Animal Models Of Seizures Research Articles

A companion to the preclinical common data elements for pharmacologic studies in animal models of seizures and epilepsy. A Report of the TASK3 Pharmacology Working Group of the ILAE/AES Joint Translational Task Force.

SummaryPreclinical pharmacology studies in animal models of seizures and epilepsy have provided a platform to identify more than 20 antiseizure drugs in recent decades. To minimize variability in lab‐to‐lab studies and to harmonize approaches to data collection and reporting methodology in pharmacologic evaluations of the next generation of therapies, we present common data elements (CDEs), case report forms (CRFs), and this companion manuscript to help with the implementation of methods for studies in established preclinical seizure and epilepsy models in adult rodents. The development of and advocacy for CDEs in preclinical research has been encouraged previously by both clinical and preclinical groups. It is anticipated that adoption and implementation of these CDEs in preclinical studies may help standardize approaches to minimize variability and increase the reproducibility of preclinical studies. Moreover, they may provide a methodologic framework for pharmacology studies in atypical animal models or models in development, which may ultimately promote novel therapy development. In the present document, we refer selectively to animal models that have a long history of preclinical use, and in some cases, are clinically validated.

Evaluation of the role of different neurotransmission systems in the anticonvulsant action of sildenafil in the 6 Hz-induced psychomotor seizure threshold test in mice

Sildenafil influences seizure activity in animal seizure models, and its both proconvulsant and anticonvulsant effects were reported. We previously found that this PDE5 inhibitor significantly increased seizure threshold for the 6 Hz-induced psychomotor seizures in mice and therefore we aimed to investigate the influence of some modulators of neurotransmitter receptors, i.e., diazepam (GABA/benzodiazepine receptor agonist), flumazenil (GABA/benzodiazepine receptor antagonist), N-methyl-d-aspartic acid (NMDA glutamate receptor agonist), CGP 37849 (NMDA receptor antagonist), metergoline (serotonin receptor antagonist), 8-cyclopentyl-1,3-dipropylxanthine (adenosine A1 receptor antagonist) and β-funaltrexamine (μ opioid receptor antagonist), on the anticonvulsant effect of sildenafil in this test. Additionally, we estimated influence of the studied compounds and their combinations with sildenafil on the muscular strength (assessed in the grip strength test) and motor coordination (assessed in the chimney test) in mice. Our results indicate that anticonvulsant properties of sildenafil in the 6 Hz test in mice might be related to its interactions with the GABAergic, glutamatergic, serotonergic and adenosinergic neurotransmission. We did not find interactions between sildenafil and μ opioid receptors. Neither the studied ligands nor their combinations with sildenafil impaired muscular strength and motor coordination. In conclusion, sildenafil has complex and extensive influence on neurotransmission and seizure generation in the CNS.

The anti-seizure effects of IV 5α-dihydroprogesterone on amygdala-kindled seizures in rats

ObjectiveThe present study investigated the anti-seizure effects of 5α-dihydroprogesterone (DHP) in an animal model of human drug-resistant focal seizures with impaired awareness. DHP was administered via the intravenous (IV) route. MethodsFemale Wistar rats were implanted with an electrode in the right basolateral amygdala. They were then kindled to 15 stage 5 seizures, stability tested, and cannulated in the jugular vein. Multiple doses of IV DHP were tested against focal electrographic seizures and secondarily generalized convulsions. The time-course of DHP’s action was also examined. ResultsThe dose-response study, done at 5 min after injection, showed a dose-dependent suppression of both generalized and focal seizures, with an ED50 of 1.69 mg/kg for the generalized convulsive seizures and an ED50 of 3.48 mg/kg for the focal electrographic seizures. Ataxia, as rated by the Löscher ataxia scale, was also seen, with a TD50 of 3.57 mg/kg.The time-response study, done at the ED75 for focal seizure suppression, showed suppression of both generalized and focal seizures from immediately after injection to about 60 min post-injection. SignificanceDHP has demonstrated anti-seizure effects in a drug-resistant model of human focal seizures with impaired awareness. Its analogs might be developed as new anti-seizure drugs.

TRPV1 mediates the anticonvulsant effects of acetaminophen in mice

ObjectiveAcetaminophen is one of the most commonly used analgesic and antipyretic drugs. It has been reported that acetaminophen has anticonvulsant effects in several animal models of seizure. An active metabolite of acetaminophen, AM404, inhibits the uptake of the endocannabinoid anandamide. However, the mechanism of the anticonvulsant effect of acetaminophen is unknown. MethodsThis study was performed to examine whether or not acetaminophen can protect against pentylenetetrazol-induced kindling in mice and to investigate the precise mechanisms of the anticonvulsant effect of acetaminophen using the fully kindled mouse models. ResultsRepeated administration of acetaminophen significantly delayed the progression of seizure severity induced by pentylenetetrazol. Additionally, acetaminophen showed a dose-dependent anticonvulsant activity against fully pentylenetetrazol-kindled seizures. AM404 also exhibited a dose-dependent anticonvulsant activity in fully kindled animals. The anticonvulsant activity of acetaminophen was antagonized by capsazepine and AMG9810, two transient receptor potential vanilloid-1 (TRPV1) antagonists. However, the transient receptor potential ankyrin 1 (TRPA1) antagonist HC030031 and CB1 receptor antagonist AM251 had no effect. ConclusionThese findings suggest that acetaminophen has an anticonvulsant effect in pentylenetetrazol-kindled mouse models and TRPV1 mediates the anticonvulsant action.

Neonatal Seizure Models to Study Epileptogenesis

Current therapeutic strategies for epilepsy include anti-epileptic drugs and surgical treatments that are mainly focused on the suppression of existing seizures rather than the occurrence of the first spontaneous seizure. These symptomatic treatments help a certain proportion of patients, but these strategies are not intended to clarify the cellular and molecular mechanisms underlying the primary process of epilepsy development, i.e., epileptogenesis. Epileptogenic changes include reorganization of neural and glial circuits, resulting in the formation of an epileptogenic focus. To achieve the goal of developing “anti-epileptogenic” drugs, we need to clarify the step-by-step mechanisms underlying epileptogenesis for patients whose seizures are not controllable with existing “anti-epileptic” drugs. Epileptogenesis has been studied using animal models of neonatal seizures because such models are useful for studying the latent period before the occurrence of spontaneous seizures and the lowering of the seizure threshold. Further, neonatal seizure models are generally easy to handle and can be applied for in vitro studies because cells in the neonatal brain are suitable for culture. Here, we review two animal models of neonatal seizures for studying epileptogenesis and discuss their features, specifically focusing on hypoxia-ischemia (HI)-induced seizures and febrile seizures (FSs). Studying these models will contribute to identifying the potential therapeutic targets and biomarkers of epileptogenesis.

Bioengineered PLGA-chitosan nanoparticles for brain targeted intranasal delivery of antiepileptic TRH analogues

The bio-engineering of nanoparticles for the transportation of various therapeutic agents specifically to brain has sparked a rapidly growing interest in the field of material chemistry. In this study, L-pGlu-(1-benzyl)–L-His–L-ProNH2 (NP-355) and L-pGlu-(2-propyl)–L-His–L-ProNH2 (NP-647) were synthesized and encapsulated in biodegradable poly-lactide-co-glycolide (PLGA) nanoparticles which were further decorated with mucoadhesive surface coating of chitosan. NP-355 and NP-647 which are analogues of thyrotropin releasing hormone, have been reported to demonstrate potential antiepileptic properties against various animal models of seizures. However, their applicability is limited by their short lives due to rapid metabolism and blood brain barrier. The treatment of disorders associated with central nervous system such as epilepsy has been a major challenge for several decades due to difficulty in delivery of drug molecules and imaging agents to brain. To overcome these issues, development of sustained release delivery system for these neuropeptides is proposed which can be administered directly from nose to brain utilizing olfactory nerve channels. The synthesized nanoparticles were evaluated for their physicochemical properties, sustained release properties, toxicity and antiepileptic potential following intranasal administration. The ability of these nanoparticles to reach the brain was evaluated by utilizing quantum dots as fluorescent probes. Our results proved that the polymeric nanoparticles can be used for successful delivery of neurological drugs to the brain.

Glial Fibrillary Acidic Protein Expression in the Hippocampal Formation of Mefloqine Induced-Seizured Rats Treated with Aqueous Leaf Extract of <em>Luffa aegyptiaca Mill</em>

This study investigates the expression of Glial Fibrillary Acidic Protein and effects of aqueous leaf extract of Luffa aegyptiaca Mill on the hippocampus of the brain of Albino Wistar rats with Mefloquine induced seizure. Thirty albino wistar rats (190-250 g) were grouped into 6 groups of 5 rats each. Group 1 was control. Group 2 rats were induced with mefloquine only (4.28 mg/kg). Group 3 were given average dose of luffa extract only (800 mg/kg). Group four rats were induced with mefloquine (4.28 mg/kg) and treated with diazepam (5 mg/kg). Group 5 rats were induced with (4.28 kg/kg) with mefloquine and treated with low dose luffa aegyptiaca mill (400 mg/kg). Group 6 were induced with mefloquine (4.28 mg/kg) and treated with high dose luffa aegyptiaca mill (1200 mg/kg). The rats were then perfused transcardially and sacrificed. Brain sections were analyzed for histological (H&E) and immunohistochemical staining using glial Fibrillary Acidic Protein (GFAP), marker for astrocytes. The histological results showed disruption of pyramidal cells layer in CA3 subfield of hippocampus and regional selectivity of pyramidal cell loss in seizured rats indicating induction of seizure with mefloquine. There was some restoration of pyramidal cells with the treated groups but no disruptions in the control group. There was less expression of GFAP positive cells in the control group and treated groups and more expression in the seizure rats. The expression of GFAP positive cells was an indication of different levels of neuroinflammation. The reactive astrocytes being predominant in the seizure group. The present study therefore provides empirical data on GFAP expression in the hippocampus of seizure animal model treated with aqueous leaf extract of luffa.

Assessment of the Anticonvulsant Potency of Ursolic Acid in Seizure Threshold Tests in Mice

Ursolic acid (UA) is a plant derived compound which is also a component of the standard human diet. It possesses a wide range of pharmacological properties, i.e., antioxidant, anti-inflammatory, antimicrobial and antitumor, which have been used in folk medicine for centuries. Moreover, influence of UA on central nervous system-related processes, i.e., pain, anxiety and depression, was proved in experimental studies. UA also revealed anticonvulsant properties in animal models of epilepsy and seizures. The aim of the present study was to investigate the influence of UA on seizure thresholds in three acute seizure models in mice, i.e., the 6 Hz-induced psychomotor seizure threshold test, the maximal electroshock threshold (MEST) test and the timed intravenous pentylenetetrazole (iv PTZ) infusion test. We also examined its effect on the muscular strength (assessed in the grip strength test) and motor coordination (estimated in the chimney test) in mice. UA at doses of 50 and 100 mg/kg significantly increased the seizure thresholds in the 6 Hz and MEST tests. The studied compound did not influence the seizure thresholds in the iv PTZ test. Moreover, UA did not affect the motor coordination and muscular strength in mice. UA displays only a weak anticonvulsant potential which is dependent on the used seizure model.

The antiepileptic and neuroprotective effect of the Buxus hyrcana Pojark hydroethanolic extract against the pentylentetrazol induced model of the seizures in the male rats

Aims: The genus Buxus grows up widespread in Europe and Western Asia. It is an important traditional plant that has been used in the treatment of many illnesses. In the present study, the effect of hydroethanolic extract of Buxus hyrcana Pojark (BHP) on the animal model of seizure was studied.Materials and Methods: In this experimental study, 42 male Wistar rats weighing 220–250 g were randomly selected and were divided into experimental and control groups (six rats per group). The experimental groups were treated by the intraperitoneal (i.p.) single injection of 150, 300, 450, 600 and 750 mg kg−1 of hydroalcoholic extracts of BHP. The control negative group received normal saline (0.9%) and the control positive group received phenobarbital (30 mg kg−1, i.p.) pre-treatment. Thirty minutes after the treatments, the seizure behaviors were evaluated by the pentylenetetrazole (PTZ) (70 mg kg−1, i.p.) challenge. In addition, after the experiment, the rats were put to death and their brains were removed for the histological study.Results: The ANOVA demonstrated that compared to the control group, all the BHP doses delayed the initiation and duration of the tonic, colonic and tonic–colonic seizures and significantly reduced the tonic and colonic seizures (p < 0.001). Furthermore, the administration of all five doses of the extract significantly prevented the production of the dark neurons (p < 0.001) in different areas of the hippocampus compared to PTZ group.Conclusion: We can conclude that the BHP extract has beneficial effects for the prevention of the PTZ induced seizure.

High frequency oscillations in epileptic rodents: Are we doing it right?

BackgroundThe detection of high-frequency oscillations (HFOs, ripples: 80–200 Hz, fast ripples: 250–500 Hz) is often based on considering ripples or fast ripples in isolation; overlapping ripples and fast ripples are excluded from further analysis. Here, we studied overlapping HFOs during spontaneous seizures in pilocarpine-treated animals. New methodSpontaneous seizures (n = 6 animals) presented with either hypersynchronous- (HYP, n = 18) or low-voltage fast-onset (LVF, n = 21) pattern. Ripples and fast ripples overlapping by more than 30% were analysed. ResultsOverlapping HFOs could show a unimodal power spectrum between 80–500 Hz (n = 188, 58.9%) or a bimodal power spectrum, with peaks in power between 80 and 200 Hz and between 250 and 500 Hz (n = 131, 41.1%,). Overlapping HFOs occurred at higher rates during HYP seizures compared to the pre-ictal period in seizure onset zones (p < 0.001) and regions of secondary spread (p < 0.001). When comparing HYP and LVF seizures, we found that overlapping HFOs occurred at higher rates before LVF seizures (p < 0.05) compared to HYP seizures but, during the ictal period, HYP seizures showed higher rates of overlapping HFOs than LVF seizures (p < 0.001). Comparison with existing methodsWe have analysed overlapping ripples and fast ripples shortly before and during seizures. ConclusionsAlthough overlapping ripples and fast ripples represent a minority of HFOs, they may provide additional information on the excitability of neuronal networks that generate seizures in animal models and patients presenting with mesial temporal lobe epilepsy.

Intramuscular allopregnanolone and ganaxolone in a mouse model of treatment-resistant status epilepticus.

Allopregnanolone (5α-pregnan-3α-ol-20-one) and its synthetic 3β-methyl analog, ganaxolone, are positive allosteric modulators of synaptic and extrasynaptic γ-aminobutyric acid (GABA)A receptors that exhibit antiseizure activity in diverse animal seizure models, including models of status epilepticus (SE). The 2 neuroactive steroids are being investigated as treatments for SE, including as a treatment for SE induced by chemical threat agents. Intramuscular injection is the preferred route of administration in the prehospital treatment of SE. The objective of this study was to assess the efficacy of intramuscular allopregnanolone and ganaxolone in the treatment of SE induced by the chemical threat agent tetramethylenedisulfotetramine (TETS). The test agents were administered 40minutes after the onset of SE when mice are refractory to treatment. Allopregnanolone and ganaxolone (each at 3mg/kg) terminated SE in, respectively, 92% and 75% of animals, and prevented mortality in 85% and 50% of animals; the mean times to termination of behavioral seizures were, respectively, 172±16 and 447±52seconds. In a separate series of experiments, mice were dosed with the neuroactive steroids by intramuscular injection, and plasma and brain levels were sampled at various time points following injection to estimate pharmacokinetic parameters. Plasma Cmax (maximum concentration) values for allopregnanolone and ganaxolone were 645 and 550ng/mL, respectively. Brain exposure of both steroids was approximately 3-fold the plasma exposure. Two-compartment pharmacokinetic analysis revealed that the central compartment Vd (volume of distribution), CL (clearance), t½ (terminal half-life), and F (intramuscular bioavailability) values for allopregnanolone and ganaxolone were, respectively, 4.95L/kg 12.88L/kg/h,16minutes, 97%, and 5.07L/kg, 8.35L/kg/h, 25minutes, 95%. Allopregnanolone and ganaxolone are effective in the treatment of TETS-induced SE when administered by the intramuscular route. Allopregnanolone is more rapidly acting and modestly more effective, possibly because it has greater potency on GABAA receptors.

Temporal analysis of hippocampal CA3 gene coexpression networks in a rat model of febrile seizures.

ABSTRACTComplex febrile seizures during infancy constitute an important risk factor for development of epilepsy. However, little is known about the alterations induced by febrile seizures that make the brain susceptible to epileptic activity. In this context, the use of animal models of hyperthermic seizures (HS) could allow the temporal analysis of brain molecular changes that arise after febrile seizures. Here, we investigated temporal changes in hippocampal gene coexpression networks during the development of rats submitted to HS. Total RNA samples were obtained from the ventral hippocampal CA3 region at four time points after HS at postnatal day (P) 11 and later used for gene expression profiling. Temporal endpoints were selected for investigating the acute (P12), latent (P30 and P60) and chronic (P120) stages of the HS model. A weighted gene coexpression network analysis was used to characterize modules of coexpressed genes, as these modules might contain genes with similar functions. The transcriptome analysis pipeline consisted of building gene coexpression networks, identifying network modules and hubs, performing gene-trait correlations and examining changes in module connectivity. Modules were functionally enriched to identify functions associated with HS. Our data showed that HS induce changes in developmental, cell adhesion and immune pathways, such as Wnt, Hippo, Notch, Jak-Stat and Mapk. Interestingly, modules involved in cell adhesion, neuronal differentiation and synaptic transmission were activated as early as 1 day after HS. These results suggest that HS trigger transcriptional alterations that could lead to persistent neurogenesis, tissue remodeling and inflammation in the CA3 hippocampus, making the brain prone to epileptic activity.

Anticonvulsant effects of acetaminophen in mice: Comparison with the effects of nonsteroidal anti-inflammatory drugs

ObjectiveThe appropriate use of analgesic drugs based on their degree of analgesia and adverse effects is important for pain management. Although it has been reported that AM404, a metabolite of acetaminophen, has anticonvulsant effects in several animal seizure models, little is known about the relation between acetaminophen and seizures. We therefore investigated the effects of acetaminophen on seizure susceptibility in several mouse seizure and epilepsy models and compared the effects with those of nonsteroidal anti-inflammatory drugs (NSAIDs). MethodsAnticonvulsant activity was evaluated in ICR mice using maximum electroshock-induced seizure tests and acute pentylenetetrazol-induced seizure tests. Electrical kindling via corneal stimulation and pentylenetetrazol administration were used to establish animal kindling epilepsy models. Proconvulsive activity was examined using an electroconvulsive shock test with low-stimulus currents. ResultsAcetaminophen showed slight, but not statistically significant, anticonvulsant activity in both the maximum electroshock-induced seizure test (300–600mg/kg i.p.) and acute pentylenetetrazol-induced seizure test (100–600mg/kg i.p.). In contrast, acetaminophen exhibited significant anticonvulsant effects in corneal electroshock-kindled and pentylenetetrazol-kindled mice (ED50 values: 251 and 310mg/kg i.p., respectively). When the proconvulsive effects of NSAIDs were examined in the low-current electroconvulsive shock-induced seizure model, the nonselective cyclooxygenase (COX)-1 and COX-2 inhibitors indomethacin, diclofenac, and loxoprofen induced dose-dependent proconvulsant activity. Celecoxib, a COX-2 selective inhibitor, had no proconvulsant activity. ConclusionThese findings suggest that acetaminophen has a significant anticonvulsant effect and that its profile is completely different from that of NSAIDs.

Interactions of aliskiren, a direct renin inhibitor, with antiepileptic drugs in the test of maximal electroshock in mice

Experimental studies showed that certain angiotensin-converting enzyme inhibitors and angiotensin AT1 receptor antagonists can decrease seizure severity in rodents. Additionally, some of these blockers of the renin-angiotensin system have been documented to enhance the anticonvulsant activity of antiepileptic drugs against maximal electroshock-induced seizures. The aim of the current study was to investigate the effect of aliskiren, a direct renin inhibitor and a novel antihypertensive drug, on the protective action of numerous antiepileptic drugs (carbamazepine, valproate, clonazepam, phenobarbital, oxcarbazepine, lamotrigine, topiramate and pregabalin) in the test of maximal electroshock in mice. The examined drugs were administered intraperitoneally. Aliskiren up to a dose of 75mg/kg did not affect the threshold for electroconvulsions, however, aliskiren (75mg/kg) enhanced the anticonvulsant action of clonazepam and valproate. Following aliskiren treatment, a higher brain concentration of valproate was noted, suggesting a pharmacokinetic interaction. In the rota-rod test, the concomitant treatment with aliskiren (50 or 75mg/kg) and clonazepam (22.6mg/kg) impaired motor coordination while clonazepam (22.6mg/kg) alone showed strong tendency towards this impairment. The combination of aliskiren (75mg/kg) with phenobarbital (25.5mg/kg) caused long-term memory deficits in the passive avoidance task. This study shows that there are no negative interactions between aliskiren and the examined antiepileptic drugs as concerns their anticonvulsant activity. Aliskiren even potentiated the anticonvulsant action of clonazepam and valproate against maximal electroshock. The impact of aliskiren alone on seizure activity or on the anticonvulsant and adverse activity of antiepileptic drugs needs further evaluation in other animal models of seizures.

Therapeutic effects of scoparone on pilocarpine (Pilo)-induced seizures in mice

Epilepsy is a common and devastating neurological disorder. Inflammatory processes and apoptosis in brain tissue have been reported in human epilepsy. Scoparone (6,7-dimethoxycoumarin) is an important chemical substance, which has multiple beneficial activities, including antitumor, anti-inflammatory and anti-coagulant properties. In our present study, we attempted to investigate if scoparone could attenuate seizures-induced blood brain barrier breakdown, inflammation and apoptosis. Pilocarpine (Pilo) and methylscopolamine were used to establish acute seizure animal model. Scoparone suppressed the leakage of blood brain barrier, inflammation and apoptosis. In hippocampus and cortex, the expression of inflammation-associated molecules, such as chemokine (CXC motif) ligand 1 (CXCL-1), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-6, hypoxia-inducible factor 1α (HIF-1α), and monocyte chemoattractant protein-1 (MCP-1), were reduced by scoparone through inactivating toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-κB) pathway. Scoparone reduced apoptotic levels in hippocampus by TUNEL analysis, along with decreased Caspase-3 and PARP cleavage. In addition, phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway in Pilo-induced acute seizures was also inactivated by scoparone. In vitro, we confirmed that scoparone inhibited LPS-caused astrocytes activation as proved by the reduced glial fibrillary acidic protein (GFAP) levels, inflammation and apoptosis, which were at least partly dependent on AKT suppression. The results above indicated that scoparone could relieve pilocarpine (Pilo)-induced seizures against neural cell inflammation and apoptosis.

The anticonvulsant activity and cerebral protection of chronic lithium chloride via NMDA receptor/nitric oxide and phospho-ERK

The underlying mechanisms for the neuroprotective effects of lithium chloride in neurodegenerative diseases such as seizures remain unknown. In present study the downstream signaling pathway of phospho-ERK/NMDA receptors/nitric oxide has been studied. For this purpose, acute and chronic effect of lithium in seizure animal model and the interaction of NMDA receptor antagonist (MK-801) and neuronal nitric oxide synthase (nNOS) inhibitor (7-NI) with these neuroprotection has been studied.Acute lithium administration showed pro-convulsive properties in pentylenetetrazole (PTZ)-induced seizure model while chronic treatment increased the seizure threshold significantly. The serum level of lithium in treated mice were 0.48 mEq/L corresponding the therapeutic range. Administration of 7-NI (30mg/kg, i.p.) and MK-801 (0.001mg/kg, i.p.) had no effect on seizure threshold, while co-administration of them before the sub-effective dose of lithium (4mg/kg, i.p.) increased the anticonvulsant effect of lithium significantly. Furthermore, acute injection of MK-801 (0.05mg/kg) or 7-NI (60mg/kg) and co-administration of them significantly suppressed the anticonvulsant effect of effective dose of lithium (10mg/kg). This data demonstrated involvement of NMDA receptors/nitric oxide pathway in anticonvulsant effect of lithium.In cerebellar granule neurons (CGNs) culture studies on glutamate excitotoxicity western blot analysis, nitrite assay by Griess reaction, cell viability and microscopic morphology evaluation has been carried out to find the role of NMDA receptor/nitric oxide and phospho-ERK signaling in lithium neuroprotection. Using MTT assay and morphologic examinations, chronic lithium treatment showed protective effects against glutamate toxicity in primary cerebellar culture neurons. The level of nitric oxide was significantly reduced in co-administration of lithium and glutamate while glutamate significantly increased levels of nitric oxide. The involvement of NMDA receptors/nitric oxide and phospho-ERK pathway in the effects of lithium on cerebellar neurons has been shown. Inhibition of ERK signaling may be reconsidered as a pharmacological approach for seizure control.

Standards for data acquisition and software-based analysis of invivo electroencephalography recordings from animals. A TASK1-WG5 report of the AES/ILAE Translational Task Force of the ILAE.

Electroencephalography (EEG)-the direct recording of the electrical activity of populations of neurons-is a tremendously important tool for diagnosing, treating, and researching epilepsy. Although standard procedures for recording and analyzing human EEG exist and are broadly accepted, there are no such standards for research in animal models of seizures and epilepsy-recording montages, acquisition systems, and processing algorithms may differ substantially among investigators and laboratories. The lack of standard procedures for acquiring and analyzing EEG from animal models of epilepsy hinders the interpretation of experimental results and reduces the ability of the scientific community to efficiently translate new experimental findings into clinical practice. Accordingly, the intention of this report is twofold: (1) to review current techniques for the collection and software-based analysis of neural field recordings in animal models of epilepsy, and (2) to offer pertinent standards and reporting guidelines for this research. Specifically, we review current techniques for signal acquisition, signal conditioning, signal processing, data storage, and data sharing, and include applicable recommendations to standardize collection and reporting. We close with a discussion of challenges and future opportunities, and include a supplemental report of currently available acquisition systems and analysis tools. This work represents a collaboration on behalf of the American Epilepsy Society/International League Against Epilepsy (AES/ILAE) Translational Task Force (TASK1-Workgroup 5), and is part of a larger effort to harmonize video-EEG interpretation and analysis methods across studies using invivo and invitro seizure and epilepsy models.

Common data elements for preclinical epilepsy research: Standards for data collection and reporting. A TASK3 report of the AES/ILAE Translational Task Force of the ILAE.

The major objective of preclinical translational epilepsy research is to advance laboratory findings toward clinical application by testing potential treatments in animal models of seizures and epilepsy. Recently there has been a focus on the failure of preclinical discoveries to translate reliably, or even to be reproduced in different laboratories. One potential cause is a lack of standardization in preclinical data collection. The resulting difficulties in comparing data across studies have led to high cost and missed opportunity, which in turn impede clinical trials and advances in medical care. Preclinical epilepsy research has successfully brought numerous antiseizure treatments into the clinical practice, yet the unmet clinical needs have prompted the reconsideration of research strategies to optimize epilepsy therapy development. In the field of clinical epilepsy there have been successful steps to improve such problems, such as generation of common data elements (CDEs) and case report forms (CRFs and standards of data collection and reporting) by a team of leaders in the field. Therefore, the Translational Task Force was appointed by the International League Against Epilepsy (ILAE) and the American Epilepsy Society (AES), in partnership with the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institutes of Health (NIH) to define CDEs for animal epilepsy research studies and prepare guidelines for data collection and experimental procedures. If adopted, the preclinical CDEs could facilitate collaborative epilepsy research, comparisons of data across different laboratories, and promote rigor, transparency, and impact, particularly in therapy development.

Assessing Levels of Awareness During Seizures in Animal Models.

Assessing Levels of Awareness During Seizures in Animal Models.

Dl-3n-butylphthalide reduces epileptiform activity through GluA2-lacking calcium-permeable AMPARs in epilepsy models.

Epilepsy is the most prevalent chronic neurological disorder, and its pathological mechanism indicates that an imbalance between excitatory and inhibitory neurotransmission leads to neuronal hyperexcitability. Previous studies have suggested that dl-3n-butylphthalide (NBP) regulates the excitatory neurotransmitter glutamate in the brains of epileptic mice, however, the mechanisms are unknown. We investigated behavioral and electrophysiological factors in rats using NBP. In an in vivo pentylenetetrazole (PTZ)-induced epileptic seizure animal model, NBP decreased the generalized tonic-clonic seizure (GTCS) severity. In an acute hippocampal slice 4-aminopyridine (4-AP) epilepsy model in vitro, NBP decreased the epileptiform activity and miniature excitatory postsynaptic current (mEPSC) amplitude; there was no change in the miniature inhibitory postsynaptic current (mIPSC) amplitude or frequency. This effect suggested changes in excitatory synaptic transmission, which was altered through postsynaptic GluA2-lacking calcium-permeable AMPA receptors (CP-AMPARs). These findings showed that NBP suppressed epileptiform activity in these epilepsy models and provided the first detailed electrophysiological analysis of the impact of NBP in epilepsy models, which may be employed in future experimental or clinical therapies for patients with epilepsy.