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1.
Molecules ; 29(11)2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38893448

RESUMO

Epilepsy is a prevalent neurological disorder characterized by recurrent seizures. Validamycin A (VA) is an antibiotic fungicide that inhibits trehalase activity and is widely used for crop protection in agriculture. In this study, we identified a novel function of VA as a potential anti-seizure medication in a zebrafish epilepsy model. Electroencephalogram (EEG) analysis demonstrated that VA reduced pentylenetetrazol (PTZ)-induced seizures in the brains of larval and adult zebrafish. Moreover, VA reduced PTZ-induced irregular movement in a behavioral assessment of adult zebrafish. The developmental toxicity test showed no observable anatomical alteration when the zebrafish larvae were treated with VA up to 10 µM within the effective range. The median lethal dose of VA in adult zebrafish was > 14,000 mg/kg. These results imply that VA does not demonstrate observable toxicity in zebrafish at concentrations effective for generating anti-seizure activity in the EEG and alleviating abnormal behavior in the PTZ-induced epileptic model. Furthermore, the effectiveness of VA was comparable to that of valproic acid. These results indicate that VA may have a potentially safer anti-seizure profile than valproic acid, thus offering promising prospects for its application in agriculture and medicine.


Assuntos
Anticonvulsivantes , Modelos Animais de Doenças , Epilepsia , Pentilenotetrazol , Peixe-Zebra , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Pentilenotetrazol/efeitos adversos , Epilepsia/tratamento farmacológico , Epilepsia/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamente , Eletroencefalografia , Ácido Valproico/farmacologia , Larva/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Inositol/análogos & derivados
2.
Sci Rep ; 14(1): 14239, 2024 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-38902338

RESUMO

Glutamatergic neurotransmission and oxidative stress are involved in the pathophysiology of seizures. Some anticonvulsants exert their effects through modulation of these pathways. Trigonelline (TRG) has been shown to possess various pharmacological effects like neuroprotection. Therefore, this study was performed to determine TRG's anticonvulsant effects, focusing on its potential effects on N-methyl-D-aspartate (NMDA) receptors, a type of glutamate receptor, and oxidative stress state in the prefrontal cortex (PFC) in PTZ-induced seizure in mice. Seventy-two male mice were randomly divided into nine groups. The groups included mice that received normal saline, TRG at doses of 10, 50, and 100 mg/kg, diazepam, NMDA (an agonist), ketamine (an antagonist), the effective dose of TRG with NMDA, as well as sub-effective dose of TRG with ketamine, respectively. All agents were administrated intraperitoneally 60 min before induction of seizures by PTZ. Latency to seizure, total antioxidant capacity (TAC), and malondialdehyde (MDA) levels in serum and PFC were measured. Furthermore, the gene expression of NR2A and NR2B, subunits of NMDA receptors, was measured in the PFC. TRG administration increased the latency to seizure onset and enhanced TAC while reducing MDA levels in both the PFC and serum. TRG also decreased the gene expression of NR2B in the PFC. Unexpectedly, the findings revealed that the concurrent administration of ketamine amplified, whereas NMDA mitigated, the impact of TRG on latency to seizure. Furthermore, NMDA diminished the positive effects of TRG on antioxidant capacity and oxidative stress, while ketamine amplified these beneficial effects, indicating a complex interaction between TRG and NMDA receptor modulation. In the gene expression of NMDA receptors, results showed that ketamine significantly decreased the gene expression of NR2B when co-administrated with a sub-effective dose of TRG. It was found that, at least partially, the anticonvulsant effect of TRG in PTZ-induced seizures in male mice was mediated by the attenuation of glutamatergic neurotransmission as well as the reduction of oxidative stress.


Assuntos
Alcaloides , Anticonvulsivantes , Estresse Oxidativo , Receptores de N-Metil-D-Aspartato , Convulsões , Animais , Receptores de N-Metil-D-Aspartato/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Anticonvulsivantes/farmacologia , Camundongos , Masculino , Alcaloides/farmacologia , Convulsões/tratamento farmacológico , Convulsões/metabolismo , Convulsões/induzido quimicamente , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Malondialdeído/metabolismo , Ketamina/farmacologia , Pentilenotetrazol/toxicidade , Antioxidantes/farmacologia
3.
Molecules ; 29(9)2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38731442

RESUMO

Two series, "a" and "b", each consisting of nine chemical compounds, with 2,3-disubstituted quinazolin-4(3H)-one scaffold, were synthesized and evaluated for their anticonvulsant activity. They were investigated as dual potential positive allosteric modulators of the GABAA receptor at the benzodiazepine binding site and inhibitors of carbonic anhydrase II. Quinazolin-4(3H)-one derivatives were evaluated in vivo (D1-3 = 50, 100, 150 mg/kg, administered intraperitoneally) using the pentylenetetrazole (PTZ)-induced seizure model in mice, with phenobarbital and diazepam, as reference anticonvulsant agents. The in silico studies suggested the compounds act as anticonvulsants by binding on the allosteric site of GABAA receptor and not by inhibiting the carbonic anhydrase II, because the ligands-carbonic anhydrase II predicted complexes were unstable in the molecular dynamics simulations. The mechanism targeting GABAA receptor was confirmed through the in vivo flumazenil antagonism assay. The pentylenetetrazole experimental anticonvulsant model indicated that the tested compounds, 1a-9a and 1b-9b, present a potential anticonvulsant activity. The evaluation, considering the percentage of protection against PTZ, latency until the onset of the first seizure, and reduction in the number of seizures, revealed more favorable results for the "b" series, particularly for compound 8b.


Assuntos
Anticonvulsivantes , Pentilenotetrazol , Receptores de GABA-A , Convulsões , Anticonvulsivantes/farmacologia , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Animais , Camundongos , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamente , Receptores de GABA-A/metabolismo , Quinazolinonas/farmacologia , Quinazolinonas/química , Quinazolinonas/síntese química , Simulação de Acoplamento Molecular , Masculino , Relação Estrutura-Atividade , Simulação de Dinâmica Molecular , Simulação por Computador , Modelos Animais de Doenças , Estrutura Molecular , Sítio Alostérico
4.
Brain Res ; 1838: 148994, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38729331

RESUMO

PTZ kindling induces oxidative stress, neuronal cell degeneration, and neurobehavioral alterations in rodents that mimic neuropsychiatric comorbidities of epilepsy, which could be initiated or aggravated by some antiepileptic drugs. Here, we investigated the effects of the methanol extract of Ficus platyphylla (FP) on severity scores for seizures, neuronal cell degeneration, and neurobehavioral alterations in rats kindled with pentylenetetrazole (PTZ) and probed the involvement of oxidative stress in these ameliorative effects of FP. FP (50 and 100 mg/kg, p.o.) ameliorated seizure severity, neuronal cell degeneration, depressive behaviors, cognitive dysfunctions, and oxidative stress in rats kindled with PTZ (42.5 mg/kg, i.p.). The findings from this study give additional insights into the potential values of FP in the treatment of persistent epilepsy and major neuropsychiatric comorbidities via modulation of oxidative stress.


Assuntos
Anticonvulsivantes , Ficus , Excitação Neurológica , Estresse Oxidativo , Pentilenotetrazol , Extratos Vegetais , Convulsões , Animais , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Excitação Neurológica/efeitos dos fármacos , Masculino , Convulsões/tratamento farmacológico , Convulsões/metabolismo , Convulsões/induzido quimicamente , Ratos , Anticonvulsivantes/farmacologia , Ratos Wistar , Modelos Animais de Doenças , Comportamento Animal/efeitos dos fármacos , Epilepsia/tratamento farmacológico , Epilepsia/induzido quimicamente
5.
Biomed Pharmacother ; 175: 116746, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38739991

RESUMO

Brain apoptosis is one of the main causes of epileptogenesis. The antiapoptotic effect and potential mechanism of Q808, an innovative anticonvulsant chemical, have never been reported. In this study, the seizure stage and latency to reach stage 2 of pentylenetetrazol (PTZ) seizure rat model treated with Q808 were investigated. The morphological change and neuronal apoptosis in the hippocampus were detected by hematoxylin and eosin (HE) and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining, respectively. The hippocampal transcriptomic changes were observed using RNA sequencing (RNA-seq). The expression levels of hub genes were verified by quantitative reverse-transcription PCR (qRT-PCR). Results revealed that Q808 could allay the seizure score and prolong the stage 2 latency in seizure rats. The morphological changes of neurons and the number of apoptotic cells in the DG area were diminished by Q808 treatment. RNA-seq analysis revealed eight hub genes, including Map2k3, Nfs1, Chchd4, Hdac6, Siglec5, Slc35d3, Entpd1, and LOC103690108, and nine hub pathways among the control, PTZ, and Q808 groups. Hub gene Nfs1 was involved in the hub pathway sulfur relay system, and Map2k3 was involved in the eight remaining hub pathways, including Amyotrophic lateral sclerosis, Cellular senescence, Fc epsilon RI signaling pathway, GnRH signaling pathway, Influenza A, Rap1 signaling pathway, TNF signaling pathway, and Toll-like receptor signaling pathway. qRT-PCR confirmed that the mRNA levels of these hub genes were consistent with the RNA-seq results. Our findings might contribute to further studies exploring the new apoptosis mechanism and actions of Q808.


Assuntos
Anticonvulsivantes , Apoptose , Epilepsia , Perfilação da Expressão Gênica , Hipocampo , Pentilenotetrazol , Ratos Sprague-Dawley , Transcriptoma , Animais , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Apoptose/efeitos dos fármacos , Anticonvulsivantes/farmacologia , Masculino , Transcriptoma/efeitos dos fármacos , Epilepsia/tratamento farmacológico , Epilepsia/induzido quimicamente , Epilepsia/genética , Perfilação da Expressão Gênica/métodos , Ratos , Modelos Animais de Doenças , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Convulsões/induzido quimicamente , Convulsões/genética , Convulsões/tratamento farmacológico
6.
Int Immunopharmacol ; 134: 112247, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38759374

RESUMO

BACKGROUND: Epilepsy is a chronic disabling disease poorly controlled by available antiseizure medications. Oridonin, a bioactive alkaloid with anti-inflammatory properties and neuroprotective effects, can inhibit the increased excitability of neurons caused by glutamate accumulation at the cellular level. However, whether oridonin affects neuronal excitability and whether it has antiepileptic potential has not been reported in animal models or clinical studies. METHOD: Pentylenetetrazol was injected into mice to create a model of chronic epilepsy. Seizure severity was assessed using the Racine scale, and the duration and latency of seizures were observed. Abnormal neuronal discharge was detected using electroencephalography, and neuronal excitability was assessed using calcium imaging. Damage to hippocampal neurons was evaluated using Hematoxylin-Eosin and Nissl staining. The expression of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome and other pyroptosis-related proteins was determined using western blotting and immunofluorescence. A neuronal pyroptosis model was established using the supernatant of BV2 cells treated with lipopolysaccharide and adenosine triphosphate to stimulate hippocampal neurons. RESULTS: Oridonin (1 and 5 mg/kg) reduced neuronal damage, increased the latency of seizures, and shortened the duration of fully kindled seizures in chronic epilepsy model mice. Oridonin decreased abnormal discharge during epileptic episodes and suppressed increased neuronal excitability. In vitro experiments showed that oridonin alleviated pyroptosis in hippocampal HT22 neurons. CONCLUSION: Oridonin exerts neuroprotective effects by inhibiting pyroptosis through the NLRP3/caspase-1 pathway in chronic epilepsy model mice. It also reduces pyroptosis in hippocampal neurons in vitro, suggesting its potential as a therapy for epilepsy.


Assuntos
Anticonvulsivantes , Modelos Animais de Doenças , Diterpenos do Tipo Caurano , Epilepsia , Hipocampo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Neurônios , Fármacos Neuroprotetores , Piroptose , Animais , Diterpenos do Tipo Caurano/farmacologia , Diterpenos do Tipo Caurano/uso terapêutico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Epilepsia/tratamento farmacológico , Piroptose/efeitos dos fármacos , Camundongos , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Masculino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/metabolismo , Pentilenotetrazol , Camundongos Endogâmicos C57BL , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Linhagem Celular , Convulsões/tratamento farmacológico
7.
Biomed Pharmacother ; 175: 116791, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38776672

RESUMO

Epilepsy is an abiding condition associated with recurrent seizure attacks along with associated neurological and psychological emanation owing to disparity of excitatory and inhibitory neurotransmission. The current study encompasses the assessment of the Nyctanthes arbor-tristis L. methanolic extract (Na.Cr) in the management of convulsive state and concomitant conditions owing to epilepsy. The latency of seizure incidence was assessed using pentylenetetrazol (PTZ) kindling models along with EEG in Na.Cr pretreated mice, trailed by behavior assessment (anxiety and memory), biochemical assay, histopathological alterations, chemical profiling through GCMS, and molecular docking. The chronic assessment of PTZ-induced kindled mice depicted salvation in a dose-related pattern and outcomes were noticeable with extract at 400 mg/kg. The extract at 400 mg/kg defends the progress of kindling seizures and associated EEG. Co-morbid conditions in mice emanating owing to epileptic outbreaks were validated by behavioral testing and the outcome depicted a noticeable defense related to anxiety (P<0.001) and cognitive deficit (P<0.001) at 400 mg/kg. The isolated brains were evaluated for oxidative stress and the outcome demonstrated a noticeable effect in a dose-dependent pattern. Treatment with Na.Cr. also preserved the brain from PTZ induced neuronal damage as indicated by histopathological analysis. Furthermore, the GCMS outcome predicted 28 compounds abundantly found in the plant. The results congregated in the current experiments deliver valued evidence about the defensive response apportioned by Na.Cr which might be due to decline in oxidative stress, AChE level, and GABAergic modulation. These activities may contribute to fundamental pharmacology and elucidate some mechanisms behind the activities of Nyctanthes arbor-tristis.


Assuntos
Anticonvulsivantes , Eletroencefalografia , Excitação Neurológica , Pentilenotetrazol , Extratos Vegetais , Convulsões , Animais , Excitação Neurológica/efeitos dos fármacos , Camundongos , Extratos Vegetais/farmacologia , Masculino , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/fisiopatologia , Anticonvulsivantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Simulação de Acoplamento Molecular , Simulação por Computador , Modelos Animais de Doenças , Estresse Oxidativo/efeitos dos fármacos , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico
8.
eNeuro ; 11(5)2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38749701

RESUMO

The voltage-gated calcium channel subunit α2δ-2 controls calcium-dependent signaling in neurons, and loss of this subunit causes epilepsy in both mice and humans. To determine whether mice without α2δ-2 demonstrate hippocampal activation or histopathological changes associated with seizure activity, we measured expression of the activity-dependent gene c-fos and various histopathological correlates of temporal lobe epilepsy (TLE) in hippocampal tissue from wild-type (WT) and α2δ-2 knock-out (CACNA2D2 KO) mice using immunohistochemical staining and confocal microscopy. Both genotypes demonstrated similarly sparse c-fos and ΔFosB expressions within the hippocampal dentate granule cell layer (GCL) at baseline, consistent with no difference in basal activity of granule cells between genotypes. Surprisingly, when mice were assayed 1 h after handling-associated convulsions, KO mice had fewer c-fos-positive cells but dramatically increased ΔFosB expression in the dentate gyrus compared with WT mice. After administration of a subthreshold pentylenetetrazol dose, however, KO mice dentate had significantly more c-fos expression compared with WT mice. Other histopathological markers of TLE in these mice, including markers of neurogenesis, glial activation, and mossy fiber sprouting, were similar between WT and KO mice, apart from a small but statistically significant increase in hilar mossy cell density, opposite to what is typically found in mice with TLE. This suggests that the differences in seizure-associated dentate gyrus function in the absence of α2δ-2 protein are likely due to altered functional properties of the network without associated structural changes in the hippocampus at the typical age of seizure onset.


Assuntos
Hipocampo , Camundongos Knockout , Proteínas Proto-Oncogênicas c-fos , Convulsões , Animais , Convulsões/metabolismo , Convulsões/genética , Convulsões/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Masculino , Canais de Cálcio/metabolismo , Canais de Cálcio/genética , Camundongos Endogâmicos C57BL , Pentilenotetrazol , Camundongos , Modelos Animais de Doenças , Neurônios/metabolismo , Neurônios/patologia , Convulsivantes/toxicidade
9.
Bioorg Chem ; 148: 107435, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38762999

RESUMO

BACKGROUND: Pyridine and its derivatives play a vital role in medicinal chemistry, serving as key scaffolds for drugs. The ability to bind to biological targets makes pyridine compounds significant, sparking interest in creating new pyridine-based drugs. Thus, the purpose of the research is to synthesize new thioalkyl derivatives of pyridine, predict their biological spectrum, study their psychotropic properties, and based on these findings, perform structure-activity relationships to assess pharmacophore functional groups. METHODS: Classical organic methods were employed for synthesizing new thioalkyl derivatives of pyridine, with a multifaceted pharmacological profiles. Various software packages and methods were employed to evaluate the biological spectrum of the newly synthesized compounds. For the evaluation of neurotropic activity of new synthesized compounds, some biological methods were used according to indicators characterizing anticonvulsant, sedative and antianxiety activity as well as side effects. RESULTS: Effective synthetic methods for 6-amino-4-phenyl-2-thio-2H-thiopyran-5-carboxylic acid ethyl ester, 2-amino substituted thiopyridine derivatives and 6-cycloamino-2-thioalkyl-4-phenylnicotinate derivatives were obtained in high yield. Predicted biological spectra and pharmacokinetic data indicated high gastrointestinal absorption and low blood-brain barrier passage for most compounds and demonstrated potential various biological effects, particularly psychotropic properties. Studied compounds demonstrated high anticonvulsant activity through antagonism with pentylenetetrazole. They exhibited low toxicity without inducing muscle relaxation in the studied doses. In psychotropic studies, the compounds displayed activating, sedative, and anxiolytic effects. Notably, the 6-amino-2-thioalkyl-4-phenylnicotinate derivatives demonstrated significant anxiolytic activity (about four times more compared to diazepam). They also exhibited pronounced sedative effects. Ethyl 2-({2-[(diphenylmethyl)amino]-2-oxoethyl}thio)-4-phenyl-6-pyrrolidin-1-ylnicotinate exhibited anxiolytic activity even two times greater than diazepam. Moreover, all studied compounds showed statistically significant antidepressant effects. Noteworthy ethyl 2-({2-oxo-2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}thio)-4-phenyl-6-pyrrolidin-1-ylnicotinate showcasing its unique psychotropic effect. CONCLUSIONS: The selected compounds demonstrate anticonvulsant properties, activating behavior, and anxiolytic effects, while simultaneously exhibiting antidepressant effects and these compounds as promising candidates for further exploration in the development of therapeutics with a broad spectrum of neuropsychiatric applications.


Assuntos
Ansiolíticos , Anticonvulsivantes , Piridinas , Relação Estrutura-Atividade , Piridinas/química , Piridinas/farmacologia , Piridinas/síntese química , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacologia , Anticonvulsivantes/química , Camundongos , Ansiolíticos/farmacologia , Ansiolíticos/síntese química , Ansiolíticos/química , Estrutura Molecular , Relação Dose-Resposta a Droga , Masculino , Convulsões/tratamento farmacológico , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/síntese química , Hipnóticos e Sedativos/química , Pentilenotetrazol
10.
Neurologia (Engl Ed) ; 39(4): 329-339, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38616060

RESUMO

INTRODUCTION: In the present study, anticonvulsant effects of aqueous extract (AE), hydro-alcoholic crude extract (HE), and its fractions (F-CHCl3, F-EtOAc, F-MeOH) of Paeonia daurica subsp. macrophylla (P. daurica ssp. macrophylla) root examined by using a pentylenetetrazol-induced model (PTZ) on mice. METHODS: HE and its fractions as well as AE, in concentrations of (100, 200 and 400mg/kg), valproate (Val) (100 and 200mg/kg), and saline (negative control) (10mg/kg) were injected intraperitoneally (i.p.) 30min before PTZ (80mg/kg, i.p.). The time taken before the onset of myoclonic convulsions (MC), MC duration, time taken before the onset of generalized tonic-clonic seizures (GTCS), the duration of GTCS, and the percentage of GTCS and mortality protection recorded. The plant's anticonvulsant mechanisms were assessed using flumazenil (5mg/kg, i.p.) before AE (100, 200, and 400mg/kg, i.p.) injection. GraphPad Prism software was used to compare the differences between various treatment groups with one-way analysis of variance (ANOVA) followed by Tukey-Krammer multiple comparison tests. RESULTS: All the plant samples except F-EtOAc significantly delayed the onset and decreased the duration of PTZ-induced MCS and GTCS, and significantly reduced the GTCS and mortality rate. Pretreatment with flumazenil diminished the significant anticonvulsant effects of AE against PTZ-induced seizures. CONCLUSIONS: It can report that extract of P. daurica ssp. macrophylla might be a helpful guide for future studies in the treatment of epilepsy.


Assuntos
Anticonvulsivantes , Paeonia , Animais , Camundongos , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Pentilenotetrazol/toxicidade , Flumazenil , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico
11.
Nan Fang Yi Ke Da Xue Xue Bao ; 44(3): 515-522, 2024 Mar 20.
Artigo em Chinês | MEDLINE | ID: mdl-38597443

RESUMO

OBJECTIVE: To explore the inhibitory effect of saikosonin a (SSa) on pentylenetetrazol-induced acute epilepsy seizures in a mouse model of depression and explore the mechanism mediating this effect. METHODS: Male C57BL/6J mouse models of depression was established by oral administration of corticosterone via drinking water for 3 weeks, and acute epileptic seizures were induced by intraperitoneal injection of a single dose of pentylenetetrazole. The effect of intraperitoneal injection of SSa prior to the treatment on depressive symptoms and epileptic seizures were assessed using behavioral tests, epileptic seizure grading and hippocampal morphology observation. ELISA was used to detect blood corticosterone levels of the mice, and RTqPCR was performed to detect the pro- and anti-inflammatory factors. Microglia activation in the mice was observed using immunofluorescence staining. RESULTS: The mouse model of corticosterone-induced depression showed body weight loss and obvious depressive behaviors with significantly increased serum corticosterone level (all P < 0.05). Compared with those with pentylenetetrazole-induced epilepsy alone, the epileptic mice with comorbid depression showed significantly shorter latency of epileptic seizures, increased number, grade and duration of of seizures, reduced Nissl bodies in hippocampal CA1 and CA3 neurons, increased number of Iba1-positive cells, and significantly enhanced hippocampal expressions of IL-1ß, IL-10, TNF-α and IFN-γ. Pretreatment of the epileptic mice with SSa significantly prolonged the latency of epileptic seizures, reduced the number, duration, and severity of seizures, increased the number of Nissl bodies, decreased the number of Iba1-positive cells, and reduced the expression levels of IL-1ß, IL-10, TNF-α, and IFN-γ in the hippocampus (P < 0.05). CONCLUSION: Depressive state aggravates epileptic seizures, increases microglia activation, and elevates inflammation levels. SSA treatment can alleviate acute epileptic seizures in mouse models of depression possibly by suppressing microglia activation-mediated inflammation.


Assuntos
Epilepsia , Ácido Oleanólico/análogos & derivados , Pentilenotetrazol , Saponinas , Masculino , Camundongos , Animais , Pentilenotetrazol/efeitos adversos , Interleucina-10 , Microglia/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Depressão , Corticosterona/metabolismo , Corticosterona/farmacologia , Corticosterona/uso terapêutico , Camundongos Endogâmicos C57BL , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/metabolismo , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Hipocampo/metabolismo , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Modelos Animais de Doenças
12.
Behav Brain Res ; 466: 114981, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38580198

RESUMO

This study verified the effects of the natural compounds berberine and hesperidin on seizure development and cognitive impairment triggered by pentylenetetrazole (PTZ) in zebrafish. Adult animals were submitted to a training session in the inhibitory avoidance test and, after 10 minutes, they received an intraperitoneal injection of 25, 50, or 100 mg/kg berberine or 100 or 200 mg/kg hesperidin. After 30 minutes, the animals were exposed to 7.5 mM PTZ for 10 minutes. Animals were submitted to the test session 24 h after the training session to verify their cognitive performance. Zebrafish larvae were exposed to 100 µM or 500 µM berberine or 10 µM or 50 µM hesperidin for 30 minutes. After, larvae were exposed to PTZ and had the seizure development evaluated by latency to reach the seizure stages I, II, and III. Adult zebrafish pretreated with 50 mg/kg berberine showed a longer latency to reach stage III. Zebrafish larvae pretreated with 500 µM berberine showed a longer latency to reach stages II and III. Hesperidin did not show any effect on seizure development both in larvae and adult zebrafish. Berberine and hesperidin pretreatments prevented the memory consolidation impairment provoked by PTZ-induced seizures. There were no changes in the distance traveled in adult zebrafish pretreated with berberine or hesperidin. In larval stage, berberine caused no changes in the distance traveled; however, hesperidin increased the locomotion. Our results reinforce the need for investigating new therapeutic alternatives for epilepsy and its comorbidities.


Assuntos
Aprendizagem da Esquiva , Berberina , Hesperidina , Pentilenotetrazol , Convulsões , Peixe-Zebra , Animais , Pentilenotetrazol/farmacologia , Berberina/farmacologia , Berberina/administração & dosagem , Hesperidina/farmacologia , Convulsões/induzido quimicamente , Convulsões/prevenção & controle , Aprendizagem da Esquiva/efeitos dos fármacos , Consolidação da Memória/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/prevenção & controle , Masculino , Modelos Animais de Doenças , Convulsivantes/farmacologia , Larva/efeitos dos fármacos , Relação Dose-Resposta a Droga , Anticonvulsivantes/farmacologia
13.
J Physiol Pharmacol ; 75(1)2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38583440

RESUMO

This study was designed to examine the anti-oxidative stress effect of dimethyl fumarate (DMF) on pentylenetetrazole (PTZ)-induced epileptic mice, and to evaluate the correlation of its mechanism with the nuclear factor E2-related factor 2 (Nrf2)-mediated signaling pathway. The experimental mice were separated into three groups: control, model, and DMF groups. Mice in the model group were administered PTZ to establish an epilepsy model, mice in the DMF group were administered DMF concurrently when modeling, and mice in the control group were administered a 0.9% NaCl solution. The latency, severity, and frequency of epileptic seizures in mice after each treatment were recorded, and the modelling success rate was computed at the conclusion of the experiment. The mice were euthanized, their levels of malondialdehyde (MDA), reactive oxygen species (ROS), superoxide dismutase (SOD), 8-hydroxy-deoxyguanosine (8-OHdG), and Nrf2 were measured, and the electron microscope was used to examine the mitochondrial damage of brain tissue. The latency of epileptic seizures was longer in the DMF group compared to the model group (P<0.05). The levels of MDA and ROS in the DMF group were lower than those in the model group (P<0.0001), and the activity of SOD in the DMF group was higher than that in the model group (P<0.0001); however, the levels of MDA and ROS were elevated and the activity of SOD was lower in both groups relative to the control group. The levels of 8-OHdG were lower in the DMF group than the model group (P<0.0001), however, the levels were higher in both groups compared to the control group. Mitochondrial abnormalities were more prevalent in the model group than in the DMF group, and more prevalent in both groups compared to the control group. The DMF group contained more Nrf2 content than the model group (P<0.0001), and both groups contained more Nrf2 than the control group. We concluded that the mechanism by which DMF reduced the level of oxidative stress in epileptic mice might involve the Nrf2-mediated signaling pathway.


Assuntos
Fumarato de Dimetilo , Epilepsia , Animais , Camundongos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Fumarato de Dimetilo/farmacologia , Fumarato de Dimetilo/uso terapêutico , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Pentilenotetrazol/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Superóxido Dismutase/metabolismo
14.
J Complement Integr Med ; 21(2): 222-229, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38661076

RESUMO

OBJECTIVES: Vitamin B7(biotin) is not synthesized in our body and is retrieved from some food products like eggs, liver, pork and leafy vegetables and as well as microbes of gut. Deficiency of biotin majorly leads to loss of hair, rashes over skin, lethargy and seizures. It is noted that biotin is an anti-oxidant and negates free radical effects. Biotin is also involved in carbon dioxide metabolism and it might alter seizure threshold. Studies also suggest its effect on lipid metabolism as well. So, the primary objective of this study was to assess the efficacy of biotin in maximal electric shock (MES) induced generalized tonic-clonic seizures (GTCS) and pentylenetetrazole (PTZ) induced absence seizures. The secondary objective is to study the effect of combined treatment of biotin and sodium valproate on seizures as well as plasma lipid profile in rats. METHODS: In our study 30 albino Wistar rats each were used in MES and PTZ model respectively. 30 rats were divided equally into following groups: I - distilled water (negative control) II - distilled water (positive control) III - sodium valproate (300 mg/kg) IV - biotin (10 mg/kg/day) V - biotin (10 mg/kg) + sodium valproate (150 mg/kg). RESULTS: We observed that the tonic hind limb extension was significantly reduced in the treatment group in MES model. Nitric oxide levels were also seen raised in combination group in MES model and all the treated groups in PTZ model. Biotin treated group showed increased high-density lipoproteins and reduced low density lipoproteins and triglycerides. CONCLUSIONS: Biotin had an additive effect to sodium valproate in both the models of epilepsy in rats. Further, it was also able to counteract hyperlipidemia cause by sodium valproate.


Assuntos
Anticonvulsivantes , Biotina , Modelos Animais de Doenças , Eletrochoque , Pentilenotetrazol , Ratos Wistar , Convulsões , Ácido Valproico , Animais , Anticonvulsivantes/farmacologia , Convulsões/tratamento farmacológico , Ácido Valproico/farmacologia , Ratos , Biotina/farmacologia , Masculino
15.
Eur J Neurosci ; 59(12): 3337-3352, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38654472

RESUMO

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is caused by a loss-of-function mutation in CDKL5 gene, encoding a serine-threonine kinase highly expressed in the brain. CDD manifests with early-onset epilepsy, autism, motor impairment and severe intellectual disability. While there are no known treatments for CDD, the use of cannabidiol has recently been introduced into clinical practice for neurodevelopmental disorders. Given the increased clinical utilization of cannabidiol, we examined its efficacy in the CDKL5R59X knock-in (R59X) mice, a CDD model based on a human mutation that exhibits both lifelong seizure susceptibility and behavioural deficits. We found that cannabidiol pre-treatment rescued the increased seizure susceptibility in response to the chemoconvulsant pentylenetetrazol (PTZ), attenuated working memory and long-term memory impairments, and rescued social deficits in adult R59X mice. To elucidate a potential mechanism, we compared the developmental hippocampal and cortical expression of common endocannabinoid (eCB) targets in R59X mice and their wild-type littermates, including cannabinoid type 1 receptor (CB1R), transient receptor potential vanilloid type 1 (TRPV1) and 2 (TRPV2), G-coupled protein receptor 55 (GPR55) and adenosine receptor 1 (A1R). Many of these eCB targets were developmentally regulated in both R59X and wild-type mice. In addition, adult R59X mice demonstrated significantly decreased expression of CB1R and TRPV1 in the hippocampus, and TRPV2 in the cortex, while TRPV1 was increased in the cortex. These findings support the potential for dysregulation of eCB signalling as a plausible mechanism and therapeutic target in CDD, given the efficacy of cannabidiol to attenuate hyperexcitability and behavioural deficits in this disorder.


Assuntos
Canabidiol , Proteínas Serina-Treonina Quinases , Convulsões , Animais , Canabidiol/farmacologia , Convulsões/tratamento farmacológico , Convulsões/genética , Convulsões/metabolismo , Camundongos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Síndromes Epilépticas/genética , Síndromes Epilépticas/tratamento farmacológico , Pentilenotetrazol , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Modelos Animais de Doenças , Técnicas de Introdução de Genes/métodos , Masculino , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Endocanabinoides/metabolismo , Comportamento Animal/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Espasmos Infantis , Receptores de Canabinoides
16.
Exp Neurol ; 377: 114794, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38685307

RESUMO

BACKGROUND: Interleukin-1 receptor-associated kinase 4 (IRAK4) plays an important role in immune modulation in various central nervous system disorders. However, IRAK4 has not been reported in epilepsy models in animal and clinical studies, nor has its involvement in regulating pyroptosis in epilepsy. METHOD: First, we performed transcriptome sequencing, quantitative real-time polymerase chain reaction, and western blot analysis on the hippocampal tissues of refractory epilepsy patients to measure the mRNA and protein levels of IRAK4 and pyroptosis-related proteins. Second, we successfully established a pentylenetetrazol (PTZ)-induced seizure mouse model. We conducted behavioral tests, electroencephalography, virus injection, and molecular biology experiments to investigate the role of IRAK4 in seizure activity regulation. RESULTS: IRAK4 is upregulated in the hippocampus of epilepsy patients and PTZ-induced seizure model mice. IRAK4 expression is observed in the hilar neurons of PTZ-induced mice. Knocking down IRAK4 in PTZ-induced mice downregulated pyroptosis-related protein expression and alleviated seizure activity. Overexpressing IRAK4 in naive mice upregulated pyroptosis-related protein expression and increased PTZ-induced abnormal neuronal discharges. IRAK4 and NF-κB were found to bind to each other in patient hippocampal tissue samples. Pyrrolidine dithiocarbamate reversed the pyroptosis-related protein expression increase caused by PTZ. PF-06650833 alleviated seizure activity and inhibited pyroptosis in PTZ-induced seizure mice. CONCLUSION: IRAK4 plays a key role in the pathological process of epilepsy, and its potential mechanism may be related to pyroptosis mediated by the NF-κB/NLRP3 signaling pathway. PF-06650833 has potential as a therapeutic agent for alleviating epilepsy.


Assuntos
Epilepsia , Hipocampo , Quinases Associadas a Receptores de Interleucina-1 , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR , Neurônios , Piroptose , Convulsões , Transdução de Sinais , Animais , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Quinases Associadas a Receptores de Interleucina-1/genética , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose/efeitos dos fármacos , Piroptose/fisiologia , Camundongos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Humanos , NF-kappa B/metabolismo , Masculino , Convulsões/metabolismo , Convulsões/induzido quimicamente , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Epilepsia/metabolismo , Epilepsia/induzido quimicamente , Feminino , Camundongos Endogâmicos C57BL , Adulto , Pentilenotetrazol/toxicidade , Adulto Jovem , Adolescente , Criança
17.
J Ethnopharmacol ; 331: 118271, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-38688356

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The use of medicinal plants for central nervous system (CNS)-related ailments, such as epilepsy and anxiety, is prevalent in South Africa. Plants from the Lamiaceae family are commonly used for their therapeutic benefits. Leonotis leonurus (L.) R.Br. has been reported in ethnobotanical literature to have anticonvulsant and anxiolytic effects through the inhalation of pyrolysis products obtained by combustion of the aerial parts. AIM AND OBJECTIVES: To explore the chemical profiles and CNS activity of the smoke extract and isolated constituents of L. leonurus in zebrafish larvae, through anticonvulsive and anxiolytic activity assays. MATERIALS AND METHODS: The smoke extract of L. leonurus was obtained through the combustion of the aerial parts of the plant using a custom-built smoke recovery apparatus. The chemical profile of the smoke constituents was determined using Ultra-Performance Liquid Chromatography coupled with Mass Spectrometry (UPLC-MS). Targeted compounds were subjected to preparative High-Performance Liquid Chromatography for separation before structure elucidation using Nuclear Magnetic Resonance (NMR). The maximum tolerated concentrations, as well as the anxiolytic activity of the smoke extract were determined in five days post fertilisation zebrafish larvae. Reverse-thigmotaxis and locomotor activity of larvae in the light/dark transition assay were used to determine anxiolytic activity. Zebrafish larvae at six days post fertilisation (dpf) were subjected to several concentrations of the smoke constituents of L. leonurus. The baseline locomotor activity of the larvae was tracked for 30 min, prior to addition of pentylenetetrazole (PTZ) to induce seizure-like behaviour in the larvae, after which the locomotor activity of the larvae was once again tracked for an additional 30 min. RESULTS: The UPLC-MS profiles of the smoke extract revealed the presence of two main compounds, leoleorin A and leoleorin B, which were targeted and isolated. Upon subjection to NMR spectroscopy for structure elucidation, the compounds were confirmed to be labdane diterpenoids. Both leoleorin A and leoleorin B, and the smoke extract displayed suppression of the PTZ induced seizure-like behaviour in zebrafish larvae. Under light and dark conditions, the smoke extract and compounds displayed potential anxiolytic activity at different concentrations. CONCLUSION: Our results suggest that the smoke constituents of L. leonurus may exert anticonvulsant and anxiolytic effects which align with the traditional indications and the mode of administration.


Assuntos
Ansiolíticos , Anticonvulsivantes , Extratos Vegetais , Convulsões , Fumaça , Peixe-Zebra , Animais , Ansiolíticos/farmacologia , Ansiolíticos/isolamento & purificação , Ansiolíticos/química , Fumaça/efeitos adversos , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Anticonvulsivantes/farmacologia , Anticonvulsivantes/isolamento & purificação , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamente , Larva/efeitos dos fármacos , Lamiaceae/química , Pentilenotetrazol , Componentes Aéreos da Planta/química , África do Sul , Comportamento Animal/efeitos dos fármacos
18.
Brain ; 147(6): 2169-2184, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38662500

RESUMO

Approximately 22% of Alzheimer's disease (AD) patients suffer from seizures, and the co-occurrence of seizures and epileptiform activity exacerbates AD pathology and related cognitive deficits, suggesting that seizures may be a targetable component of AD progression. Given that alterations in neuronal excitatory:inhibitory (E:I) balance occur in epilepsy, we hypothesized that decreased markers of inhibition relative to those of excitation would be present in AD patients. We similarly hypothesized that in 5XFAD mice, the E:I imbalance would progress from an early stage (prodromal) to later symptomatic stages and be further exacerbated by pentylenetetrazol (PTZ) kindling. Post-mortem AD temporal cortical tissues from patients with or without seizure history were examined for changes in several markers of E:I balance, including levels of the inhibitory GABAA receptor, the sodium potassium chloride cotransporter 1 (NKCC1) and potassium chloride cotransporter 2 (KCC2) and the excitatory NMDA and AMPA type glutamate receptors. We performed patch-clamp electrophysiological recordings from CA1 neurons in hippocampal slices and examined the same markers of E:I balance in prodromal 5XFAD mice. We next examined 5XFAD mice at chronic stages, after PTZ or control protocols, and in response to chronic mTORC1 inhibitor rapamycin, administered following kindled seizures, for markers of E:I balance. We found that AD patients with comorbid seizures had worsened cognitive and functional scores and decreased GABAA receptor subunit expression, as well as increased NKCC1/KCC2 ratios, indicative of depolarizing GABA responses. Patch clamp recordings of prodromal 5XFAD CA1 neurons showed increased intrinsic excitability, along with decreased GABAergic inhibitory transmission and altered glutamatergic neurotransmission, indicating that E:I imbalance may occur in early disease stages. Furthermore, seizure induction in prodromal 5XFAD mice led to later dysregulation of NKCC1/KCC2 and a reduction in GluA2 AMPA glutamate receptor subunit expression, indicative of depolarizing GABA receptors and calcium permeable AMPA receptors. Finally, we found that chronic treatment with the mTORC1 inhibitor, rapamycin, at doses we have previously shown to attenuate seizure-induced amyloid-ß pathology and cognitive deficits, could also reverse elevations of the NKCC1/KCC2 ratio in these mice. Our data demonstrate novel mechanisms of interaction between AD and epilepsy and indicate that targeting E:I balance, potentially with US Food and Drug Administration-approved mTOR inhibitors, hold therapeutic promise for AD patients with a seizure history.


Assuntos
Doença de Alzheimer , Camundongos Transgênicos , Convulsões , Animais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Convulsões/metabolismo , Convulsões/fisiopatologia , Camundongos , Masculino , Humanos , Feminino , Pentilenotetrazol/toxicidade , Idoso , Modelos Animais de Doenças , Excitação Neurológica/efeitos dos fármacos , Idoso de 80 Anos ou mais
19.
Neurochem Int ; 176: 105725, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38561151

RESUMO

Epilepsy constitutes a global health concern, affecting millions of individuals and approximately one-third of patients exhibit drug resistance. Recent investigations have revealed alterations in cerebral iron content in both epilepsy patients and animal models. However, the extant literature lacks a comprehensive exploration into the ramifications of modulating iron homeostasis as an intervention in epilepsy. This study investigated the impact of deferasirox, a iron ion chelator, on epilepsy. This study unequivocally substantiated the antiepileptic efficacy of deferasirox in a kainic acid-induced epilepsy model. Furthermore, deferasirox administration mitigated seizure susceptibility in a pentylenetetrazol-induced kindling model. Conversely, the augmentation of iron levels through supplementation has emerged as a potential exacerbating factor in the precipitating onset of epilepsy. Intriguingly, our investigation revealed a hitherto unreported discovery: ITPRIP was identified as a pivotal modulator of excitatory synaptic transmission, regulating seizures in response to deferasirox treatment. In summary, our findings indicate that deferasirox exerts its antiepileptic effects through the precise targeting of ITPRIP and amelioration of cerebral iron homeostasis, suggesting that deferasirox is a promising and novel therapeutic avenue for interventions in epilepsy.


Assuntos
Anticonvulsivantes , Encéfalo , Deferasirox , Epilepsia , Quelantes de Ferro , Ferro , Proteínas de Membrana , Animais , Masculino , Camundongos , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Deferasirox/farmacologia , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Ferro/metabolismo , Quelantes de Ferro/farmacologia , Quelantes de Ferro/uso terapêutico , Excitação Neurológica/efeitos dos fármacos , Pentilenotetrazol/toxicidade , Ratos Sprague-Dawley , Proteínas de Membrana/efeitos dos fármacos , Proteínas de Membrana/metabolismo
20.
Int J Mol Sci ; 25(6)2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38542281

RESUMO

Epilepsy ranks as the second-most prevalent neurological disease, and is characterized by seizures resulting in neurobiological and behavioral impairment. Naturally occurring in coffee beans or tea leaves, the alkaloid caffeine (CAF) is the most prevalent global stimulant. Caffeine has been observed to influence epileptic seizures and the efficacy of antiepileptic medications, with a notable impact on topiramate (TPM). This study aimed to explore the influence of CAF on TPM's anticonvulsant effects in zebrafish larvae within a PTZ-induced seizure model, concurrently determining TPM concentrations through a sophisticated analytical approach based on ultrahigh-performance liquid chromatography and subsequent mass spectrometric detection. Zebrafish larvae four days post-fertilization were incubated for 18 h with varying doses of TPM or combinations of CAF + TPM, and locomotor activity was then assessed. Seizures were induced by introducing a PTZ solution to achieve a final concentration of 20 mM. Utilizing liquid chromatography-mass spectrometry (LC-MS/MS), TPM levels in the larvae were quantified. CAF co-administration (especially in higher doses) with TPM caused a decrease in the average locomotor activity in the larvae compared to TPM alone. Moreover, CAF decreased TPM levels in the larvae at all investigated doses. In conclusion, these findings offer a novel perspective on the interplay between CAF and TPM, shedding light on previously unexplored facets. The potential impact of CAF consumption in assisting with epileptic seizure control, unless proven otherwise, suggests a noteworthy consideration for future research and clinical practices.


Assuntos
Epilepsia , Peixe-Zebra , Animais , Topiramato/uso terapêutico , Pentilenotetrazol/toxicidade , Cafeína/farmacologia , Cafeína/uso terapêutico , Cromatografia Líquida , Frutose/efeitos adversos , Espectrometria de Massas em Tandem , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Anticonvulsivantes/efeitos adversos , Epilepsia/tratamento farmacológico
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