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Seizure Jan 2015Pentylenetetrazole and maximal electroshock rodent seizure models are commonly used to detect antiepileptic efficacy in drug development. The aim of this research was to...
PURPOSE
Pentylenetetrazole and maximal electroshock rodent seizure models are commonly used to detect antiepileptic efficacy in drug development. The aim of this research was to evaluate the predictive capabilities of pentylenetetrazole and maximal electroshock models in estimating human exposures required for antiepileptic efficacy through a survey of current literature.
METHODS
A literature search was undertaken to identify articles describing pentylenetetrazole or maximal electroshock models in rat or mice, where at least one of nine pre-selected antiepileptic drugs based on evidence of efficacy were used. Exposures at the median doses of the approved human dose range for these drugs were compared to exposures at doses that inhibit maximal response by 50% (ED50s) from the pentylenetetrazole and maximal electroshock models. Ratios of the human to rodent exposures were calculated and summarised statistically and graphically.
RESULTS
Across the nine antiepileptic drugs investigated, the average (standard deviation) ratio of exposures comparing the median human efficacious dose to mice ED50 dose was 1.4 (3.9) for the pentylenetetrazole model and 3.8 (3.1) for the maximal electroshock model. In the rat, ratios in the maximal electroshock and pentylenetetrazole model were 4.1 (2.1) and a range of 1-2, respectively.
CONCLUSION
Based on the nine antiepileptic drugs investigated, the pentylenetetrazole model appeared to predict human exposures more accurately than the maximal electroshock model. There did not appear to be differences between rat and mice in either of the seizure models, therefore both species could be used equally. Both the pentylenetetrazole and maximal electroshock models are useful tools in screening compounds in early drug discovery.
Topics: Animals; Anticonvulsants; Convulsants; Databases, Bibliographic; Disease Models, Animal; Electroshock; Humans; Mice; Pentylenetetrazole; Rats; Seizures
PubMed: 25564315
DOI: 10.1016/j.seizure.2014.11.006 -
Pharmacological Reports : PR Oct 2022The treatment of epilepsy during early life poses unique challenges-first-line therapies leave many individuals with poorly controlled seizures. In response to the...
BACKGROUND
The treatment of epilepsy during early life poses unique challenges-first-line therapies leave many individuals with poorly controlled seizures. In response to the pharmaco-resistance of current first-line anti-seizure drugs (ASDs) during early life, new therapies have emerged. One such therapy is cannabidiol (CBD). While well studied in adult models of epilepsy, it is poorly studied in immature animals. Here we assessed the efficacy of CBD in immature rodent models of the epilepsies.
METHODS
Pups were pre-treated with CBD (1, 10, 50, 100, 200 mg/kg) and assessed for anticonvulsant efficacy using two well-established anti-seizure screening models: the pentylenetetrazole (PTZ) and maximal electroshock (MES) models. We assessed drug efficacy in postnatal day (P)7 and P21 rats.
RESULTS
In the PTZ model, CBD delayed seizure onset in adolescent but not neonatal rats. By contrast, higher doses of CBD reduced seizure duration in both neonatal and adolescent rats in the MES model. The effects of CBD in both models were modest but consistent.
CONCLUSION
Efficacy of CBD increased in older as compared to younger animals, producing an age-, model-, and dose-dependent suppression of seizures. These data suggest neonatal seizures (modeled by P7 treatment) may be less responsive to CBD. They also suggest preferential efficacy against tonic seizures as compared to partial motor seizures.
Topics: Rats; Animals; Cannabidiol; Pentylenetetrazole; Anticonvulsants; Disease Models, Animal; Epilepsy
PubMed: 36220975
DOI: 10.1007/s43440-022-00413-9 -
International Journal of Molecular... Apr 2023This article discusses the potential of Zebrafish (ZF) (Danio Rerio), as a model for epilepsy research. Epilepsy is a neurological disorder affecting both children and... (Review)
Review
This article discusses the potential of Zebrafish (ZF) (Danio Rerio), as a model for epilepsy research. Epilepsy is a neurological disorder affecting both children and adults, and many aspects of this disease are still poorly understood. In vivo and in vitro models derived from rodents are the most widely used for studying both epilepsy pathophysiology and novel drug treatments. However, researchers have recently obtained several valuable insights into these two fields of investigation by studying ZF. Despite the relatively simple brain structure of these animals, researchers can collect large amounts of data in a much shorter period and at lower costs compared to classical rodent models. This is particularly useful when a large number of candidate antiseizure drugs need to be screened, and ethical issues are minimized. In ZF, seizures have been induced through a variety of chemoconvulsants, primarily pentylenetetrazol (PTZ), kainic acid (KA), and pilocarpine. Furthermore, ZF can be easily genetically modified to test specific aspects of monogenic forms of human epilepsy, as well as to discover potential convulsive phenotypes in monogenic mutants. The article reports on the state-of-the-art and potential new fields of application of ZF research, including its potential role in revealing epileptogenic mechanisms, rather than merely assessing iatrogenic acute seizure modulation.
Topics: Animals; Child; Humans; Zebrafish; Anticonvulsants; Epilepsy; Seizures; Pentylenetetrazole; Disease Models, Animal
PubMed: 37175408
DOI: 10.3390/ijms24097702 -
Journal of Integrative Neuroscience Jan 2022Vanillic acid (VA) exhibited antioxidant and neuroprotective properties in some neurodegenerative disorders. So, the current study examined the neuroprotective potential...
Vanillic acid (VA) exhibited antioxidant and neuroprotective properties in some neurodegenerative disorders. So, the current study examined the neuroprotective potential of VA as an antiepileptic agent in pentylenetetrazole (PTZ)-induced epileptic rats and the prospective role of Insulin like growth factor-1 (IGF-1) and nuclear factor-2 erythroid-related factor-2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in this respect. Thirty male albino rats were equally subdivided into 3 groups; (1) normal control (NC) group, (2) PTZ-group: received PTZ (50 mg/Kg, i.p. every other day) for 14 days, and (3) PTZ + VA group: received PTZ and VA (50 mg/Kg daily for 2 weeks). The seizure score and latency were evaluated after PTZ injection. Also, the markers of oxidative stress (malondialdehyde (MDA), catalase, and reduced glutathione (GSH)), histopathological examination, the expression of glial fibrillary acidic protein (GFAP) (a marker of astrocytes) IGF-1, Nrf2, and HO-1 were assessed in the brain tissues by the end of the experiment. PTZ caused significant decrease in seizure latency and significant increase in seizure score by the end of the experiment ( 0.01). This was associated with significant increase in MDA and GFAP with significant decrease in GSH, total antioxidant capacity (TAC) and IGF-1 in brain tissues compared to normal group ( 0.01). On the other hand, treatment with VA caused significant attenuation in PTZ-induced seizures which was associated with significant improvement in oxidative stress markers and downregulation in GFAP and upregulation of Nrf2, HO-1 and IGF-1 in CA3 hippocampal region ( 0.01). VA showed neuroprotective and anti-epileptic effects against PTZ-induced epilepsy which probably might be due to its antioxidant properties and upregulation of Nrf2/HO-1 pathway and IGF-1.
Topics: Animals; Anticonvulsants; Antioxidants; Convulsants; Disease Models, Animal; Epilepsy; Heme Oxygenase (Decyclizing); Insulin-Like Growth Factor I; Male; NF-E2-Related Factor 2; Pentylenetetrazole; Rats; Signal Transduction; Vanillic Acid
PubMed: 35164451
DOI: 10.31083/j.jin2101015 -
PloS One 2023Phosphodiesterase 5 inhibitors (PDE5i) are the first line treatment for erectile dysfunction; however, several articles and case reports have shown central nervous...
BACKGROUND
Phosphodiesterase 5 inhibitors (PDE5i) are the first line treatment for erectile dysfunction; however, several articles and case reports have shown central nervous system effects, that can cause seizures in susceptible patients. This study aims to describe the changes caused by the use of Sildenafil and Tadalafil through the analysis of abnormalities expressed in the electrocorticogram (ECoG) of rats and evaluate the seizure threshold response and treatment of seizures with anticonvulsants.
MATERIALS AND METHODS
The study used 108 rats (Wistar). Before surgery for electrode placement in dura mater, the animals were randomly separated into 3 experiments for electrocorticogram analysis. Experiment 1: ECoG response to using PD5i (Sildenafil 20mg/kg and Tadalafil 2.6mg/kg p.o.). Experiment 2: ECoG response to the use of PD5i in association with Pentylenetetrazole (PTZ-30 mg/kg i.p.), a convulsive model. Experiment 3: ECoG response to anticonvulsant treatment (Phenytoin, Phenobarbital and Diazepam) of seizures induced by association IPDE5 + PTZ. All recordings were made thirty minutes after administration of the medication and analyzed for ten minutes, only once. We considered statistical significance level of *p<0.05, **p<0.01 and ***p < 0.001.
RESULTS
After administration of Sildenafil and Tadalafil, there were increases in the power of recordings in the frequency bands in oscillations in alpha (p = 0.0920) and beta (p = 0.602) when compared to the control group (p<0.001). After the use of Sildenafil and Tadalafil associated with PTZ, greater potency was observed in the recordings during seizures (p<0.001), however, the Sildenafil group showed greater potency when compared to Tadalafil (p<0.05). Phenobarbital and Diazepam showed a better response in controlling discharges triggered by the association between proconvulsant drugs.
CONCLUSIONS
PDE5i altered the ECoG recordings in the rats' motor cortexes, demonstrating cerebral asynchrony and potentiating the action of PTZ. These findings demonstrate that PDE5i can lower the seizure threshold.
Topics: Animals; Male; Rats; Anticonvulsants; Diazepam; Pentylenetetrazole; Phenobarbital; Phosphodiesterase 5 Inhibitors; Rats, Wistar; Seizures; Sildenafil Citrate; Tadalafil
PubMed: 38033148
DOI: 10.1371/journal.pone.0294754 -
Brazilian Journal of Medical and... 2022Seizures are a disorder caused by structural brain lesions, life-threatening metabolic derangements, or drug toxicity. The present study describes the behavior related...
Seizures are a disorder caused by structural brain lesions, life-threatening metabolic derangements, or drug toxicity. The present study describes the behavior related to proconvulsant activity induced by thiocolchicoside (TCC) in rats and investigates the electrocorticographic patterns of this behavior and the effectiveness of classic antiepileptic drugs used to control these seizures. Forty-nine adult male Wistar rats were used and divided into two phases of our experimental design: 1) evaluation of seizure-related behavior and electrocorticographic patterns induced by TCC and 2) evaluation of the efficacy of classical antiepileptic drugs to control the proconvulsive activity caused by TCC. Our results showed that TCC induced tonic-clonic seizures that caused changes in electrocorticographic readings, characteristic of convulsive activity, with average amplitude greater than that induced by pentylenetetrazole. Treatment with anticonvulsants, especially diazepam, reduced the electrocorticographic outbreaks induced by TCC. The results suggested that TCC caused seizures with increased power in brain oscillations up to 40 Hz and that diazepam may partially reverse the effects.
Topics: Animals; Anticonvulsants; Benzodiazepines; Colchicine; Male; Pentylenetetrazole; Rats; Rats, Wistar; Seizures
PubMed: 35239777
DOI: 10.1590/1414-431X2021e11771 -
Disease Models & Mechanisms Oct 2022Manipulating firing-rate neuronal homeostasis, which enables neurons to regulate their intrinsic excitability, offers an attractive opportunity to prevent seizures....
Manipulating firing-rate neuronal homeostasis, which enables neurons to regulate their intrinsic excitability, offers an attractive opportunity to prevent seizures. However, to date, no drug-based interventions have been reported that manipulate this type of neuronal homeostatic mechanism. Here, we used a combination of Drosophila and mouse, and, in the latter, both a pentylenetetrazole (PTZ)-induced seizure model and an electrically induced seizure model for refractory seizures to evaluate the anticonvulsant efficacy of a novel class of anticonvulsant compounds, based on 4-tert-butyl-benzaldehyde (4-TBB). The mode of action included increased expression of the firing rate homeostatic regulator Pumilio (PUM). Knockdown of pum expression, in Drosophila, blocked anticonvulsive effects of 4-TBB, while analysis of validated PUM targets in mouse brain revealed significant reductions following exposure to this compound. A structure-activity study identified the active parts of the molecule and, further, showed that the pyrazole analogue demonstrates highest efficacy, being active against both PTZ-induced and electrically induced seizures. This study provides a proof of principle that anticonvulsant effects can be achieved through regulation of firing rate neuronal homeostasis and identifies a possible chemical compound for future development.
Topics: Animals; Anticonvulsants; Benzaldehydes; Drosophila; Homeostasis; Mice; Neurons; Pentylenetetrazole; Pyrazoles; Seizures
PubMed: 36073607
DOI: 10.1242/dmm.049703 -
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 -
CNS Neuroscience & Therapeutics Aug 2020A large amount of literature has indicated that excitatory synaptic transmission plays a crucial role in epilepsy, but the detailed pathogenesis still needs to be...
INTRODUCTION
A large amount of literature has indicated that excitatory synaptic transmission plays a crucial role in epilepsy, but the detailed pathogenesis still needs to be clarified.
METHODS
In the present study, we used samples from patients with temporal lobe epilepsy, pentylenetetrazole-kindled mice, and Mg -free-induced epileptic cultured hippocampal neurons to detect the expression pattern of STK24. Then, the whole-cell recording was carried out after STK24 overexpression in the Mg -free-induced epileptic cultured hippocampal neurons. In addition, coimmunoprecipitation was performed to detect the association between endogenous STK24 and main subunits of NMDARs and AMPARs in the hippocampus of PTZ-kindled mice.
RESULTS
Here, we reported that STK24 was specifically located in epileptic neurons of human and pentylenetetrazole-kindled mice. Meanwhile, the expression of STK24 was significantly down-regulated in these samples which are mentioned above. Besides, we found that the amplitude of miniature excitatory postsynaptic currents was increased in STK24 overexpressed epileptic hippocampal cultured neurons, which means the excitatory synaptic transmission was changed. Moreover, the coimmunoprecipitation, which further supported the previous experiment, indicated an association between STK24 and the subunits of the NMDA receptor.
CONCLUSION
These findings expand our understanding of how STK24 involved in the excitatory synaptic transmission in epilepsy and lay a foundation for exploring the possibility of STK24 as a drug target.
Topics: Adolescent; Adult; Animals; Animals, Newborn; Cells, Cultured; Child; Epilepsy; Epilepsy, Temporal Lobe; Excitatory Postsynaptic Potentials; Female; Hippocampus; Humans; Male; Mice; Mice, Inbred C57BL; Neurons; Pentylenetetrazole; Protein Serine-Threonine Kinases; Young Adult
PubMed: 32436359
DOI: 10.1111/cns.13391 -
Biomedicine & Pharmacotherapy =... Jan 2024Chemical kindling is broadly used experimental model to investigate novel treatments on the process of epileptogenesis and coexisting behavioral comorbidities. The...
Chemical kindling is broadly used experimental model to investigate novel treatments on the process of epileptogenesis and coexisting behavioral comorbidities. The current study aimed to investigate the low dose perampanel (PER) (0.125 and 0.5 mg/kg) and pregabalin (PG) (15 mg/kg) as standalone treatments and in combination on kindling-induced seizure progression with concurrent electroencephalographic alterations. Mice were subjected to pentylenetetrazole (PTZ)-induced kindling followed by neurobehavioral assessment for anxiety-like activity and cognitive deficit through behavioral experiments. The monotherapy with PER at 0.5 mg/kg and PG at 15 mg/kg delayed the kindling process but PRP+PG yielded pronounced benefits and hindered the development of seizures of higher severity. PER+PG combination relieved the animals from anxiety-like behavior in various employed anxiogenic tests. Furthermore, the kindling-associated cognitive deficit was protected by PER+PG combination as increased alteration behavior, discrimination index and latencies to enter the dark zone were noted in y-maze, object recognition and passive avoidance tests, respectively while shorter escape latencies were noted in water maze. The brain samples of kindled mice had elevated malondialdehyde and reduced catalase, superoxide dismutase and glutathione peroxidase enzymes while treatment with PER and PG combination shielded the mice from heightened kindling-associated oxidative stress. Overall, the findings of the present study illustrate that concurrent administration of PER and PG effectively hindered the process of epileptogenesis by protecting neuronal excitability and brain oxidative stress. The results predict the dominance of PER and PG combination over monotherapy which might serve as an effective novel combination to combat drug resistance and behavioral disorders in epileptic patients.
Topics: Humans; Mice; Animals; Pentylenetetrazole; Pregabalin; Seizures; Epilepsy; Kindling, Neurologic; Oxidative Stress; Anticonvulsants
PubMed: 38101280
DOI: 10.1016/j.biopha.2023.115935