Experimental Seizure Models Research Articles

Chronic levetiracetam decreases hippocampal and testicular aromatase expression in normal but not kainic acid-induced experimental model of acute seizures in rats.

Reproductive disorders are more common in men with epilepsy taking anticonvulsant medications. Antiseizure/anticonvulsant drugs and seizures in medial temporal lobe structures may cause gonadal dysfunction, including infertility, decreased libido, and potency. Levels of circulating bioavailable testosterone are affected by the aromatase enzyme, which converts testosterone into estrogen and may be affected by seizure medications. However, the relationship of anticonvulsant drugs with central aromatase levels is not clear. This study investigated the possible effects of the highly efficient, new-generation antiseizure/anticonvulsant drug levetiracetam on central and gonadal aromatase expression and gonadal tissue functionality at 27 and 54 mg/kg/day doses. Epileptogenesis was generated in male Wistar rats by an intraperitoneal injection of the excitotoxic agent kainic acid. Aromatase levels were 1.5 times higher in the brain cortex of the kainic acid groups after 4 weeks and the hippocampus after 4 and 8 weeks compared with the controls. Decreased basal aromatase levels were observed after 1 week of levetiracetam treatment (27 mg/kg/day). Administration of 27 mg/kg/day levetiracetam did not alter vas deferens contractions at 1, 4, or 8 weeks compared with the controls. No histological changes were observed in the vas deferens, epididymis, or testis after 8 weeks of levetiracetam administration at both doses. Administration of 27 and 54 mg/kg/day levetiracetam downregulated testis aromatase expression at 8 weeks compared with the controls. These results suggest that levetiracetam decreases aromatase levels in the testis and increases the seizure threshold by a possible decrease in systemic estradiol levels.

Expression and function of the metabotropic purinergic P2Y receptor family in experimental seizure models and patients with drug-refractory epilepsy.

ATP is released into the extracellular space during pathologic processes including increased neuronal firing. Once released, ATP acts on P2 receptors including ionotropic P2X and metabotropic P2Y receptors, resulting in changes to glial function and neuronal network excitability. Evidence suggests an involvement of P2Y receptors in the pathogenesis of epilepsy, but there has been no systematic effort to characterize the expression and function of the P2Y receptor family during seizures and in experimental and human epilepsy. Status epilepticus was induced using either intra-amygdala kainic acid or pilocarpine to characterize the acute- and long-term changes in hippocampal P2Y expression. P2Y expression was also investigated in brain tissue from patients with temporal lobe epilepsy. Finally, we analyzed the effects of two specific P2Y agonists, ADP and UTP, on seizure severity and seizure-induced cell death. Both intra-amygdala kainic acid and pilocarpine-induced status epilepticus increased the transcription of the uracil-sensitive P2Y receptors P2ry2 , P2ry4 , and P2ry6 and decreased the transcription of the adenine-sensitive P2Y receptors P2ry1 , P2ry12 , P2ry13 . Protein levels of P2Y1 , P2Y2 , P2Y4 , and P2Y6 were increased after status epilepticus, whereas P2Y12 expression was decreased. In the chronic phase, P2ry1 , P2ry2 , and P2ry6 transcription and P2Y1 , P2Y2 , and P2Y12 protein levels were increased with no changes for the other P2Y receptors. In hippocampal samples from patients with temporal lobe epilepsy, P2Y1 and P2Y2 protein expression was increased, whereas P2Y13 levels were lower. Demonstrating a functional contribution of P2Y receptors to seizures, central injection of ADP exacerbated seizure severity, whereas treatment with UTP decreased seizure severity during status epilepticus in mice. The present study is the first to establish the specific hippocampal expression profile and function of the P2Y receptor family after experimental status epilepticus and in human temporal lobe epilepsy and offers potential new targets for seizure control and disease modification.

Therapeutic effects of anti-HMGB1 monoclonal antibody on pilocarpine-induced status epilepticus in mice

Inflammatory processes in brain tissue have been described in human epilepsy of various etiologies and in experimental models of seizures. High mobility group box-1 (HMGB1) is now recognized as representative of damage-associated molecular patterns (DAMPs). In the present study, we focused on whether anti-HMGB1 antibody treatment could relieve status epilepticus- triggered BBB breakdown and inflammation response in addition to the seizure behavior itself. Pilocarpine and methyl-scopolamine were used to establish the acute seizure model. Anti-HMGB1 mAb showed inhibitory effects on leakage of the BBB, and on the HMGB1 translocation induced by pilocarpine. The expression of inflammation-related factors, such as MCP-1, CXCL-1, TLR-4, and IL-6 in hippocampus and cerebral cortex were down-regulated by anti-HMGB1 mAb associated with the number of activated astrocytes, microglial cells as well as the expression of IL-1β. Both hematoxylin & eosin and TUNEL staining showed that the apoptotic cells could be reduced after anti-HMGB1 mAb treatment. The onset and latency of Racine stage five were significantly prolonged in the anti-HMGB1 mAb group. These results suggested that anti-HMGB1 mAb prevented the BBB permeability, reduced HMGB1 translocation while inhibiting the expression of inflammation-related factors, protected against neural cell apoptosis and prolonged Racine stage 5 seizure onset and latency.

Foxp3 exhibits antiepileptic effects in ictogenesis involved in TLR4 signaling.

Inflammatory processes play critical roles in epileptogenesis, but the exact mechanisms that underlie these processes are still not completely understood. In this study, we investigated the role of forkhead transcription factor 3 (Foxp3), a transcription factor that is involved in T-cell differentiation, in epileptogenesis. In both human epileptic tissues and experimental seizure models, we found significant up-regulation of Foxp3 in neurons and glial cells. Of importance, Foxp3-/- mice were susceptible to kainic acid-induced seizures, whereas overexpression of Foxp3 reduced acute seizure occurrence and decreased chronic seizure recurrence. In addition, in vitro experiments revealed that Foxp3 inhibited neuronal excitability via glial cells and not neurons. The protective effects of Foxp3 were manifested as a reduction in glial cell activation and proinflammatory cytokine production and increased neuronal survival. Moreover, we showed that beneficial effects of Foxp3 involved the attenuation of TLR4 signaling and inflammation, which led to the inactivation of NR2B-containing NMDA receptors. These results suggest that Foxp3 in glial cells may play an antiepileptic role in epileptogenesis and may act as a modulator of TLR4. Taken together, our results indicate that Foxp3 may represent a novel therapeutic target for achieving anticonvulsant effects in patients with epilepsy that is currently resistant to drugs.-Wang, F.-X., Xiong, X.-Y., Zhong, Q., Meng, Z.-Y., Yang, H., Yang, Q.-W. Foxp3 exhibits antiepileptic effects in ictogenesis involved in TLR4 signaling.

Intra-hippocampal microinjection of oxytocin produced antiepileptic effect on the pentylenetetrazol-induced epilepsy in rats.

In addition to its role as a circulating hormone, oxytocin can also act as a neurotransmitter and a neuromodulator within the brain. In this study, we investigated the intra-hippocampal effect of oxytocin on an experimental seizure model induced by pentylenetetrazole (PTZ) in rats. We also used atosiban (oxytocin antagonist), diazepam and flumazenil (gamma-aminobutyric acid or GABA-benzodiazepine receptor agonist and antagonist, respectively) to clarify the involved mechanism. In ketamine-xylazine anesthetized rats, the right and left sides of the dorsal hippocampus (CA1) were implanted with two guide cannulas. Epileptic behaviors were induced by intraperitoneal (ip) injection of PTZ (60mg/kg), and the latency time to onset of first myoclonic jerk, and the duration of epileptic seizures were determined for 30min. Intra-hippocampal microinjections of oxytocin at doses of 10 and 20ng/site, diazepam (100 and 200ng/site) and co-administration of their ineffective doses significantly (p<0.01) increased the onset of first myoclonic jerk and decreased duration of epileptic seizure. Antiepileptic effects of oxytocin (20ng/site) were inhibited by atosiban (20 and 40ng/site) and flumazenil (100 and 200ng/site) pretreatments. On the other hand, prior administration of flumazenil (100 and 200ng/site) and atosiban (20 and 40ng/site) prevented the antiepileptic effects induced by diazepam (100 and 200ng/site). The results of the present study showed that at the level of the hippocampus oxytocin suppressed the severity of epileptic behaviors. A hippocampal GABA-benzodiazepine receptor mechanism may be involved in antiepileptic effect of oxytocin.

The intrahippocampal kainate mouse model of mesial temporal lobe epilepsy: Lack of electrographic seizure-like events in sham controls.

SummaryObjectiveThere is an ongoing debate about definition of seizures in experimental models of acquired epilepsy and how important adequate sham controls are in this respect. For instance, several mouse and rat strains exhibit high‐voltage rhythmic spike or spike‐wave discharges in the cortical electroencephalogram (EEG), which has to be considered when using such strains for induction of epilepsy by status epilepticus, traumatic brain injury, or other means. Mice developing spontaneous recurrent nonconvulsive and convulsive seizures after intrahippocampal injection of kainate are increasingly being used as a model of mesial temporal lobe epilepsy. We performed a prospective study in which EEG alterations occurring in this model were compared with the EEGs in appropriate sham controls, using hippocampal electrodes and video‐EEG monitoring.MethodsExperiments with intrahippocampal kainate (or saline) injections started when mice were about 8 weeks of age. Continuous video‐EEG recording via hippocampal electrodes was performed 6 weeks after surgery in kainate‐injected mice and sham controls, that is, at an age of about 14 weeks. Three days of continuous video‐EEG monitoring were compared between kainate‐injected mice and experimental controls.ResultsAs reported previously, kainate‐injected mice exhibited two types of highly frequent electrographic seizures: high‐voltage sharp waves, which were often monomorphic, and polymorphic hippocampal paroxysmal discharges. In addition, generalized convulsive clinical seizures were infrequently observed. None of these electrographic or electroclinical seizures were observed in sham controls. The only infrequently observed EEG abnormalities in sham controls were isolated spikes or spike clusters, which were also recorded in epileptic mice.SignificanceThis study rigorously demonstrates, by explicit comparison with the EEGs of sham controls, that the nonconvulsive paroxysmal events observed in this model are consequences of the induced epilepsy and not features of the EEG expected to be seen in some experimental control mice or unintentionally induced by surgical procedures.

In silico Screening and Evaluation of the Anticonvulsant Activity of Docosahexaenoic Acid-Like Molecules in Experimental Models of Seizures

In silico Screening and Evaluation of the Anticonvulsant Activity of Docosahexaenoic Acid-Like Molecules in Experimental Models of Seizures

6 Hz corneal kindling triggers schizophrenia-like behaviors in fully kindled mice and differential c-fos immunoreactivity in distinct brain regions.

Event Abstract Back to Event 6 Hz corneal kindling triggers schizophrenia-like behaviors in fully kindled mice and differential c-fos immunoreactivity in distinct brain regions. Giulia Albertini1*, Laura Walrave1, Thomas Demuyser2, Dimitri De Bundel1, Ann Massie3 and Ilse J. Smolders1 1 Vrije Universiteit Brussel, Department of Pharmaceutical Chemistry and Drug Analysis, Belgium 2 University Hospital Brussels, Department of Clinical Biology, Belgium 3 Vrije Universiteit Brussel, Department of Pharmaceutical Biotechnology and Molecular Biology, Belgium Epilepsies are a heterogeneous group of neurological disorders characterized by recurrent and spontaneous bursts of neuronal hyperactivity, commonly known as seizures. Together with chronic unpredictable seizures, a variety of comorbidities, such as memory and cognitive dysfunctions and psychiatric symptoms, affects 1 in 2 patients with epilepsy, further deteriorating their quality of life. Experimental models of seizures and epilepsy that mimic neurological and psychiatric comorbidities represent therefore unique tools in epilepsy research. Kindling models are based on the paradigm that repetition of sub-convulsive electrical or chemical stimulations produces a progressive increase in epileptic response, eventually driving bilateral clonic seizures. Due to the clinical phenomenology, pharmacology and focal activation of these seizures which closely reproduce the clinical condition, kindling has been widely used to model chronic induced seizures. Recently the 6 Hz corneal kindling model has been described as a non-invasive, inexpensive and reliable alternative to well-established models of epilepsy. However, due to its novelty, an in-depth characterization of this model has not yet been provided. In this study, after inducing the “fully kindled state” (defined as 10 consecutive generalized seizures) in male NMRI mice via repetitive sub-convulsive corneal stimulations, we performed an elaborate battery of behavioral tests. Besides leading to a decreased seizure threshold, 6 Hz corneal kindling induces an abnormal behavioral phenotype, including hyperactivity, an increased sensitivity to the central nervous system stimulant amphetamine (0.5 mg/Kg), anhedonic-like behavior as well as deficits in short and long term memory. Motivated by these findings, we quantified c-fos+ cells (an early marker of neuronal activation) throughout the brain of corneal kindled and mock-stimulated mice. We show that, besides increasing neuronal activation in limbic regions such as hippocampus, amygdala, cingulate, entorhinal and piriform cortices, 6 Hz corneal kindling also enhances c-fos immunoreactivity in the motor cortex. Moreover, c-fos+ cells are decreased in the orbital cortex of kindled mice, a region involved in social cognition and associated with the negative symptoms of schizophrenia. Overall, we provide evidence that 6 Hz corneal kindling induces schizophrenia-like behavioral changes accompanied by differential activation of relevant brain regions. 6Hz corneal kindling could therefore be used to model epilepsy and schizophrenia comorbidity, known to share a biological basis. Keywords: Epilepsy, Behavior, Schizophrenia, mouse models, 6 Hz corneal kindling, c-Fos immunoreactivity Conference: 12th National Congress of the Belgian Society for Neuroscience, Gent, Belgium, 22 May - 22 May, 2017. Presentation Type: Oral Presentation Topic: Cognition and Behavior Citation: Albertini G, Walrave L, Demuyser T, De Bundel D, Massie A and Smolders IJ (2019). 6 Hz corneal kindling triggers schizophrenia-like behaviors in fully kindled mice and differential c-fos immunoreactivity in distinct brain regions.. Front. Neurosci. Conference Abstract: 12th National Congress of the Belgian Society for Neuroscience. doi: 10.3389/conf.fnins.2017.94.00051 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 24 Apr 2017; Published Online: 25 Jan 2019. * Correspondence: Miss. Giulia Albertini, Vrije Universiteit Brussel, Department of Pharmaceutical Chemistry and Drug Analysis, Brussels, 1090, Belgium, galberti@vub.ac.be Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Giulia Albertini Laura Walrave Thomas Demuyser Dimitri De Bundel Ann Massie Ilse J Smolders Google Giulia Albertini Laura Walrave Thomas Demuyser Dimitri De Bundel Ann Massie Ilse J Smolders Google Scholar Giulia Albertini Laura Walrave Thomas Demuyser Dimitri De Bundel Ann Massie Ilse J Smolders PubMed Giulia Albertini Laura Walrave Thomas Demuyser Dimitri De Bundel Ann Massie Ilse J Smolders Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

ПСИХОТРОПНІ ВЛАСТИВОСТІ ПОТЕНЦІЙНОГО АНТИКОНВУЛЬСАНТА 1-(4-МЕТОКСИФЕНІЛ)-5-{2-[4-(4-МЕТОКСИФЕНІЛ)ПІПЕРАЗИН-1-ІЛ]-2-ОКСОЕТИЛ}- 1,5-ДИГІДРО-4H-ПІРАЗОЛО[3,4-D]ПІРИДИН-4-ОНУ

Вивчено психотропні властивості та взаємодію з речовинами пригнічувального типу нового похідного піримідину - 1-(4-метоксифеніл)-5-{2-[4-(4-метокси-феніл)піперазин-1-іл]-2-оксоетил}-1,5-дигідро-4Н-піразоло [3,4- D]піридин-4-ону в дозі 200 мг/кг, який в попередніх дослідженнях виявив протисудомну дію на рівні вальпроату натрію (300 мг/кг). Встановлено, що сполука чинить виразну седативну дію, виявляє антиамнестичні властивості та слабкий анксіолітичний ефект. Крім того, досліджувана сполука не впливає на депресивну поведінку, не чинить негативного впливу на тонус скелетних м'язів та координацію рухів, а також не потенціює депримуючий вплив етанолу.

In silico Screening and Evaluation of the Anticonvulsant Activity of Docosahexaenoic Acid-Like Molecules in Experimental Models of Seizures.

Background:Resistance to antiepileptic drugs and the intolerability in 20-30% of the patients raises demand for developing new drugs with improved efficacy and safety. Acceptable anticonvulsant activity, good tolerability, and inexpensiveness of docosahexaenoic acid (DHA) make it as a good candidate for designing and development of the new anticonvulsant medications.Methods:Ten DHA-based molecules were screened based on in silico screening of DHA-like molecules by root-mean-square deviation of atomic positions, the biological activity score of Professional Association for SQL Server, and structural requirements suggested by pharmacophore design. Anticonvulsant activity was tested against clonic seizures induced by pentylenetetrazole (PTZ, 60 mg/kg, i.p.) and tonic seizures induced by maximal electroshock (MES, 50 mA, 50 Hz, 1 ms duration) by intracerebroventricular (i.c.v.) injection of the screened compounds to mice.Results:Among screened compounds, 4-Phenylbutyric acid, 4-Biphenylacetic acid, phenylacetic acid, and 2-Phenylbutyric acid showed significant protective activity in pentylenetetrazole test with ED50 values of 4, 5, 78, and 70 mM, respectively. In MES test, shikimic acid and 4-tert-Butylcyclo-hexanecarboxylic acid showed significant activity with ED50 values 29 and 637 mM, respectively. Effective compounds had no mortality in mice up to the maximum i.c.v. injectable dose of 1 mM.Conclusion:Common electrochemical features and three-dimensional spatial structures of the effective compounds suggest the involvement of the anticonvulsant mechanisms similar to the parent compound DHA.

Enhance in pentylenetetrazole or maximal electro shock induced seizures in experimental models of ulcerative colitis: An interplay of altered cytokines level, adhesion molecules, blood brain barrier disruption

Enhance in pentylenetetrazole or maximal electro shock induced seizures in experimental models of ulcerative colitis: An interplay of altered cytokines level, adhesion molecules, blood brain barrier disruption

PATHOLOGICAL CHANGES DEVELOPMENT IN THE HEART WITH UNDERLYING CONVULSIVE SYNDROME MODEL OF VARIOUS ETIOLOGIES.

The basic mechanisms of myocardial damage were determined experimentally in case of electroconvulsive (n = 30) and corazole (n = 20) induced seizures in Wistar rats by histochemical, pathological, electron microscopy and biochemical methods. It has been founded that pathological changes in the myocardium underlying with electroconvulsive and corazole induced seizures have unidirectional origin; nevertheless electrocohvulsive model has more intensity. It has been shown that structural base of myocardial pathology development results in parallel changes of microvessels and contractile myocardium with the main focus on development of contractile changes of cardiomyocytes and intramuscular capillaries spasm, which causes blood flow impairment and reducing supply of oxygen to the working cells. Structural changes in the myocardium develop due to energy shifts which have been elucidated by confirmed decrease SDG in cardiac activity (control 2,65±0,03 act. Units; electroconvulsive model 2,15±0,02 act. Units; and corazole model 2,25±0,02 act. Units), and increased - LDH (control 2,20±0,01 act. Units. electroconvulsive model 2,55±0,01 act. Units; corazole model 2,45±0,01 act. Units.) histochemically, showing evidence of hypoxia progression in the myocardium tissue. It has been also shown processes of increasing degradation as well as reducing synthesis of ATP biochemically(43% electroconvulsive model and 41% corazole model). All this results indicate the presence of hypoenergetics in case of elec- troconvulsive and corazole experimental models of seizures. The received results of complex researches allow considering that adequate and rational treatment and prevention of seizures (large and small epilepsy) requires anticonvulsants choose as well as drug correction of the most affected parts of energy metabolism via afitihypoxants and antioxidants administration. Key words: electroconvulsive and carozole convulsive syn- dromes; heart; metabolism; structure; pathogenesis.

Antiepileptic effect of fisetin in iron-induced experimental model of traumatic epilepsy in rats in the light of electrophysiological, biochemical, and behavioral observations

Background: Traumatic epilepsy is defined by episodes of recurring seizures secondary to severe brain injury. Though drugs are found effective to control seizures, their long-term use have been observed to increase reactive oxygen species in animals. Flavonoid fisetin, a natural bioactive phytonutrient reported to exert anticonvulsive effect in experimental seizure models. But, trauma-induced seizures could not be prevented by anticonvulsants was reported in some clinical studies.Objective: To study the effect of fisetin on epileptiform electrographic activity in iron-induced traumatic epilepsy and also the probable reason behind the effect in rats.Methods: Fisetin pretreatment (20 mg/kg body wt., p.o.) of rats for 12 weeks were chosen followed by injecting iron (5 µl, 100 mM) stereotaxically to generate iron-induced epilepsy. Experimental design include electrophysiological study (electroencephalograph in correlation with multiple unit activity (MUA) in the cortex and CA1 subfield of the hippocampus; spectral analysis of seizure and seizure-associated behavioral study (Morris water maze for spatial learning, open-field test for anxiety) and biochemical study (lipid peroxidation, Na+,K+-ATPase activity) in both the cortex and the hippocampus.Results: Fisetin pretreatment was found to prevent the development of iron-induced electrical seizure and decrease the corresponding MUA in the cortex (*P˂0.05) as well as in the hippocampus (***P˂0.001). Fisetin pretreatment decreased the lipid peroxides (*P˂0.05) and retained the Na+,K+-ATPase activity (*P˂0.05) which was found altered in the epileptic animals and also found to attenuate the seizure-associated cognitive dysfunctions.Conclusion: This study demonstrated the antiepileptic action of fisetin in iron-induced model of epileptic rats by inhibiting oxidative stress.

Effect of Neonatal Seizures on the Synaptic Plasticity of Rat Somatosensory Cortex

Using an experimental model of neonatal recurrent seizures, we investigated the influence of epileptic seizures on the various forms of synaptic plasticity in neurons of the somatosensory cortex. We have found that early seizures do not affect the post-tetanic potentiation of the amplitude of the postsynaptic potentials and the depression of postsynaptic potentials during high-frequency stimulation. However, they result in the chronic increase in the long-term potentiation of synaptic transmission. The changes in synaptic plasticity may affect the processing of the sensory information in patients with a history of recurrent seizures during early development.

Anticonvulsant efficacy of melatonin in an experimental model of hyperthermic febrile seizures

IntroductionThe anticonvulsant effects of melatonin (MT) have been demonstrated in several different experimental seizure models. Thus, the present study aimed to determine the anticonvulsant efficacy of MT, the optimum time for its administration prior to the induction of a seizure, and its effective dose in a rat model of hyperthermic febrile seizures (FSs). MethodsThe present study included 72 male Sprague–Dawley rat pups divided into eight groups. The seizures were induced by keeping the rats in 45°C water and the experiments were performed in two steps. In the first step, the control group was given a vehicle injection and the study groups were given a MT injection (150mg/kg, intraperitoneal [i.p.]) at either 5, 10, or 15min prior to the induction of the seizure to determine the anticonvulsant effects of MT and its optimum time of administration. In the second step, a vehicle injection and three different doses of MT (80, 100, and 150mg/kg, i.p.) were administered 15min prior to the induction of the seizure to determine the dose at which anticonvulsant effects could be achieved. The anticonvulsant effects were assessed based on the latency of the FSs. ResultsIn the first-step experiments, the FS latency of the control group was 143.4±15.3s and the latencies of the groups given melatonin at either 5, 10, or 15min prior to the seizure were 174.2±28.9, 177.4±21.0, and 193.7±17.6s, respectively. Compared with the control group, the latencies for each of the study groups were significantly longer (p<0.001), with the longest latency observed in the group given melatonin 15min before the seizure. In the second-step experiments, the FS latencies of the groups that were given 80, 100, and 150mg/kg of MT 15min before the seizure were 238.7±4.0, 240.0±0.0, and 193.7±17.6s, respectively. These latencies were significantly longer than those of the control group (172.3±30.3s, p<0.001). ConclusionThe present study demonstrated that MT exerts anticonvulsant effects in a rat model of hyperthermic FSs and achieved its optimum efficacy at a dose of 80mg/kg when administered 15min prior to the induction of a seizure.

Forebrain‐independent generation of hyperthermic convulsions in infant rats

SummaryFebrile seizures are the most common type of convulsive events in children. It is generally assumed that the generalization of these seizures is a result of brainstem invasion by the initial limbic seizure activity. Using precollicular transection in 13‐day‐old rats to isolate the forebrain from the brainstem, we demonstrate that the forebrain is not required for generation of tonic–clonic convulsions induced by hyperthermia or kainate. Compared with sham‐operated littermate controls, latency to onset of convulsions in both models was significantly shorter in pups that had undergone precollicular transection, indicating suppression of the brainstem seizure network by the forebrain in the intact animal. We have shown previously that febrile seizures are precipitated by hyperthermia‐induced respiratory alkalosis. Here, we show that triggering of hyperthermia‐induced hyperventilation and consequent convulsions in transected animals are blocked by diazepam. The present data suggest that the role of endogenous brainstem activity in triggering tonic–clonic seizures should be re‐evaluated in standard experimental models of limbic seizures. Our work sheds new light on the mechanisms that generate febrile seizures in children and, therefore, on how they might be treated.

Cerebral Response to Peripheral Challenge with a Viral Mimetic.

It has been well established that peripheral inflammation resulting from microbial infections profoundly alters brain function. This review focuses on experimental systems that model cerebral effects of peripheral viral challenge. The most common models employ the induction of the acute phase response via intraperitoneal injection of a viral mimetic, polyinosinic-polycytidylic acid (PIC). The ensuing transient surge of blood-borne inflammatory mediators induces a "mirror" inflammatory response in the brain characterized by the upregulated expression of a plethora of genes encoding cytokines, chemokines and other inflammatory/stress proteins. These inflammatory mediators modify the activity of neuronal networks leading to a constellation of behavioral traits collectively categorized as the sickness behavior. Sickness behavior is an important protective response of the host that has evolved to enhance survival and limit the spread of infections within a population. However, a growing body of clinical data indicates that the activation of inflammatory pathways in the brain may constitute a serious comorbidity factor for neuropathological conditions. Such comorbidity has been demonstrated using the PIC paradigm in experimental models of Alzheimer's disease, prion disease and seizures. Also, prenatal or perinatal PIC challenge has been shown to disrupt normal cerebral development of the offspring resulting in phenotypes consistent with neuropsychiatric disorders, such as schizophrenia and autism. Remarkably, recent studies indicate that mild peripheral PIC challenge may be neuroprotective in stroke. Altogether, the PIC challenge paradigm represents a unique heuristic model to elucidate the immune-to-brain communication pathways and to explore preventive strategies for neuropathological disorders.

EFFECT OF NEONATAL SEIZURES ON THE SYNAPTIC PLASTICITY OF RAT SOMATOSENSORY CORTEX

Using an experimental model of neonatal recurrent seizures we investigated the influence of epileptic seizures in the various forms of synaptic plasticity in neurons of the somatosensory cortex. We found that early seizures do not affect the post-tetanic potentiation of the amplitude of the postsynaptic potentials and the depression of postsynaptic potentials during high-frequency stimulation. However they result in the chronic increase of the long-term potentiation of synaptic transmission. These changes of synaptic plasticity may affect the processing of the sensory information in patients with a history of recurrent seizures during early development.

Identification of a neurovascular signaling pathway regulating seizures in mice.

ObjectiveA growing body of evidence suggests that increased blood–brain barrier (BBB) permeability can contribute to the development of seizures. The protease tissue plasminogen activator (tPA) has been shown to promote BBB permeability and susceptibility to seizures. In this study, we examined the pathway regulated by tPA in seizures.MethodsAn experimental model of kainate-induced seizures was used in genetically modified mice, including mice deficient in tPA (tPA−/−), its inhibitor neuroserpin (Nsp−/−), or both (Nsp:tPA−/−), and in mice conditionally deficient in the platelet-derived growth factor receptor alpha (PDGFRα).ResultsCompared to wild-type (WT) mice, Nsp−/− mice have significantly reduced latency to seizure onset and generalization; whereas tPA−/− mice have the opposite phenotype, as do Nsp:tPA−/− mice. Furthermore, interventions that maintain BBB integrity delay seizure propagation, whereas osmotic disruption of the BBB in seizure-resistant tPA−/− mice dramatically reduces the time to seizure onset and accelerates seizure progression. The phenotypic differences in seizure progression between WT, tPA−/−, and Nsp−/− mice are also observed in electroencephalogram recordings in vivo, but absent in ex vivo electrophysiological recordings where regulation of the BBB is no longer necessary to maintain the extracellular environment. Finally, we demonstrate that these effects on seizure progression are mediated through signaling by PDGFRα on perivascular astrocytes.InterpretationTogether, these data identify a specific molecular pathway involving tPA-mediated PDGFRα signaling in perivascular astrocytes that regulates seizure progression through control of the BBB. Inhibition of PDGFRα signaling and maintenance of BBB integrity might therefore offer a novel clinical approach for managing seizures.

Low dose zinc supplementation beneficially affects seizure development in experimental seizure models in rats.

The role of zinc in seizure models and with antiepileptic drugs sodium valproate (SV) and phenytoin (PHT) was studied using experimental models of seizures in rats. Male Wistar rats, 150-250g were administered zinc 2, 20, and 200mg/kg, orally for 14days. Sixty minutes after the last dose of zinc, rats were challenged with pentylenetetrazole (PTZ, 60mg/kg, ip) or maximal electroshock (MES, 70mA, 0.2s duration). In another group, SV (150/300mg/kg, ip) or PHT (40mg/kg, ip) was administered after 30min of zinc administration followed by seizure challenge. Zinc pretreatment at all doses had no effect on MES seizures. In PTZ seizures, with the lowest dose used, i.e., 2mg/kg, a protective effect was observed. Neither the protection offered by the 100% anticonvulsant dose of SV (300mg/kg) in PTZ seizures was affected by pre-treatment with zinc nor a combination of subanticonvulsant dose of SV (150mg/kg) and zinc offer any statistically significant advantage over either drug alone. The combination of phenytoin with zinc had no effect on any of the parameters tested. Apart from this, chronic zinc administration hampered development of chemically (PTZ)-kindled seizures in rats. Zinc supplementation is unlikely to have any undesirable effect when used in epileptics rather it may offer advantage in epileptic and seizure prone patients.