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Brain and Behavior Dec 2023Epilepsy is one of the most common neurological diseases, while over one third of adults with epilepsy still have inadequate seizure control. Although mutations in...
INTRODUCTION
Epilepsy is one of the most common neurological diseases, while over one third of adults with epilepsy still have inadequate seizure control. Although mutations in salt-inducible kinases (SIKs) have been identified in epileptic encephalopathy, it is not known whether blocking SIKs can prevent pentylenetetrazole (PTZ)-induced seizures.
METHODS
We first determined the time course of SIKs (including SIK 1, 2, and 3) in the hippocampus of PTZ treated mice. And then, we evaluated the effects of anti-epilepsy drug valproate acid (VPA) on the expression of SIK 1, 2, and 3 in the hippocampus of PTZ treated mice. Next, we investigated the effect of different dose of SIKs inhibitor YKL-06-061 on the epileptic seizures and neuronal activation by determining the expression of immediate early genes (IEGs) in the PTZ treated mice.
RESULTS
We found that PTZ selectively induced enhanced expression of SIK1 in the hippocampus, which was blocked by VPA treatment. Notably, YKL-06-061 decreased seizure activity and prevented neuronal overactivity, as indicated by the reduced expression of IEGs in the hippocampus and prefrontal cortex.
CONCLUSION
Our findings provide the first evidence that SIK1 affects gene regulation in neuronal hyperactivity, which is involved in seizure behavior. Targeting SIK1 through the development of selective inhibitors may lead to disease-modifying therapies that reduce epilepsy progression.
Topics: Mice; Animals; Pentylenetetrazole; Seizures; Epilepsy; Valproic Acid; Hippocampus; Anticonvulsants; Disease Models, Animal
PubMed: 37919236
DOI: 10.1002/brb3.3305 -
Molecules (Basel, Switzerland) Mar 2020The κ-opioid receptor has recently gained attention as a new molecular target in the treatment of many psychiatric and neurological disorders including epilepsy....
The κ-opioid receptor has recently gained attention as a new molecular target in the treatment of many psychiatric and neurological disorders including epilepsy. Salvinorin A is a potent plant-derived hallucinogen that acts as a highly selective κ-opioid receptor agonist. It has unique structure and pharmacological properties, but its influence on seizure susceptibility has not been studied so far. Therefore, the aim of the present study was to investigate the effect of salvinorin A on seizure thresholds in three acute seizure tests in mice. We also examined its effect on muscular strength and motor coordination. The obtained results showed that salvinorin A (0.1-10 mg/kg, i.p.) did not significantly affect the thresholds for the first myoclonic twitch, generalized clonic seizure, or forelimb tonus in the intravenous pentylenetetrazole seizure threshold test in mice. Likewise, it failed to affect the thresholds for tonic hindlimb extension and psychomotor seizures in the maximal electroshock- and 6 Hz-induced seizure threshold tests, respectively. Moreover, no changes in motor coordination (assessed in the chimney test) or muscular strength (assessed in the grip-strength test) were observed. This is a preliminary report only, and further studies are warranted to better characterize the effects of salvinorin A on seizure and epilepsy.
Topics: Animals; Diterpenes, Clerodane; Drug Evaluation, Preclinical; Electroshock; Injections, Intravenous; Male; Mice; Muscle, Skeletal; Pentylenetetrazole; Seizures
PubMed: 32155979
DOI: 10.3390/molecules25051204 -
International Journal of Biological... 2021Epilepsy is a chronic encephalopathy and one of the most common neurological disorders. Death-associated protein kinase 1 (DAPK1) expression has been shown to be...
Epilepsy is a chronic encephalopathy and one of the most common neurological disorders. Death-associated protein kinase 1 (DAPK1) expression has been shown to be upregulated in the brains of human epilepsy patients compared with those of normal subjects. However, little is known about the impact of DAPK1 on epileptic seizure conditions. In this study, we aim to clarify whether and how DAPK1 is regulated in epilepsy and whether targeting DAPK1 expression or activity has a protective effect against epilepsy using seizure animal models. Here, we found that cortical and hippocampal DAPK1 activity but not DAPK1 expression was increased immediately after convulsive pentylenetetrazol (PTZ) exposure in mice. However, DAPK1 overexpression was found after chronic low-dose PTZ insults during the kindling paradigm. The suppression of DAPK1 expression by genetic knockout significantly reduced PTZ-induced seizure phenotypes and the development of kindled seizures. Moreover, pharmacological inhibition of DAPK1 activity exerted rapid antiepileptic effects in both acute and chronic epilepsy mouse models. Mechanistically, PTZ stimulated the phosphorylation of NR2B through DAPK1 activation. Combined together, these results suggest that DAPK1 regulation is a novel mechanism for the control of both acute and chronic epilepsy and provide new therapeutic strategies for the treatment of human epilepsy.
Topics: Animals; Death-Associated Protein Kinases; Disease Models, Animal; Epilepsy; Hippocampus; Kindling, Neurologic; Male; Mice; Mice, Inbred C57BL; Pentylenetetrazole; Receptors, N-Methyl-D-Aspartate; Seizures
PubMed: 34239362
DOI: 10.7150/ijbs.59922 -
Molecules (Basel, Switzerland) Feb 2016New benztriazoles with a mercapto-triazole and other heterocycle substituents were synthesized and evaluated for their anticonvulsant activity and neurotoxicity by using...
New benztriazoles with a mercapto-triazole and other heterocycle substituents were synthesized and evaluated for their anticonvulsant activity and neurotoxicity by using the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ), and rotarod neurotoxicity (TOX) tests. Among the compounds studied, compound 2-((1H-1,2,4-triazol-3-yl)thio)-N-(6-((3-fluorobenzyl) oxy)benzo[d]thiazol-2-yl)acetamide (5i) and 2-((1H-1,2,4-triazol-3-yl)thio)-N-(6-((4-fluorobenzyl)oxy) benzo[d] thiazol-2-yl)acetmide (5j) were the most potent, with an ED50 value of 50.8 mg/kg and 54.8 mg/kg in the MES test and 76.0 mg/kg and 52.8 mg/kg in the scPTZ seizures test, respectively. They also showed lower neurotoxicity and, therefore a higher protective index. In particular, compound 5j showed high protective index (PI) values of 8.96 in the MES test and 9.30 in the scPTZ test, which were better than those of the standard drugs used as positive controls in this study.
Topics: Animals; Anticonvulsants; Benzothiazoles; Convulsants; Disease Models, Animal; Drug Design; Electroshock; Humans; Injections, Intraperitoneal; Mice; Molecular Structure; Pentylenetetrazole; Rotarod Performance Test; Seizures; Structure-Activity Relationship; Toxicity Tests, Acute
PubMed: 26938519
DOI: 10.3390/molecules21030164 -
Journal of Neurotrauma Jul 2013The present study tested a hypothesis that early identification of injury severity with quantitative magnetic resonance imaging (MRI) provides biomarkers for predicting...
The present study tested a hypothesis that early identification of injury severity with quantitative magnetic resonance imaging (MRI) provides biomarkers for predicting increased seizure susceptibility and epileptogenesis after traumatic brain injury (TBI). TBI was induced by lateral fluid percussion injury (FPI) in adult rats. Quantitative T2, T1ρ, and diffusion were assessed with MRI at 9 days, 23 days, or 2 months post-TBI in the perilesional cortex, thalamus, and hippocampus. Seizure susceptibility was assessed at 12 months after TBI using the pentylenetetrazol seizure-susceptibility test. At 9 and 23 days post-TBI, a change in T1ρ of the perilesional cortex showed the greatest predictive value for increased seizure susceptibility at 12 months post-TBI [area under the curve (AUC), 0.929 and 0.952, respectively; p<0.01]. At 2 months post-TBI, Dav in the thalamus was the best of the biomarkers analyzed (AUC, 0.988; p<0.05). The highest predictive value of all biomarkers was achieved by combining the measurement of Dav in the perilesional cortex and the thalamus at 2 months post-TBI (AUC, 1.000; p<0.01). Our results provide proof-of-concept evidence that clinically relevant MRI biomarkers predict increased seizure susceptibility after experimental TBI.
Topics: Animals; Area Under Curve; Biomarkers; Brain Injuries; Brain Mapping; Convulsants; Diffusion Tensor Imaging; Electroencephalography; Epilepsy; Magnetic Resonance Imaging; Male; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Seizures
PubMed: 23469770
DOI: 10.1089/neu.2012.2815 -
Drug Design, Development and Therapy 2016Phenytoin (PHT), valproic acid, and modern antiepileptic drugs (AEDs), eg, remacemide, loreclezole, and safinamide, are only effective within a maximum of 70%-80% of...
Phenytoin (PHT), valproic acid, and modern antiepileptic drugs (AEDs), eg, remacemide, loreclezole, and safinamide, are only effective within a maximum of 70%-80% of epileptic patients, and in many cases the clinical use of AEDs is restricted by their side effects. Therefore, a continuous need remains to discover innovative chemical entities for the development of active and safer AEDs. Ligands targeting central histamine H receptors (HRs) for epilepsy might be a promising therapeutic approach. To determine the potential of HRs ligands as new AEDs, we recently reported that no anticonvulsant effects were observed for the ()-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propanamide (). In continuation of our research, we asked whether anticonvulsant differences in activities will be observed for its -enantiomer, namely, ()-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propaneamide () and analogs thereof, in maximum electroshock (MES)-, pentylenetetrazole (PTZ)-, and strychnine (STR)-induced convulsion models in rats having PHT and valproic acid (VPA) as reference AEDs. Unlike the -enantiomer (), the results show that animals pretreated intraperitoneally (ip) with the -enantiomer (10 mg/kg) were moderately protected in MES and STR induced models, whereas proconvulsant effect was observed for the same ligand in PTZ-induced convulsion models. However, animals pretreated with intraperitoneal doses of 5, 10, or 15 mg/kg of structurally bulkier ()-enantiomer (), in which 3-piperidinopropan-1-ol in ligand was replaced by (4-(3-(piperidin-1-yl)propoxy)phenyl)methanol, and its ()-enantiomer () significantly and in a dose-dependent manner reduced convulsions or exhibited full protection in MES and PTZ convulsions model, respectively. Interestingly, the protective effects observed for the ()-enantiomer () in MES model were significantly greater than those of the standard HR inverse agonist/antagonist pitolisant, comparable with those observed for PHT, and reversed when rats were pretreated with the selective HR agonist -(α)-methyl-histamine. Comparisons of the observed antagonistic in vitro affinities among the ligands - revealed profound stereoselectivity at human HRs with varying preferences for this receptor subtype. Moreover, the in vivo anticonvulsant effects observed in this study for ligands - showed stereoselectivity in different convulsion models in male adult rats.
Topics: Animals; Anticonvulsants; Benzylamines; Dose-Response Relationship, Drug; Electroshock; Histamine H3 Antagonists; Humans; Ligands; Pentylenetetrazole; Phenytoin; Piperidines; Rats; Receptors, Histamine H3; Stereoisomerism; Valproic Acid
PubMed: 27853355
DOI: 10.2147/DDDT.S114147 -
Medical Science Monitor : International... Mar 2015Montelukast is an antiinflammatory drug with an antioxidant property. In this study, we aimed to reveal whether montelukast has a preventive effect against seizures and...
BACKGROUND
Montelukast is an antiinflammatory drug with an antioxidant property. In this study, we aimed to reveal whether montelukast has a preventive effect against seizures and post-seizure oxidative stress in pentylenetetrazol (PTZ)-induced seizures in rats.
MATERIAL AND METHODS
Of the 48 male Sprague-Dawley rats used in the study, 24 were assigned to EEG recordings (group A) and 24 were assigned to behavioral studies (group B). In group A, the electrodes were implanted on dura over the left frontal cortex for EEG recording. After 10 days, in group A, i.p. saline, 25, 50, or 100 mg/kg montelukast+35 mg/kg PTZ was administered to the rats. EEG was recorded and spike percentage was evaluated. In group B, i.p. saline, 25, 50, or 100 mg/kg montelukast+70 mg/kg PTZ was administered to the rats. Racine's Convulsion Scale (RCS) and onset times of first myoclonic jerk (FMJ) was used to evaluate the seizures. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels were determined in the brain tissue of animals.
RESULTS
Animals treated with 50 or 100 mg/kg montelukast had significantly lower RCS and significantly increased FMJ onset time compared to the saline-treated animals. Moreover, groups given 25, 50, or 100 mg/kg montelukast had significantly lower MDA and higher SOD levels compared to the saline-treated group. The differences were more pronounced in the 100 mg/kg montelukast-pretreated group (p<0.001).
CONCLUSIONS
Montelukast showed anticonvulsant action and led to amelioration of oxidative stress markers in PTZ-induced seizures in rats.
Topics: Acetates; Action Potentials; Animals; Brain; Cyclopropanes; Electroencephalography; Male; Malondialdehyde; Pentylenetetrazole; Quinolines; Rats, Sprague-Dawley; Seizures; Sulfides; Superoxide Dismutase; Time Factors
PubMed: 25803241
DOI: 10.12659/MSM.892932 -
Journal of Chemical Neuroanatomy Sep 2023Epilepsy is a common chronic brain disease. Despite the availability of various anti-seizure drugs, approximately 30 % of patients do not respond to treatment. Recent...
BACKGROUND AND OBJECTIVE
Epilepsy is a common chronic brain disease. Despite the availability of various anti-seizure drugs, approximately 30 % of patients do not respond to treatment. Recent research suggests that Kalirin plays a role in regulating neurological function. However, the pathogenesis of Kalirin in epileptic seizures remains unclear. This study aims to investigate the role and mechanism of Kalirin in epileptogenesis.
MATERIALS AND METHODS
An epileptic model was induced by intraperitoneal injection of pentylenetetrazole (PTZ). Endogenous Kalirin was inhibited using shRNA. The expression of Kalirin, Rac1, and Cdc42 in the hippocampal CA1 region was measured using Western blotting. Spine and synaptic structures were examined using Golgi staining and electron microscopy. Moreover, the necrotic neurons in CA1 were examined using HE staining.
RESULTS
The results indicated that the epileptic score increased in epileptic animals, while inhibition of Kalirin decreased the epileptic scores and increased the latent period of the first seizure attack. Inhibition of Kalirin attenuated the increases in Rac1 expression, dendritic spine density, and synaptic vesicle number in the CA1 region induced by PTZ. However, the increase in Cdc42 expression was not affected by the inhibition of Kalirin.
CONCLUSION
This study suggests that Kalirin is involved in the development of seizures by modulating the activity of Rac1, providing a novel anti-epileptic target.
Topics: Animals; CA1 Region, Hippocampal; Epilepsy; Neurons; Pentylenetetrazole; rac1 GTP-Binding Protein; Signal Transduction; Protein Serine-Threonine Kinases; Guanine Nucleotide Exchange Factors
PubMed: 37196826
DOI: 10.1016/j.jchemneu.2023.102289 -
Medecine Sciences : M/S Apr 2010Trisomy 21 was first described as a syndrome in the middle of the nineteenth century and associated to a chromosomic anomaly one hundred years later: the most salient... (Review)
Review
Trisomy 21 was first described as a syndrome in the middle of the nineteenth century and associated to a chromosomic anomaly one hundred years later: the most salient feature of this syndrome is a mental retardation of variable intensity. Molecular mapping and DNA sequencing have allowed identifying the gene content of chromosome 21. Molecular quantitative analyses indicated that trisomy is inducing an overexpression for a large part of the triplicated genes and deregulates also pathways involving non HSA21 genes. Together with the physiological description of murine models overexpressing orthologous genes, these data have allowed to elaborate hypotheses on the cause of cognitive impairment. From these hypotheses and using murine models it is now possible to assess the efficiency of various therapeutic strategies. This paper reviews these new perspectives starting from the strategies targeting the level of HSA21 RNAs or HSA21 proteins; then it describes methods targeting activities either of proteins involved in cell cycle pathways or of proteins controlling the synaptic plasticity. It is promising that strategies targeting specific genes or specific pathways are already giving positive results.
Topics: Animals; Catechin; Chromosomes, Human, Pair 21; Disease Models, Animal; Down Syndrome; Droxidopa; Drug Delivery Systems; Fluoxetine; Forecasting; Gene Expression Regulation; Genetic Association Studies; Genetic Therapy; Hedgehog Proteins; Humans; Memantine; Mice; Mice, Transgenic; Models, Genetic; Neuronal Plasticity; Neurotransmitter Agents; Pentylenetetrazole; Phenotype; Signal Transduction
PubMed: 20412741
DOI: 10.1051/medsci/2010264371 -
Pharmacological Reports : PR 2006The aim of this study was to model fluoxetine-induced increase in anxiety appearing in the initial phase of the treatment with this antidepressant drug. The effects of...
The aim of this study was to model fluoxetine-induced increase in anxiety appearing in the initial phase of the treatment with this antidepressant drug. The effects of acute administration of fluoxetine given alone and co-administered with a subthreshold dose of pentetrazole (PTZ), a proconvulsant agent with well recognized anxiogenic properties, were examined in the open field test of neophobia in rats. It was found that a single injection of fluoxetine at the dose of 5 and 10 mg/kg did not change motor and exploratory behavior of rats. Furthermore, fluoxetine (10.0 mg/kg) co-administered with a subthreshold dose of PTZ (10.0 mg/kg) had a strong and selective inhibitory influence on rat exploratory behavior. Pharmacokinetic study did not show any changes in brain concentration of PTZ in fluoxetine-pretreated animals. The central mechanism of the reported effects might involve stimulation of 5-HT2C receptors by fluoxetine in animals with PTZ-induced decrease in the threshold for emotional arousal. The present data describe a new animal model to study the central action of antidepressants reflecting dysphoric-like effects observed in the initial phase of the treatment.
Topics: Animals; Antidepressive Agents; Anxiety; Behavior, Animal; Dose-Response Relationship, Drug; Fluoxetine; Male; Models, Animal; Motor Activity; Pentylenetetrazole; Rats; Rats, Wistar
PubMed: 16531638
DOI: No ID Found