na(+) , K(+) -ATPase and δ-ALA-D inhibitions and Mg(2+) -ATPase stimulation. The oxidative stress plays an important signaling role in pilocarpine-induced seizures, and antioxidant drugs might be considered as therapeutical tools in this pathology.

The effect of N-methyl-D-aspartate receptor antagonists on D,L-homocysteine thiolactone induced seizures in adult rats

The aim of our study was to investigate the effects of ifenprodil and MK-801 on D,L-homocysteine thiolactone induced seizures in adult rats.Male Wistar rats were divided into following groups: 1. Saline-treated (C, n=10); 2. D,L-homocysteine thiolactone 8 mmol/kg, i.p. (H, n=7); 3. Ifenprodil 20 mg/kg i.p. (IF, n=8); 4. MK-801 0.5 mg/kg, i.p. (MK, n=8) and 5. Groups that received IF or MK 30 minutes prior to H (IFH, n=8 and MKH, n=8). Seizure behavior was assessed by incidence, latency, number and intensity of seizure episodes. Seizure severity was described by a descriptive scale with grades 0-4. Lethality in experimental group was recorded 90 min and 24 h upon D,L-homocysteine thiolactone administration.There were no behavioral signs of seizure activity in groups C, IF and MK.Pre-treatment with MK-801 (MKH) showed tendency to reduced incidence of convulsions, latency to the first seizure onset and the severity of seizure episodes, but statistical significance was not attained comparing to the H group. However, median number of seizure episodes was significantly decreased in MKH (p<0.05), comparing to the H group. On the other hand, ifenprodil (IFH) decreased the latency to the first seizure onset and increased the median number of seizure episodes (p<0.05). The majority of seizure episodes in IFH (72.1%, p<0.05) and MKH (73.1%, p<0.05) groups was grade 2 and significantly different comparing to the H (36.0%). Our findings suggest that MK-801 has a mild anticonvulsive effect on D,L-homocysteine thiolactone induced seizures in adult rats.

Neonatal sensory deprivation promotes development of absence seizures in adult rats with genetic predisposition to epilepsy

Absence epilepsy has age-related onset. In a WAG/Rij rat genetic model, absence seizures appear after puberty and they are increased with age. It is known that (1) epileptic activity in WAG/Rij rats is initiated at the perioral area in the somatosensory cortex; (2) sensory deprivation, i.e., whisker trimming during the critical period of development, could enhance excitatory activity in the somatosensory cortex. It is hypothesized that the cortex may become more excitable after neonatal vibrissae removal, and this may precipitate absence seizures in adult rats. We found that whisker trimming during the first postnatal weeks caused more rapid development of EEG seizure activity in adult WAG/Rij rats. Epileptic discharges in the trimmed rats were more numerous (vs control), showed longer duration and often appeared in desynchronized and drowsy EEG. The number of absence-like spindle-shaped EEG events (spike–wave spindles) in the whisker-trimmed rats was higher than in control, especially during the intermediate sleep state. An age-dependent increase of intermediate sleep state was found in the trimmed rats, but not in the intact animals. We discuss epigenetic factors that can modulate absence epilepsy in genetically prone subjects.

Δ9‐Tetrahydrocannabivarin suppresses in vitro epileptiform and in vivo seizure activity in adult rats

We assessed the anticonvulsant potential of the phytocannabinoid Δ⁹-tetrahydrocannabivarin (Δ⁹-THCV) by investigating its effects in an in vitro piriform cortex (PC) brain slice model of epileptiform activity, on cannabinoid CB1 receptor radioligand-binding assays and in a generalized seizure model in rats. Δ⁹-THCV was applied before (10 μm Δ⁹-THCV) or during (10-50 μm Δ⁹-THCV) epileptiform activity induced by Mg²(+) -free extracellular media in adult rat PC slices and measured using multielectrode array (MEA) extracellular electrophysiologic techniques. The actions of Δ⁹-THCV on CB1 receptors were examined using [³H]SR141716A competition binding and [³⁵S]GTPγS assays in rat cortical membranes. Effects of Δ⁹-HCV (0.025-2.5 mg/kg) on pentylenetetrazole (PTZ)-induced seizures in adult rats were also assessed. After induction of stable spontaneous epileptiform activity, acute Δ⁹ -THCV application (≥ 20 μm) significantly reduced burst complex incidence and the amplitude and frequency of paroxysmal depolarizing shifts (PDSs). Furthermore, slices pretreated with 10 μm Δ⁹-THCV prior to induction of epileptiform activity exhibited significantly reduced burst complex incidence and PDS peak amplitude. In radioligand-binding experiments, Δ⁹-THCV acted as a CB1 receptor ligand, displacing 0.5 nm [³H]SR141716A with a Ki∼290 nm, but exerted no agonist stimulation of [³⁵S]GTPγS binding. In PTZ-induced seizures in vivo, 0.25 mg/kg Δ⁹-THCV significantly reduced seizure incidence. These data demonstrate that Δ⁹-THCV exerts antiepileptiform and anticonvulsant properties, actions that are consistent with a CB1 receptor-mediated mechanism and suggest possible therapeutic application in the treatment of pathophysiologic hyperexcitability states.

12. Dose-dependent anticonvulsive effect of valproate on D,L homocysteine-thiolactone induced seizures in adult rats

12. Dose-dependent anticonvulsive effect of valproate on D,L homocysteine-thiolactone induced seizures in adult rats