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Epilepsy & Behavior : E&B Jun 2019Seizure severity in experimental models of epilepsy is often evaluated by means of the Racine scale, in spite of the use of seizure induction methods that are different...
Seizure severity in experimental models of epilepsy is often evaluated by means of the Racine scale, in spite of the use of seizure induction methods that are different from those of the original paper by Racine in 1972. In such cases, the use of this scale is not always justified because some seizure behaviors are significantly different from those originally described or not present at all. Correspondingly, the pentylenetetrazole (PTZ) model, which is frequently used for antiepileptic drug research, lacked an adequate assessment tool to measure seizure severity. In 2009, an adapted intensity scale for PTZ-induced seizures was already designed for rats. Here, we evaluated electroencephalographic (EEG) and behavioral parameters after a single PTZ injection, to determine whether this scale is also suitable for use in mouse studies. We found that the scale designed for rats is quite robust and can thus be applied to score seizure severity in mice. Yet, certain convulsive behaviors and EEG characteristics were distinct between species. Therefore, a species-specific scale was designed, which included the concomitant EEG characteristic next to the behavioral expressions we observed, in order to establish a user-friendly scoring scale for PTZ-induced seizures in mice. To evaluate applicability, we utilized the scale in a seizure susceptibility study of a transgenic mouse model. We demonstrated that the maximum severity scores obtained with the newly revised Racine scale highly correlated with the administered dose. Hence, the revised scale differentiates well between different classes of seizure severity.
Topics: Animals; Convulsants; Disease Models, Animal; Electroencephalography; Female; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pentylenetetrazole; Random Allocation; Seizures; Severity of Illness Index
PubMed: 31026782
DOI: 10.1016/j.yebeh.2019.02.029 -
Current Neuropharmacology 2022Epilepsy is a devastating neurological disorder. Current anti-convulsant drugs are only effective in about 70% of patients, while the rest remain drug-resistant. Thus,...
Epilepsy is a devastating neurological disorder. Current anti-convulsant drugs are only effective in about 70% of patients, while the rest remain drug-resistant. Thus, alternative methods have been explored to control seizures in these drug-resistant patients. One such method may be through the utilization of fruit phytochemicals. These phytochemicals have been reported to have beneficial properties such as anti-convulsant, anti-oxidant, and anti-inflammatory activities. However, some fruits may also elicit harmful effects. This review aims to summarize and elucidate the anti- or pro-convulsant effects of fruits used in relation to seizures in hopes of providing a good therapeutic reference to epileptic patients and their carers. Three databases, SCOPUS, ScienceDirect, and PubMed, were utilized for the literature search. Based on the PRISMA guidelines, a total of 40 articles were selected for critical appraisal in this review. Overall, the extracts and phytochemicals of fruits managed to effectively reduce seizure activities in various preclinical seizure models, acting mainly through the activation of the inhibitory neurotransmission and blocking the excitatory neurotransmission. Only star fruit has been identified as a pro-convulsant fruit due to its caramboxin and oxalate compounds. Future studies should focus more on utilizing these fruits as possible treatment strategies for epilepsy.
Topics: Convulsants; Epilepsy; Fruit; Humans; Phytochemicals; Seizures
PubMed: 34517803
DOI: 10.2174/1570159X19666210913120637 -
Disease Models & Mechanisms Jul 2021Danio rerio (zebrafish) are a powerful experimental model for genetic and developmental studies. Adaptation of zebrafish to study seizures was initially established...
Danio rerio (zebrafish) are a powerful experimental model for genetic and developmental studies. Adaptation of zebrafish to study seizures was initially established using the common convulsant agent pentylenetetrazole (PTZ). Larval PTZ-exposed zebrafish exhibit clear behavioral convulsions and abnormal electrographic activity, reminiscent of interictal and ictal epileptiform discharge. By using this model, our laboratory developed simple locomotion-based and electrophysiological assays to monitor and quantify seizures in larval zebrafish. Zebrafish also offer multiple advantages for rapid genetic manipulation and high-throughput phenotype-based drug screening. Combining these seizure assays with genetically modified zebrafish that represent Dravet syndrome, a rare genetic epilepsy, ultimately contributed to a phenotype-based screen of over 3500 drugs. Several drugs identified in these zebrafish screens are currently in clinical or compassionate-use trials. The emergence of this 'aquarium-to-bedside' approach suggests that broader efforts to adapt and improve upon this zebrafish-centric strategy can drive a variety of exciting new discoveries.
Topics: Animals; Anticonvulsants; Epilepsy; Pentylenetetrazole; Seizures; Zebrafish
PubMed: 34231838
DOI: 10.1242/dmm.049080 -
Scientific Reports Mar 2017GABA receptor-mediated inhibition depends on the maintenance of low level intracellular [Cl] concentration, which in adult depends on neuron specific K-Cl...
GABA receptor-mediated inhibition depends on the maintenance of low level intracellular [Cl] concentration, which in adult depends on neuron specific K-Cl cotransporter-2 (KCC2). Previous studies have shown that KCC2 was downregulated in both epileptic patients and various epileptic animal models. However, the temporal relationship between KCC2 downregulation and seizure induction is unclear yet. In this study, we explored the temporal relationship and the influence of KCC2 downregulation on seizure induction. Significant downregulation of plasma membrane KCC2 was directly associated with severe (Racine Score III and above) behavioral seizures in vivo, and occurred before epileptiform bursting activities in vitro induced by convulsant. Overexpression of KCC2 using KCC2 plasmid effectively enhanced resistance to convulsant-induced epileptiform bursting activities in vitro. Furthermore, suppression of membrane KCC2 expression, using shRNA plasmid in vitro and shRNA containing lentivirus in vivo, induced spontaneous epileptiform bursting activities in vitro and Racine III seizure behaviors accompanied by epileptic EEG in vivo. Our findings novelly demonstrated that altered expression of KCC2 is not the consequence of seizure occurrence but likely is the contributing factor.
Topics: Animals; Cells, Cultured; Convulsants; Disease Models, Animal; Down-Regulation; Electroencephalography; Epilepsy; Genetic Predisposition to Disease; Humans; RNA, Small Interfering; Rats; Rats, Sprague-Dawley; Symporters; K Cl- Cotransporters
PubMed: 28279020
DOI: 10.1038/s41598-017-00196-7 -
Metabolic Brain Disease Feb 2015Epilepsy is a family of brain disorders with a largely unknown etiology and high percentage of pharmacoresistance. The clinical manifestations of epilepsy are seizures,... (Review)
Review
Epilepsy is a family of brain disorders with a largely unknown etiology and high percentage of pharmacoresistance. The clinical manifestations of epilepsy are seizures, which originate from aberrant neuronal synchronization and hyperexcitability. Reactive astrocytosis, a hallmark of the epileptic tissue, develops into loss-of-function of glutamine synthetase, impairment of glutamate-glutamine cycle and increase in extracellular and astrocytic glutamate concentration. Here, we argue that chronically elevated intracellular glutamate level in astrocytes is instrumental to alterations in the metabolism of glycogen and leads to the synthesis of polyglucosans. Unaccessibility of glycogen-degrading enzymes to these insoluble molecules compromises the glycogenolysis-dependent reuptake of extracellular K(+) by astrocytes, thereby leading to increased extracellular K(+) and associated membrane depolarization. Based on current knowledge, we propose that the deterioration in structural homogeneity of glycogen particles is relevant to disruption of brain K(+) homeostasis and increased susceptibility to seizures in epilepsy.
Topics: Animals; Astrocytes; Convulsants; Disease Susceptibility; Epilepsy; Gliosis; Glucans; Glutamate-Ammonia Ligase; Glutamates; Glutamine; Glycogen; Glycogen Synthase Kinase 3; Homeostasis; Humans; Membrane Potentials; Methionine Sulfoximine; Molecular Structure; Neurons; Potassium; Seizures; Sleep; Sleep Deprivation; Structure-Activity Relationship
PubMed: 24643875
DOI: 10.1007/s11011-014-9524-5 -
Brazilian Journal of Medical and... 2021We aimed to reveal the anti-convulsant effects sulfasalazine and its mechanism in pentylenetetrazole (PTZ)-induced seizures in rats. Forty-eight male Wistar albino rats...
We aimed to reveal the anti-convulsant effects sulfasalazine and its mechanism in pentylenetetrazole (PTZ)-induced seizures in rats. Forty-eight male Wistar albino rats (200-250 g) were randomly divided into two groups: 24 for electroencephalography (EEG) recording (group A) and 24 for behavioral studies (group B). About 70 mg/kg PTZ was used for behavioral studies after sulfasalazine administration and 35 mg/kg PTZ was used for EEG recording after sulfasalazine administration. Electrodes were implanted on the dura mater over the left frontal cortex and the reference electrode was implanted over the cerebellum for EEG recording. Racine's convulsion scale, first myoclonic jerk onset time, spike percentages, brain malondialdehyde (MDA), superoxide dismutase (SOD), and prostaglandin F2α (PGF2α) levels were evaluated between the groups. First myoclonic jerk onset time was significantly shorter in the saline group than both 250 and 500 mg/kg sulfasalazine groups (P<0.05). Racine's convulsion scores were significantly lower in the 250 and 500 mg/kg sulfasalazine groups than the saline group (P<0.05, P<0.001). The two sulfasalazine groups had lower spike percentages than the saline group (P<0.05). Significantly lower MDA and PGF2α levels were observed in the 250 and 500 mg/kg sulfasalazine groups compared with the saline group (P<0.05, P<0.001, respectively). SOD increased significantly in both sulfasalazine groups compared with the PTZ+saline group (P<0.05). Our study demonstrated that sulfasalazine had protective effects on PTZ-induced convulsions by protecting against oxidative and inflammatory damage associated with PTZ.
Topics: Animals; Male; Rats; Pentylenetetrazole; Rats, Sprague-Dawley; Rats, Wistar; Seizures; Sulfasalazine
PubMed: 34878064
DOI: 10.1590/1414-431X2021e11541 -
Annals of Clinical and Translational... Jul 2021To confirm the critical factors affecting seizure susceptibility in acute pentylenetetrazole (PTZ) mouse epilepsy models and evaluate the prior literature for these... (Review)
Review
OBJECTIVE
To confirm the critical factors affecting seizure susceptibility in acute pentylenetetrazole (PTZ) mouse epilepsy models and evaluate the prior literature for these factors.
METHODS
Serial cohorts of wild-type mice administered intraperitoneal (IP)-PTZ were aggregated and analyzed by multivariate logistic regression for the effect of sex, age, background strain, dose, and physiologic stress (i.e., EEG implantation and/or single-housing) on seizure response. We assessed the reporting of these factors in a comprehensive literature review over the last 10 years (2010-2020).
RESULTS
We conducted aggregated analysis of pooled data of 307 mice (220 C57BL/6J mice and 87 mixed background mice; 202 males, 105 females) with median age of 10 weeks (range: 6-49 weeks) with acute PTZ injection (dose range 40-65 mg/kg). Significance in multivariate analysis was found between seizures and increased PTZ dose (odds ratio (OR) 1.149, 95% confidence interval (CI) 1.102-1.205), older age (OR 1.1, 95% CI 1.041-1.170), physiologic stress (OR 17.36, 95% CI 7.349-44.48), and mixed background strain (OR 0.4725, 95% CI 0.2315-0.9345). Literature review identified 97 papers using acute PTZ-seizure models. Age, housing, sex, and background were omitted by 61% (59/97), 51% (49/97), 18% (17/97), and 8% (8/97) papers, respectively. Only 17% of publications specified all four factors (16/97).
INTERPRETATION
Our analysis and literature review demonstrate a critical gap in standardization of acute PTZ-induced seizure paradigm in mice. We recommend that future studies specify and control for age, background strain, sex, and housing conditions of experimental animals.
Topics: Age Factors; Animals; Convulsants; Electroencephalography; Female; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Inbred CBA; Pentylenetetrazole; Seizures; Sex Factors; Social Isolation; Species Specificity
PubMed: 34102033
DOI: 10.1002/acn3.51375 -
The Journal of Pharmacology and... Feb 2019Convulsant effects of abused synthetic cannabinoid (SCB) drugs have been reported in humans and laboratory animals, but the mechanism of these effects is not known. We...
Convulsant effects of abused synthetic cannabinoid (SCB) drugs have been reported in humans and laboratory animals, but the mechanism of these effects is not known. We compared convulsant effects of partial CB1R agonist ∆-tetrahydrocannabinol (THC), full CB1R agonist SCBs JWH-018 and 5F-AB-PINACA, and classic chemical convulsant pentylenetetrazol (PTZ) using an observational rating scale in mice. THC did not elicit convulsions, but both SCBs did so as effectively as and more potently than PTZ. SCB-elicited convulsions were attenuated by the CB1R antagonist rimonabant or by THC, or by dose regimens of THC and JWH-018, which downregulate and desensitize CB1Rs. None of these treatments altered the convulsant effects of PTZ, although diazepam attenuated PTZ-elicited convulsions without altering SCB-induced convulsant effects. Repeated administration of a subthreshold dose of PTZ kindled convulsant effects, but this was not observed with the SCBs, and no cross-kindling was observed. Repeated administration of the SCBs resulted in tolerance to convulsant effects, but no cross-tolerance to PTZ was observed. Inhibition on Phase I metabolism via nonselective inhibition of CYP450s with 1-aminobenzotriazole potentiated the hypothermic effects of the SCBs and protected against the convulsant effects of JWH-018, but not those of 5F-AB-PINACA or PTZ. Incubation of human liver microsomes with the SCBs showed that JWH-018 is eliminated via oxidation, whereas 5F-AB-PINACA is not. These studies suggest that SCB-elicited convulsions are mediated by high intrinsic efficacy at CB1Rs and that benzodiazepines may not be effective treatments. Finally, drug metabolism may dramatically modulate the convulsant effects of some, but not all, SCBs.
Topics: Animals; Convulsants; Dose-Response Relationship, Drug; Humans; Illicit Drugs; Indazoles; Indoles; Male; Mice; Microsomes, Liver; Naphthalenes; Receptor, Cannabinoid, CB1; Seizures; Valine
PubMed: 30420360
DOI: 10.1124/jpet.118.251157 -
Journal of Pharmacological and... 2018Traditionally, rat hippocampal tissue slice models are used as an in vitro electrophysiology assay to assess seizurogenic potential in early drug development despite... (Comparative Study)
Comparative Study
INTRODUCTION
Traditionally, rat hippocampal tissue slice models are used as an in vitro electrophysiology assay to assess seizurogenic potential in early drug development despite non-clinical species-specific differences noted during in vivo seizure studies.
METHODS
Hippocampal tissue slices were acutely isolated from rats, minipigs, dogs and nonhuman primates (NHP). Population spikes (PS) were evoked through stimulation of the CA3 Schaffer collateral pathway and recorded using in vitro electrophysiological techniques via an extracellular electrode placed within the CA1 stratum pyramidale cell body layer.
RESULTS
Hippocampal slices, across all species, displayed a concentration-dependent increase in PS area and number with the pro-convulsant pentylenetetrazol (PTZ; 0.1-10mM). Beagle dogs exhibited higher sensitivities to PTZ-induced changes in PS area and number compared to both rats and NHPs which presented nuanced differences in their responsiveness to PTZ modulation. Minipigs were comparatively resistant to PTZ-induced changes in both PS area and number. Rat and NHP hippocampal tissues were further characterized with the pro-convulsant agents 4-aminopyradine (4-AP; 1-100μM) and cefazolin (0.001-10mM). Rats possessed higher sensitivities to 4-AP- and cefazolin-induced changes to both PS area and number whereas NHP displayed greater modulation in PS duration. The anti-convulsant agents, diazepam (10-500μM) and lidocaine (1-500μM), were also tested on either rat and/or NHP tissue with both drugs repressing PS activation at high concentrations.
DISCUSSION
Hippocampal tissue slices, across all species, possessed distinct sensitivities to pro- and anti-convulsant agents which may benefit the design of non-clinical seizure liability studies and their associated data interpretation.
Topics: Animals; Anticonvulsants; Convulsants; Dogs; Dose-Response Relationship, Drug; Hippocampus; Macaca fascicularis; Organ Culture Techniques; Pentylenetetrazole; Rats, Sprague-Dawley; Seizures; Species Specificity; Swine; Swine, Miniature
PubMed: 29155282
DOI: 10.1016/j.vascn.2017.11.003 -
Kidney International. Supplement Feb 2001Epileptic and cognitive symptomatologies are among the most typical manifestations of uremic encephalopathy. Several guanidino compounds (GCs) may play an important role... (Review)
Review
Epileptic and cognitive symptomatologies are among the most typical manifestations of uremic encephalopathy. Several guanidino compounds (GCs) may play an important role in the etiology of uremic encephalopathy. Four GCs appeared to be highly increased as well in serum, cerebrospinal fluid, and brain of uremic patients, whereas the levels of other metabolically relevant GCs were not or only moderately increased and others were even decreased. These highly increased compounds or "uremic" GCs are creatinine (CTN), guanidine (G), guanidinosuccinic acid (GSA), and methylguanidine (MG). All four compounds were shown to be experimental convulsants in brain concentrations similar to those found in uremic brain. We have described a possible mechanism for the contribution of GCs to uremic hyperexcitability, referring to the in vitro effects of uremic GCs on inhibitory and excitatory amino acid receptors. The excitatory effects of uremic GCs on the central nervous system may be explained by the activation of N-methyl-D-aspartate (NMDA) receptors by GSA, concomitant inhibition of GABA(A) receptors by uremic GCs, and other depolarizing effects. These effects might also indicate the putative contribution of uremic GCs to the etiology of uremic encephalopathy.
Topics: Animals; Brain; Brain Diseases, Metabolic; Convulsants; Guanidines; Humans; Models, Neurological; Neurotoxins; Receptors, Amino Acid; Tissue Distribution; Uremia
PubMed: 11168988
DOI: 10.1046/j.1523-1755.2001.59780077.x