-
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 -
Biomedicine & Pharmacotherapy =... Sep 2023Albizia adianthifolia (Schumach.) (Fabaceae) is a medicinal herb used for the treatment of epilepsy and memory impairment. This study aims to investigate the...
Ameliorative effects of Albizia adianthifolia aqueous extract against pentylenetetrazole-induced epilepsy and associated memory loss in mice: Role of GABAergic, antioxidant defense and anti-inflammatory systems.
Albizia adianthifolia (Schumach.) (Fabaceae) is a medicinal herb used for the treatment of epilepsy and memory impairment. This study aims to investigate the anticonvulsant effects of Albizia adianthifolia aqueous extract against pentylenetetrazole (PTZ)-induced spontaneous convulsions in mice; and determine whether the extract could mitigate memory impairment, oxidative/nitrergic stress, GABA depletion and neuroinflammation. Ultra-high performance liquid chromatography/mass spectrometry analysis was done to identify active compounds from the extract. Mice were injected with PTZ once every 48 h until kindling was developed. Animals received distilled water for the normal group and negative control groups, doses of extract (40, 80, or 160 mg/kg) for the test groups and sodium valproate (300 mg/kg) for the positive control group. Memory was measured using Y maze, novel object recognition (NOR) and open field paradigms, while the oxidative/nitrosative stresses (MDA, GSH, CAT, SOD and NO), GABAergic transmission (GABA, GABA-T and GAD) and neuro-inflammation (TNF-α, IFN-γ, IL- 1β, and IL-6) were determined. Brain photomicrograph was also studied. Apigenin, murrayanine and safranal were identified in the extract. The extract (80-160 mg/kg) significantly protected mice against seizures and mortality induced by PTZ. The extract significantly increased the spontaneous alternation and the discrimination index in the Y maze and NOR tests, respectively. PTZ kindling induced oxidative/nitrosative stress, GABA depletion, neuroinflammation and neuronal cells death was strongly reversed by the extract. The results suggest that the anticonvulsant activity of Albizia adianthifolia extract is accompanied by its anti-amnesic property, and may be supported by the amelioration of oxidative stress, GABAergic transmission and neuroinflammation.
Topics: Mice; Animals; Pentylenetetrazole; Antioxidants; Anticonvulsants; Albizzia; Neuroinflammatory Diseases; Plant Extracts; Epilepsy; Seizures; Kindling, Neurologic; Memory Disorders; Oxidative Stress; Amnesia; Water; gamma-Aminobutyric Acid; Anti-Inflammatory Agents
PubMed: 37392651
DOI: 10.1016/j.biopha.2023.115093 -
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 -
Expert Reviews in Molecular Medicine Mar 2016miR-124, a brain-specific microRNA, was originally considered as a key regulator in neuronal differentiation and the development of the nervous system. Here we showed... (Review)
Review
miR-124, a brain-specific microRNA, was originally considered as a key regulator in neuronal differentiation and the development of the nervous system. Here we showed that miR-124 expression was suppressed in patients with epilepsy and rats after drug induced-seizures. Intrahippocampal administration of a miR-124 duplex led to alleviated seizure severity and prolonged onset latency in two rat models (pentylenetetrazole- and pilocarpine-induced seizures), while miR-124 inhibitor led to shortened onset latency in pilocarpine-induced seizure rat models. Moreover, the result of local field potentials (LFPs) records further demonstrated miR-124 may have anti-epilepsy function. Inhibition of neuronal firing by miR-124 was associated with the suppression of mEPSC, AMPAR- and NMDAR-mediated currents, which were accompanied by decreased surface expression of NMDAR. In addition, miR-124 injection resulted in decreased activity and expression of cAMP-response element-binding protein1 (CREB1). a key regulator in epileptogenesis. A dual-luciferase reporter assay was used to confirm that miR-124 targeted directly the 3'UTR of CREB1 gene and repressed the CREB1 expression in HEK293T cells. Immunoprecipitation studies confirmed that the CREB1 antibody effectively precipitated CREB1 and NMDAR1 but not GLUR1 from rat brain hippocampus. These results revealed a previously unknown function of miR-124 in neuronal excitability and provided a new insight into molecular mechanisms underlying epilepsy.
Topics: Action Potentials; Animals; Cyclic AMP Response Element-Binding Protein; Epilepsy; Gene Expression Regulation; HEK293 Cells; Hippocampus; Humans; MicroRNAs; Neurons; Pentylenetetrazole; Pilocarpine; Rats; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Signal Transduction
PubMed: 26996991
DOI: 10.1017/erm.2016.3 -
Biomedicine & Pharmacotherapy =... Dec 2023A series of 3-aminopyrrolidine-2,5-dione derivatives was synthesized and tested for anticonvulsant activity. Succinimide derivatives were obtained from a simple...
A series of 3-aminopyrrolidine-2,5-dione derivatives was synthesized and tested for anticonvulsant activity. Succinimide derivatives were obtained from a simple solvent-based reaction and a mechanochemical aza-Michael reaction of maleimide or its N-substituted derivatives with selected amines. The structure of the compounds was confirmed by spectroscopic methods (NMR, FT-IR, HPLC, ESI-MS, EA and XRD for four compounds). The cytotoxic activity of the succinimide derivatives was evaluated using HepG2 cells for hepatocytotoxicity and SH-SY5Y cells for neurocytotoxicity. None of the studied compounds showed hepatocytotoxicity and two showed neurocytotoxicity. Initial anticonvulsant screening was performed in mice using the psychomotor seizure test (6 Hz, 32 mA). The selected compounds were evaluated in the following acute models of epilepsy: the maximal electroshock test, psychomotor seizure test (6 Hz, 44 mA), subcutaneous pentylenetetrazole seizure test, and acute neurotoxicity (rotarod test). The most active compound 3-((4-chlorophenyl)amino)pyrrolidine-2,5-dione revealed antiseizure activity in all seizure models (including pharmacoresistant seizures) and showed better median effective doses (ED) and protective index values than the reference compound, ethosuximide. Furthermore, 3-(benzylamino)pyrrolidine-2,5-dione and 3-(phenylamino)pyrrolidine-2,5-dione exhibited antiseizure activity in the 6 Hz and MES tests, and 3-(butylamino)-1-phenylpyrrolidine-2,5-dione and 3-(benzylamino)-1-phenylpyrrolidine-2,5-dione exhibited antiseizure activity in the 6 Hz test. All active compounds demonstrated low in vivo neurotoxicity in the rotarod test and yielded favourable protective indices.
Topics: Humans; Mice; Animals; Anticonvulsants; Spectroscopy, Fourier Transform Infrared; Neuroblastoma; Seizures; Ethosuximide; Pentylenetetrazole; Structure-Activity Relationship; Molecular Structure
PubMed: 37879208
DOI: 10.1016/j.biopha.2023.115749 -
International Journal of Molecular... Sep 2023Epilepsy is a chronic condition characterized by recurrent spontaneous seizures. The interaction between astrocytes and neurons has been suggested to play a role in the...
Epilepsy is a chronic condition characterized by recurrent spontaneous seizures. The interaction between astrocytes and neurons has been suggested to play a role in the abnormal neuronal activity observed in epilepsy. However, the exact way astrocytes influence neuronal activity in the epileptogenic brain remains unclear. Here, using the PTZ-induced kindling mouse model, we evaluated the interaction between astrocyte and synaptic function by measuring astrocytic Ca activity, neuronal excitability, and the excitatory/inhibitory balance in the hippocampus. Compared to control mice, hippocampal slices from PTZ-kindled mice displayed an increase in glial fibrillary acidic protein (GFAP) levels and an abnormal pattern of intracellular Ca-oscillations, characterized by an increased frequency of prolonged spontaneous transients. PTZ-kindled hippocampal slices also showed an increase in the E/I ratio towards excitation, likely resulting from an augmented release probability of excitatory inputs without affecting inhibitory synapses. Notably, the alterations in the release probability seen in PTZ-kindled slices can be recovered by reducing astrocyte hyperactivity with the reversible toxin fluorocitrate. This suggests that astroglial hyper-reactivity enhances excitatory synaptic transmission, thereby impacting the E/I balance in the hippocampus. Altogether, our findings support the notion that abnormal astrocyte-neuron interactions are pivotal mechanisms in epileptogenesis.
Topics: Mice; Animals; Pentylenetetrazole; Astrocytes; Epilepsy; Kindling, Neurologic; Seizures; Hippocampus
PubMed: 37833953
DOI: 10.3390/ijms241914506 -
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 -
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 -
International Immunopharmacology Mar 2024Epilepsy is a severe neurological disorder associated with substantial morbidity and mortality. Vanillin (Van) is a natural phenolic aldehyde with beneficial...
Ameliorative effects of vanillin against pentylenetetrazole-induced epilepsy and associated memory loss in mice: The role of Nrf2/HO-1/NQO1 and HMGB1/RAGE/TLR4/NFκB pathways.
BACKGROUND
Epilepsy is a severe neurological disorder associated with substantial morbidity and mortality. Vanillin (Van) is a natural phenolic aldehyde with beneficial pharmacological properties. This study investigated the neuroprotective effects of Van in epilepsy and elucidated its mechanism of action.
METHODS
Swiss albino mice were divided into the following five groups: "normal group", 0.9 % saline; "pentylenetetrazole (PTZ) group", intraperitoneal administration of 35 mg/kg PTZ on alternate days up to 42 days; and "PTZ + Van 20", "PTZ + Van 40", and "PTZ + sodium valproate (Val)" groups received PTZ injections in conjunction withVan 20 mg, Van 40 mg/kg, and Val 300 mg/kg, respectively. Behavioural tests and hippocampal histopathological analysis were performed in all groups. The Nrf2/HO-1/NQO1 and HMGB1/RAGE/TLR4/NFκB pathways, oxidative stress, neuro-inflammation, and apoptotic markers were analysed. Furthermore, brain acetylcholinesterase (AChE) activity and levels of dopamine (DA), gamma-aminobutyric acid GABA, and serotonin 5-HT were assessed.
RESULTS
Van prolonged seizure manifestations and improved electroencephalogram (EEG)criteriain conjunction with 100 mg/kg PTZ once daily. Van administration increased Nrf2/HO-1/NQO1 levels, with subsequent attenuation of malondialdehyde (MDA) and nitric oxide (NO) levels with elevated glutathione (GSH) levels and intensified superoxide dismutase (SOD) and catalase activities. Van reduced the gene and protein expression of HMGB1/RAGE/TLR4/NFκB and decreased the levels of inflammatory and apoptotic markers. In addition, Van reduced AChE activity, and elevated glial fibrillary acidic proteins (GFAP) increased neurotransmitter and brain-derived neurotrophic factors (BDNF).
CONCLUSION
By increasing Nrf2/HO-1/NQO1 levels and downregulating the HMGB1/RAGE/TLR4/ NFκB pathway, Van offered protection in PTZ-kindled mice with subsequent attenuation in lipid peroxidation, upregulation in antioxidant enzyme activities, and reduction in inflammation and apoptosis.
Topics: Mice; Animals; Pentylenetetrazole; NF-E2-Related Factor 2; Toll-Like Receptor 4; HMGB1 Protein; Acetylcholinesterase; Epilepsy; Antioxidants; Oxidative Stress; Memory Disorders; Glutathione; Inflammation; Benzaldehydes
PubMed: 38335655
DOI: 10.1016/j.intimp.2024.111657 -
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