Antidepressant and Anxiolytic Effects of L-Methionine in the WAG/Rij Rat Model of Depression Comorbid with Absence Epilepsy.

Depression is a severe and widespread psychiatric disease that often accompanies epilepsy. Antidepressant treatment of depression comorbid with epilepsy is a major concern due to the risk of seizure aggravation. SAMe, a universal methyl donor for DNA methylation and the synthesis of brain monoamines, is known to have high antidepressant activity. This study aimed to find out whether L-methionine (L-MET), a precursor of SAMe, can have antidepressant and/or anxiolytic effects in the WAG/Rij rat model of depression comorbid with absence epilepsy. The results indicate that L-MET reduces the level of anxiety and depression in WAG/Rij rats and suppresses associated epileptic seizures, in contrast to conventional antidepressant imipramine, which aggravates absence seizures. The antidepressant effect of L-MET was comparable with that of the conventional antidepressants imipramine and fluoxetine. However, the antidepressant profile of L-MET was more similar to imipramine than to fluoxetine. Taken together, our findings suggest that L-MET could serve as a promising new antidepressant drug with anxiolytic properties for the treatment of depression comorbid with absence epilepsy. Increases in the level of monoamines and their metabolites-DA, DOPAC, HVA, NA, and MHPG-in several brain structures, is suggested to be a neurochemical mechanism of the beneficial phenotypic effect of L-MET.

Maternal Methyl-Enriched Diet Increases DNMT1, HCN1, and TH Gene Expression and Suppresses Absence Seizures and Comorbid Depression in Offspring of WAG/Rij Rats.

The reduced expression of the HCN1 ion channel in the somatosensory cortex (SSC) and mesolimbic dopamine deficiency are thought to be associated with the genesis of spike-wave discharges (SWDs) and comorbid depression in the WAG/Rij rat model of absence epilepsy. This study aimed to investigate whether the maternal methyl-enriched diet (MED), which affects DNA methylation, can alter DNMT1, HCN1, and TH gene expression and modify absence seizures and comorbid depression in WAG/Rij offspring. WAG/Rij mothers were fed MED (choline, betaine, folic acid, vitamin B12, L-methionine, zinc) or a control diet for a week before mating, during pregnancy, and for a week after parturition. MED caused sustained suppression of SWDs and symptoms of comorbid depression in the offspring. Disease-modifying effects of MED were associated with increased expression of the DNMT1 and HCN1 genes in the SSC and hippocampus, as well as DNMT1, HCN1, and TH genes in the nucleus accumbens. No changes in gene expression were detected in the hypothalamus. The results indicate that maternal MED can suppress the genetic absence epilepsy and comorbid depression in offspring. Increased expression of the DNMT1, HCN1, and TH genes is suggested to be a molecular mechanism of this beneficial phenotypic effect.

Localizing and lateralizing values of postictal behavioral impairments in epileptic rats.

Transient postictal behavioral impairments in patients with epilepsy provide clues to seizure localization, but no attempt has been made previously to study the localization/lateralization value of postseizure motor disturbances in experimental models of epilepsy. The present study investigated relation of postictal motor deficit to seizure localization in the rat model of sound-induced reflex epilepsy. Sound-induced motor seizures started with a focal brainstem seizure (running) and progressed to a secondarily generalized seizure. Depending on innate or acquired seizure susceptibility of rats, focal brainstem seizures secondarily generalized within the brainstem (brainstem-generalized seizures) or spread to the forebrain (focal or generalized forebrain seizures). All sound-induced seizures were followed by catalepsy and abnormal limb posturing. The duration of the postictal catalepsy and the pattern of the posture abnormality depended on brainstem or forebrain localization of secondarily generalized seizures. Brainstem-driven seizures induced long-lasting whole-body catalepsy and cataleptic limb posture in the postictal period. Secondary seizure generalization to the forebrain led to shortening postictal catalepsy and development of rigid limb posturing. Asymmetric limb posturing was always observed after focal forebrain seizures, and the postictal asymmetry was closely linked to ictal asymmetry of the earliest running seizure phase, predicting lateralization of the seizure-onset side. This is the first demonstration of circuit-specific postictal behavioral impairments and their localization and lateralization values in epileptic rats.

H1 histamine receptor densities are increased in brain regions of rats with genetically generalized epilepsies.

Genetic animal models for convulsive, non-convulsive and mixed types of generalized epilepsies were used to establish putative histaminergic brain sites involved in the control of different types of epilepsy. Age matched rats of the KM strain (audiogenic seizures, AGS), WAG/Rij strain (absence seizures) and the WAG/Rij-AGS substrain (mixed model) were compared with a control group of Wistar rats on regional binding densities of H1 histamine receptors. Coronal slices of adult brains of the four groups were labeled with 3H pyrilamine, an antagonist of H1 histamine receptor and density of receptors was quantified with image analyses. All three groups of epileptic rats showed an increase in the density of H1 histamine receptor binding in the frontal motor cortex and interposed nucleus of cerebellum compared to the non-epileptic control group. Audiogenic epilepsy was characterized by increased H1 histamine receptor density in the frontal cortical and hippocampal regions, and in two midbrain (interpedunculus and lateral vestibular) nuclei. Absence epilepsy was characterized by a decrease in substantia nigra pars compacta, while the mixed model showed an elevation of H1 histamine receptor binding density in limbic regions such as the shell of the nucleus accumbens and the ventral tegmental area. It can be concluded that common changes in H1 histamine receptors can be found in genetic epilepsy models irrespective of the seizure type, and that each type of generalized epilepsy has its own pattern of H1 histamine receptor changes. It is speculated that H1 histamine receptors play a role in the brain's endogenous epilepsy control system.

Pro-epileptic effects of the cannabinoid receptor antagonist SR141716 in a model of audiogenic epilepsy.

Endocannabinoid system and its CB1 receptors are suggested to provide endogeneous protection against seizures. The present study examines whether CB1 receptors contribute to resistance to seizures and kindling epileptogenesis in a model of audiogenic epilepsy. Three groups of Wistar rats were used: rats unsusceptible to audiogenic seizures, rats with acquired resistance to audiogenic seizures and rats with reproducible audiogenic running seizures. Chronic treatment with the CB1 receptor antagonist SR141716 (5 daily dosing of 30mg/kg) did not change innate resistance to audiogenic seizures in non-epileptic rats but reverted acquired seizure resistance in rats which lost their epileptic sensitivity with repeated testing. In the latter rats, audiogenic running seizures reappeared for at least two weeks after the end of treatment. In rats with reproducible seizure response, acutely, SR lengthened audiogenic seizures due to prolongation or appearance, de novo, of post-running limbic clonus without any effect on running seizure per se. This limbic component mimicked audiogenic kindling and indicated propagation of sound-induced brainstem seizure to the limbic forebrain. After chronic SR administration the incidence of the limbic clonus remained to be increased for at least two weeks. The present study supports the hypothesis about a role of CB1 receptors in endogeneous anticonvulsive mechanisms of the brain.

Histaminergic modulation of acoustically induced running behavior in rats.

Explosive running is a reliable initial component of audiogenic seizures (AS) induced by acoustic stimulation in genetically prone rodents. This profound locomotor activation is usually considered as a convulsive manifestation of AS although some studies attribute running to a panic-like response. Increase in central histamine activity has been shown to suppress clonic and tonic seizures. The present study examined the involvement of histaminergic mechanisms in the expression of running component of AS. Metoprine, an inhibitor of histamine-N-methyltransferase, was used to increase brain histamine level. Running was induced 4 and 24 h after intraperitoneal injection of metoprine or vehicle in rats of different strains. A brief sound stimulation elicited running followed by clonic-tonic convulsions in Krushinsky-Molodkina (KM) rats or running alone in AS-prone Wistar and WAG/Rij rats. In KM rats, metoprine exerted opposite effects on the main phases of AS. It increased the duration of running and decreased the duration and severity of clonic-tonic convulsions. In Wistar rats, metoprine produced a remarkable aggravation of running leading to its 2- to 3-fold prolongation. In WAG/Rij rats with mixed seizures (absence and audiogenic), the drug caused either aggravation or suppression of running behavior. These results suggest specific role for histaminergic system in the expression of behavioral components of AS. Suppressive role of histamine in clonic-tonic seizures is associated with facilitation of running suggesting specific effects of histamine on brainstem neuronal networks underlying these phases of AS. Possible roles of histaminergic mechanisms in seizure, motor and aversive aspects of sound-induced running are discussed.

Vigabatrin in low doses selectively suppresses the clonic component of audiogenically kindled seizures in rats.

PURPOSE: The effect of systemic administration of the gamma-aminobutyric acid (GABA)-transaminase inhibitor vigabatrin (VGB) on different components of convulsions was tested in the model of audiogenically kindled seizures, which consist of brainstem (running, tonus) and forebrain (clonus) elements. METHODS: Audiogenically susceptible rats of Krushinsky-Molodkina (KM), Wistar, and WAG/Rij strains received repeated sound stimulation (60 dB, 10-80 kHz) until kindled audiogenic seizures were reliably elicited. Kindled audiogenic seizures consisted of running, tonic, and generalized clonic phases in KM rats (severe audiogenic seizures) and of running and Racine stage 5 facial/forelimb clonus in Wistar and WAG/Rij rats (moderate seizures). Vehicle, 100, or 200 mg/kg of VGB was intraperitoneally injected 2, 4 and 24 h before the induction of kindled audiogenic seizures. RESULTS: At both doses, VGB did not change the seizure latency and the duration of running and tonic convulsions, but suppressed clonic ones in all rat strains. In KM rats, the mean duration of posttonic clonus was significantly reduced at 24 h after 100 mg/kg and from 4 h after 200 mg/kg. In Wistar and WAG/Rij rats, the mean duration of facial/forelimb clonus was reduced from 4 and 2 h after 100- and 200-mg/kg administration, respectively; 24 h after the high-dose injection, clonus was completely blocked in all rats of both strains. No difference in efficacy of VGB between Wistar and WAG/Rij rats was observed. CONCLUSIONS: VGB more effectively suppresses clonic convulsions than running and tonic ones in audiogenically kindled rats. It is supposed that this selective anticonvulsive effect of VGB results from different sensitivities of forebrain and brainstem epileptic networks to the presumed GABA enhancement.

Mixed forms of epilepsy in a subpopulation of WAG/Rij rats.

Mixed forms of epilepsy in patients are often refractory. Therefore, animal models of comorbid convulsive and nonconvulsive seizure are needed for experimental research. Susceptibility to audiogenic convulsions was studied in a large group of young and adult WAG/Rij rats with inherited absence epilepsy. In 30% of adult rats, sound stimulation provoked audiogenic seizures of moderate intensity. The seizures had two excitation periods separated by a remarkably stable "arrest" of paroxysmal movements. Up to 20% of young WAG/Rij rats were also susceptible to audiogenic seizures, with a longer latency, lower intensity, and more simple seizure patterns. No difference in manifestations of spike-wave discharges was observed between the WAG/Rij rats with and without audiogenic seizures. This subpopulation of WAG/Rij rats genetically predisposed to absence and audiogenic seizures is proposed as an animal model suitable for investigation of basal mechanisms and pharmacological profiles of this mixed form of epilepsy.