RESUMO
Astrocytes and microglia can adopt two distinct phenotypes in various pathological processes: neurotoxic A1/M1 and neuroprotective A2/M2. Recent evidence suggests that these cells play a significant role in epileptogenesis. The objective of this study was to characterize the phenotype of astrocytes and microglial cells in the hippocampus and temporal cortex of young male Wistar rats at 3 h, 1, 3, and 7 days after pentylenetetrazole-induced seizures. RT-qPCR was employed to examine the expression of glial genes (Gfap, Aif1, Slc1a1, Slc1a2, Slc1a3, Itpr2, Gdnf, Bdnf, Fgf2, Tgfb, Il1b, Tnf, Il1rn, Lcn2, S100a10, Nlrp3, Arg1). The most notable alterations in the expression of glial genes were observed on the first day following seizures in the temporal cortex. An increase in the expression of the Gfap, Slc1a2, Slc1a1, Il1b, Tnfa, Bdnf, and Fgf2 genes, and the A2 astrocyte condition marker S100a10, was observed. An increase in the expression of the Gfap and Slc1a2 genes was observed in the hippocampus on the first day after seizures. However, in contrast to the changes observed in the cortex, the changes in the hippocampus were opposite for the Il1rn, Bdnf, Tgfb, and Arg1 genes. Nevertheless, the alterations in GFAP and EAAT2 protein levels were not corroborated by Western blot analysis. Conversely, a more comprehensive immunohistochemical analysis confirmed an augmentation in the number of GFAP-positive cells in the hippocampus 1 day after seizures. Based on the presented evidence, we can conclude that a single convulsive seizure episode in 3-week-old rats results in transient astroglial activation and polarization to a neuroprotective phenotype (A2).
Assuntos
Astrócitos , Hipocampo , Microglia , Pentilenotetrazol , Ratos Wistar , Convulsões , Lobo Temporal , Animais , Masculino , Hipocampo/metabolismo , Hipocampo/patologia , Astrócitos/metabolismo , Astrócitos/patologia , Convulsões/induzido quimicamente , Convulsões/metabolismo , Convulsões/patologia , Ratos , Pentilenotetrazol/toxicidade , Microglia/metabolismo , Microglia/patologia , Lobo Temporal/metabolismo , Lobo Temporal/patologia , FenótipoRESUMO
An intravenous (IV) administration of midazolam may result in seizure-like activity or movement. This report describes 5 neonates who developed seizure-like movements after IV midazolam injection. The patients presented between 2019 and 2022 and were admitted to a neonatal intensive care unit located within an academic centre in Muscat, Oman. The abnormal movements occurred shortly after IV bolus administration of midazolam. None of the patients experienced seizure-like movements after receiving midazolam infusions. The seizure-like movements were aborted either spontaneously or by antiseizure medications. In addition, seizure recurrence was not observed in any of the infants during the later stages of their treatment. Since this adverse effect might be related to the speed of the bolus administration, IV midazolam must be given as a slow bolus over 2-3 minutes followed by a slow flush of normal saline. To prevent midazolam's potential adverse effect on newborns, neonatal caregivers must be aware of it.
Assuntos
Midazolam , Convulsões , Humanos , Midazolam/efeitos adversos , Midazolam/farmacologia , Midazolam/administração & dosagem , Midazolam/uso terapêutico , Recém-Nascido , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Masculino , Feminino , Omã , Hipnóticos e Sedativos/efeitos adversos , Unidades de Terapia Intensiva Neonatal , Anticonvulsivantes/efeitos adversosRESUMO
This work provides insight into carbamazepine polymorphs (Forms I, II, III, IV, and V), with reports on the cytoprotective, exploratory, motor, CNS-depressant, and anticonvulsant properties of carbamazepine (CBZ), carbamazepine formulation (CBZ-F), topiramate (TOP), oxcarbazepine (OXC), and diazepam (DZP) in mice. Structural analysis highlighted the significant difference in molecular conformations, which directly influence the physicochemical properties; and density functional theory description provided indications about CBZ reactivity and stability. In addition to neuron viability assessment in vitro, animals were treated orally with vehicle 10 mL/kg, as well as CBZ, CBZ-F, TOP, OXC, and DZP at the dose of 5 mg/kg and exposed to open-field, rotarod, barbiturate sleep induction and pentylenetetrazol (PTZ 70 mg/kg)-induced seizure. The involvement of GABAergic mechanisms in the activity of these drugs was evaluated with the intraperitoneal pretreatment of flumazenil (2 mg/kg). The CBZ, CBZ-F, and TOP mildly preserved neuronal viability. The CBZ-F and the reference AEDs potentiated barbiturate sleep, altered motor activities, and attenuated PTZ-induced convulsion. However, flumazenil pretreatment blocked these effects. Additional preclinical assessments could further establish the promising utility of CBZ-F in clinical settings while expanding the scope of AED formulations and designs.
Assuntos
Anticonvulsivantes , Carbamazepina , Carbamazepina/farmacologia , Carbamazepina/análogos & derivados , Animais , Camundongos , Anticonvulsivantes/farmacologia , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamente , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oxcarbazepina/farmacologia , Diazepam/farmacologia , Masculino , Pentilenotetrazol , Sobrevivência Celular/efeitos dos fármacos , Topiramato/farmacologia , Barbitúricos/farmacologiaRESUMO
Epilepsy is a chronic neurological disorder characterized by recurrent seizures that affects over 70 million people worldwide. Although many antiepileptic drugs that block seizures are available, they have little effect on preventing and curing epilepsy, and their side effects sometimes lead to serious morbidity. Therefore, prophylactic agents with anticonvulsant properties and no adverse effects need to be identified. Recent studies on probiotic administration have reported a variety of beneficial effects on the central nervous system via the microbiota-gut-brain axis. In this study, we investigated the effects of the oral administration of Bifidobacterium breve strain A1 [MCC1274] (B. breve A1) on tonic-clonic seizure in a pentylenetetrazole (PTZ)-induced kindling mouse (KD mouse) model. We found that the oral administration of B. breve A1 every other day for 15 days significantly reduced the seizure score, which gradually increased with repetitive injections of PTZ in KD mice. The administration of B. breve A1, but not saline, to KD mice significantly increased the level of Akt Ser473 phosphorylation (p-Akt) in the hippocampus; this increase was maintained for a minimum of 24 h after PTZ administration. Treatment of B. breve A1-administered KD mice with the selective inhibitor of integrin-linked kinase (ILK) Cpd22 significantly increased the seizure score and blocked the antiepileptic effect of B. breve A1. Moreover, Cpd22 blocked the B. breve A1-induced increase in hippocampal p-Akt levels. These results suggest that the ILK-induced phosphorylation of Akt Ser473 in the hippocampus might be involved in the antiepileptic effect of B. breve A1.
Assuntos
Bifidobacterium breve , Modelos Animais de Doenças , Excitação Neurológica , Pentilenotetrazol , Probióticos , Proteínas Serina-Treonina Quinases , Convulsões , Transdução de Sinais , Animais , Probióticos/administração & dosagem , Probióticos/farmacologia , Camundongos , Convulsões/metabolismo , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamente , Bifidobacterium breve/metabolismo , Masculino , Transdução de Sinais/efeitos dos fármacos , Administração Oral , Excitação Neurológica/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , FosforilaçãoRESUMO
Drug-induced convulsion is a serious concern in drug development, such that the convulsion liability of drug candidates must be evaluated in preclinical safety studies. However, information on the differences among species regarding their sensitivity to convulsions induced by convulsant drugs in humans remains limited. Here, we selected 11 test articles from several pharmacological classes and compared the sensitivities of three types of laboratory animal to convulsion. All 11 test articles were examined in mice via intraperitoneal injection and in rats via intravenous bolus; and 6 of the 11 test articles, selected mainly based on availabilities of data on drug plasma concentrations in humans at convulsion, were examined in non-human primates (NHPs) via intravenous infusion. Plasma concentrations of the test articles shortly after convulsion onset or 5 min after administration were measured. All 11 articles tested in mice, 10 of 11 articles tested in rats, and all 6 articles tested in NHPs induced convulsion with premonitory signs. Although there was a general tendency that rats and NHPs exhibited convulsions at lower plasma drug concentrations than did mice, the plasma concentrations at convulsion onset were generally comparable, within 3-fold differences, across the animal species. We conclude that the mice, rats, and NHPs examined in the present study generally showed similar sensitivities to convulsion induced by the test articles. Thus, each of these laboratory animals can be used for the assessment of convulsion risk in the early stages of drug development, depending on throughput, cost, and test article-specific requirements.
Assuntos
Avaliação Pré-Clínica de Medicamentos , Convulsões , Especificidade da Espécie , Animais , Convulsões/induzido quimicamente , Medição de Risco , Camundongos , Ratos , Masculino , Convulsivantes/toxicidade , Humanos , Animais de Laboratório , Injeções IntraperitoneaisRESUMO
BACKGROUND: Aprepitant (APR), a neurokinin 1 receptor antagonist, is an approved drug for treating chemotherapy-induced nausea and vomiting. OBJECTIVES: Investigate the beneficial roles of APR alone or in combination with sodium valproate (VPA) against lithium pilocarpine [li-pilo]-induced seizures, behavioral changes, and cognitive deficits. METHODS: Thirty male mice were divided into five groups, each containing 6. "Vehicle Group I," "Control Group II "li-pilo, " Valproate (VPA) group III (400 mg/kg/i.p.), "APR group IV, " and "Combination Group V." Videos of mice were recorded, and they were watched for episodes of spontaneous recurring seizures (SRS). Behavioral Tests were performed. At the end of the study, animal brains were taken for biochemical assays and gene expression studies. RESULTS: APR partially protected against SRS with partial restoration of average behavioral and standard cognitive skills associated with a significant increase in brain SOD activity and a significant decrease in MDA, IL-1ß, NF-ÐB, and SP-3 levels in relation to the control group. Interestingly, a combination of APR with VPA in epileptic mice showed complete protection against li-pilo-induced behavioral changes and cognitive deficits, a significant increase in brain SOD activity, and a considerable decrease in MDA, IL-1ß, NF-ΚB, and SP levels to normal. CONCLUSION: Using APR as an adjuvant to VPA is more effective in protecting against li-pilo-induced seizures, behavioral changes, and cognitive deficits due to its antioxidant, anti-inflammatory, and NK1 antagonist effects than using APR alone as drug therapy.
Assuntos
Anticonvulsivantes , Aprepitanto , Modelos Animais de Doenças , Epilepsia , Pilocarpina , Convulsões , Ácido Valproico , Animais , Masculino , Aprepitanto/farmacologia , Camundongos , Ácido Valproico/farmacologia , Anticonvulsivantes/farmacologia , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Epilepsia/tratamento farmacológico , Epilepsia/induzido quimicamente , Pilocarpina/toxicidade , Morfolinas/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Aprendizagem em Labirinto/efeitos dos fármacos , Superóxido Dismutase/metabolismoRESUMO
Introduction: The effects of methylphenidate, a stimulant often prescribed for the treatment of attention-deficit/hyperactivity disorder (ADHD), on the development of central nervous system oxygen toxicity (COT) have not been experimentally evaluated. Methods: The records of all pure-oxygen-rebreather divers evaluated at our institution from 1975-2022 were assessed. Cases of COT were defined as a new onset of tinnitus, tunnel vision, myoclonus, headache, nausea, loss of consciousness, or seizures resolving within 15 minutes from breathing normobaric air, and matched 4:1 with similar controls. Any medications issued to the diver in the preceding three months, including methylphenidate, were recorded. In the animal arm of this study, male mice were exposed to increasing doses of methylphenidate orally, with subsequent exposure to hyperbaric O2 until clinically evident seizures were recorded. Results: Seventy-five cases of COT were identified in divers, occurring at a median of 80 (range 2-240) minutes after dive initiation at a median depth of 5 m (2-13). Hypercarbia was documented in 11 (14.7%) cases. Prescription of methylphenidate in the preceding three months was not associated with increased risk (OR 0.72, 95% CI 0.16-3.32) of COT. In mice, increasing methylphenidate exposure dose was associated with significantly longer mean COT latency time being 877 s (95% CI 711-1,043) with doses of 0 mg·kg⻹; 1,312 s (95% CI 850-1,773) when given 0.75 mg·kg⻹; and 1,500 s (95% CI 988-2,012) with 5 mg·kg⻹ (F = 4.635, P = 0.014). Conclusions: Observational human data did not demonstrate an association between methylphenidate and an increased risk of COT. Methylphenidate exposure in mice prolongs COT latency and may have protective effects against COT.
Assuntos
Estimulantes do Sistema Nervoso Central , Mergulho , Metilfenidato , Oxigênio , Metilfenidato/farmacologia , Animais , Masculino , Estimulantes do Sistema Nervoso Central/farmacologia , Camundongos , Adulto , Humanos , Convulsões/induzido quimicamente , Feminino , Pessoa de Meia-Idade , Oxigenoterapia Hiperbárica , Adulto Jovem , Fatores de TempoRESUMO
Sulfuryl fluoride is a kind of pesticide with strong permeability, convenient use at low temperature, non-corrosive and other characteristics, which can kill food pests and has strong lethality to termites. In acute sulfuryl fluoride poisoning, patients can see recurrent convulsions, epileptic electroencephalogram abnormalities such as matrix spikes or high amplitude spikes. In this paper, a patient with sulfuryl fluoride poisoning with convulsion-based mental system symptoms was reported, and after clinical treatment with dexamethasone and phenobarbital sodium, the patient was cured and discharged.
Assuntos
Convulsões , Humanos , Convulsões/induzido quimicamente , Masculino , Intoxicação por Gás , Adulto , Ácidos Sulfínicos/intoxicação , Recidiva , Praguicidas/intoxicaçãoRESUMO
Recently a novel genetically modified mouse strain with serum carboxylesterase knocked-out and the human acetylcholinesterase gene knocked-in (KIKO) was created to simulate human responses to nerve agent (NA) exposure and its standard medical treatment. A1 adenosine receptor (A1AR) agonist N-bicyclo-(2.2.1)-hept-2-yl-5'-chloro-5'-deoxyadenosine (ENBA) alone is a potent anticonvulsant and neuroprotectant (A/N) in both rat and KIKO mouse soman (GD) seizure models. In this study we utilized the KIKO mouse to evaluate further the basic pharmacologic A/N effects of ENBA as an adjunct to standard NA medical treatments (i.e., atropine sulfate, pralidoxime chloride [2-PAM], and midazolam). Male mice, implanted with cortical electroencephalographic (EEG) electrodes, were pretreated with asoxime (HI-6) and exposed to an epileptogenic dose of GD (33 µg/kg, s.c.) or saline (sham exposure) and then treated 15 min after seizure onset with ENBA at 15 mg/kg, i.p. (a minimum efficacy dose in suppressing NA-induced seizure) alone or as an adjunct to standard medical treatments. We collected EEG activity, seizure suppression outcomes, daily body temperature and weight, heart rate, toxic signs, neuropathology, and lethality data for up to 14 days. Without ENBA, death from NA exposure was 45%, while with ENBA, either alone or in combination with midazolam, the survival improved to 80% and 90%, respectively. Additionally, seizure was suppressed quickly and permanently, toxic signs, hypothermia, and bradycardia recovered by 48 h, and no neuropathology was evident. Our findings confirmed that ENBA is a potent A/N adjunct for delayed medical treatments of NA exposure.
Assuntos
Acetilcolinesterase , Agonistas do Receptor A1 de Adenosina , Modelos Animais de Doenças , Convulsões , Soman , Animais , Soman/toxicidade , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Masculino , Agonistas do Receptor A1 de Adenosina/farmacologia , Humanos , Camundongos , Acetilcolinesterase/metabolismo , Eletroencefalografia , Adenosina/análogos & derivados , Adenosina/farmacologia , Camundongos Knockout , Anticonvulsivantes/farmacologia , Anticonvulsivantes/toxicidadeRESUMO
Kruppel-like factor 4 (Klf4) is a transcription factor that is involved in neuronal regeneration and the development of glutamatergic systems. However, it is unknown whether Klf4 is involved in acute seizure. To investigate the potential role of Klf4 in pentylenetetrazol (PTZ)-induced seizure, western blotting, immunofluorescence, behaviour test and electrophysiology were conducted in this study. We found that Klf4 protein and mRNA expression were increased in both the hippocampus (HP) and prefrontal cortex (PFC) after PTZ-induced seizure in mice. HP-specific knockout (KO) of Klf4 in mice decreased protein expression of Klf4 and the down-stream Klf4 target tumour protein 53 (TP53/P53). These molecular changes are accompanied by increased seizure latency, reduced immobility time in the forced swimming test and tail suspension test. Reduced hippocampal protein levels for synaptic proteins, including glutamate receptor 1 (GRIA1/GLUA1) and postsynaptic density protein 95 (DLG4/PSD95), were also observed after Klf4-KO, while increased mRNA levels of complement proteins were observed for complement component 1q subcomponent A (C1qa), complement component 1q subcomponent B (C1qb), complement component 1q subcomponent C (C1qc), complement component 3 (C3), complement component 4A (C4a) and complement component 4B (C4b). Moreover, c-Fos expression induced by PTZ was reduced by hippocampal conditional KO of Klf4. Electrophysiology showed that PTZ-induced action potential frequency was decreased by overexpression of Klf4. In conclusion, these findings suggest that Klf4 plays an important role in regulating PTZ-induced seizures and therefore constitutes a new molecular target that should be explored for the development of antiepileptic drugs.
Assuntos
Hipocampo , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like , Camundongos Knockout , Pentilenotetrazol , Convulsões , Animais , Fator 4 Semelhante a Kruppel/metabolismo , Convulsões/metabolismo , Convulsões/induzido quimicamente , Convulsões/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Camundongos , Hipocampo/metabolismo , Masculino , Córtex Pré-Frontal/metabolismo , Camundongos Endogâmicos C57BL , Modelos Animais de DoençasRESUMO
Epilepsy, frequently comorbid with anxiety, is a prevalent neurological disorder. Available drugs often have side effects that hinder adherence, creating a need for new treatments. Potassium channel activators have emerged as promising candidates for treating both epilepsy and anxiety. This study aimed to evaluate the potential anticonvulsant and anxiolytic effects of pinacidil, an ATP-sensitive potassium channel activator used as antihypertensive, in rats. Our results indicate that pinacidil at 10 mg/kg (i.p.) fully protected animals from seizures induced by pentylenetetrazol (PTZ) and provided 85.7%, 100% and 100% protection against pilocarpine-induced seizures at 2.5, 5 and 10 mg/kg (i.p.), respectively. Although the 2.5 and 5 mg/kg (i.p) doses did not significantly protect the animals from PTZ-induced seizures, they did significantly increase the latency to the first seizure. Pinacidil also demonstrated mild anxiolytic activity, particularly at 10 mg/kg (i.p), evidenced by increased time spent in the open or illuminated areas of the Elevated Plus Maze (EPM) and Light-Dark Box (LDB) and increased exploratory activity in the Open Filed, EPM and LDB. Pinacidil did not affect locomotor performance, supporting its genuine anticonvulsant effects. This study holds significant medical and pharmaceutical value by characterizing pinacidil's anticonvulsant and anxiolytic effects and highlighting its potential for therapeutic repositioning.
Assuntos
Ansiolíticos , Anticonvulsivantes , Modelos Animais de Doenças , Pentilenotetrazol , Pinacidil , Convulsões , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Masculino , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamente , Camundongos , Ratos , Pinacidil/farmacologia , Reposicionamento de Medicamentos , Ansiedade/tratamento farmacológico , Pilocarpina , Comportamento Animal/efeitos dos fármacos , Ratos WistarRESUMO
The coronaridine congeners catharanthine and 18-methoxycoronaridine (18-MC) display sedative, anxiolytic, and antidepressant properties by acting on mechanisms involving GABAergic and/or monoaminergic transmissions. Here, we expanded their pharmacological properties by studying their anticonvulsant activity in male and female mice using the pentylenetetrazole (PTZ)-induced seizure test. To determine potential neurochemical mechanisms, the effect of congeners on monoamine content and kainic acid (KA)-induced epileptiform discharge was studied in the hippocampus. The behavioral results showed that coronaridine congeners induce acute anticonvulsant activity in a dose-dependent but sex-independent manner. Repeated treatment with a subthreshold dose (20 mg/kg) of each congener produced anticonvulsant activity in a sex-independent manner, but was significantly higher in male mice when compared to its acute effect. Using a behaviourally relevant regimen, we found that PTZ increased dopamine metabolites and serotonin tissue content. Coronaridine congeners, which induced distinct effects on monoamines, blunted the effect of PTZ instead of potentiating it, suggesting the existence of another mechanism in their anticonvulsant activity. The electrophysiological results indicated that both congeners inhibit KA-induced epileptiform discharges in hippocampal slices. A key aspect of this study is that the activity of both congeners was observed only in the presence of GABA, supporting the notion that hippocampal GABAAR potentiation plays an important role. Our study showed that coronaridine congeners induce acute anticonvulsant activity in a sex-independent manner. However, a comparatively higher susceptibility was observed in male mice after repeated treatment. The underlying hippocampal mechanisms mainly involve GABAAR potentiation, whereas monoamines play a minor role in the anticonvulsive action.
Assuntos
Anticonvulsivantes , Hipocampo , Receptores de GABA-A , Convulsões , Animais , Masculino , Anticonvulsivantes/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Camundongos , Feminino , Receptores de GABA-A/metabolismo , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamente , Convulsões/metabolismo , Convulsões/fisiopatologia , Pentilenotetrazol , Ibogaína/análogos & derivados , Ibogaína/farmacologia , Relação Dose-Resposta a DrogaRESUMO
BACKGROUND: Over the years, reports have associated fluoroquinolones (FQ) with seizures. The incidence and whether FQ compared to non-epileptogenic antibiotic are associated with increased risk of seizures has yet to be examined. METHODS: A retrospective observational study of hospitalized patients treated with FQ (ofloxacin, ciprofloxacin, levofloxacin, moxifloxacin) or macrolides (MA: azithromycin or roxithromycin) between January 2009 and January 2021 in a large tertiary academic medical centre. The outcome was the occurrence of a seizure during treatment. The Naranjo scale was used to assess causality between FQ treatment and seizures. Comparative analysis was conducted using propensity score matching to correct for possible bias due to non-random selection, followed by inverse probability weighting (IPW) to estimate the difference in seizure risk between FQ and MA. RESULTS: Overall, 52â722 patients were treated with FQ during a total of 178â982 days. Mean age was 65 (±19) years and 47% were females. Thirty-three patients (0.06%) experienced a seizure, yielding an incidence of 1:5422 treatment days. Causality was deemed probable and possible among 9/33 and 24/33, respectively. The MA group composed of 8522 patients treated during 17â954 treatment days. Mean age was 65 (±21) years, 49% were females. Six (0.07%) patients experienced each a single seizure. IPW estimated OR for seizures among the FQ versus MA group was 1.44 (95%CI 0.59-3.5, Pâ=â0.42). DISCUSSION: The incidence of FQ associated seizures among hospitalized patients is low and the risk did not significantly exceed that under macrolides. Our results provide evidence for clinicians and decision-makers when balancing fluoroquinolones risks and benefits.
Assuntos
Antibacterianos , Fluoroquinolonas , Convulsões , Humanos , Feminino , Masculino , Estudos Retrospectivos , Fluoroquinolonas/efeitos adversos , Fluoroquinolonas/uso terapêutico , Idoso , Convulsões/induzido quimicamente , Convulsões/epidemiologia , Pessoa de Meia-Idade , Antibacterianos/efeitos adversos , Idoso de 80 Anos ou mais , Incidência , Fatores de Risco , Macrolídeos/efeitos adversos , Macrolídeos/uso terapêutico , AdultoRESUMO
Epilepsy, a neurological disorder characterized by excessive neuronal activity and synchronized electrical discharges, ranks among the most prevalent global neurological conditions. Despite common use, antiepileptic drugs often result in adverse effects and lack effectiveness in controlling seizures in temporal lobe epilepsy (TLE) patients. Recent research explored the potential of occidentalin-1202, a peptide inspired by Polybia occidentalis venom, in safeguarding Wistar rats from chemically induced seizures. The present study evaluated the new analog from occidentalin-1202 named NOR-1202 using acute and chronic pilocarpine-induced models and an acute kainic acid (KA) male mice model. NOR-1202 was administered through the intracerebroventricular (i.c.v.), subcutaneous, or intraperitoneal routes, with stereotaxic procedures for the i.c.v. injection. In the acute pilocarpine-induced model, NOR-1202 (i.c.v.) protected against generalized seizures and mortality but lacked systemic antiepileptic activity. In the KA model, it did not prevent generalized seizures but improved survival. In the chronic TLE model, NOR-1202's ED50 did not differ significantly from the epileptic or healthy groups regarding time spent in spontaneous recurrent seizures during the five-day treatment. However, the NOR-1202 group exhibited more seizures than the healthy group on the second day of treatment. In summary, NOR-1202 exhibits antiepileptic effects against chemoconvulsant-induced seizures, but no effect was observed when administered systemically.
Assuntos
Anticonvulsivantes , Modelos Animais de Doenças , Convulsões , Animais , Masculino , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Camundongos , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamente , Pilocarpina , Ácido Caínico/análogos & derivados , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Peptídeos/administração & dosagem , Epilepsia do Lobo Temporal/tratamento farmacológico , Epilepsia do Lobo Temporal/induzido quimicamenteRESUMO
Collagen VI (Col-VI) is an extracellular matrix protein primarily known for its bridging role in connective tissues that has been suggested to play a neuroprotective role. In the present study we report increased mRNA and protein expression of Col-VI in the hippocampus and cortex at a late stage of epileptogenesis in a post-status epilepticus (SE) model of epilepsy and in brain tissue from patients with epilepsy. We further present a novel finding that exposure of mouse hippocampal slices to Col-VI augments paired-pulse facilitation in Schaffer collateral-CA1 excitatory synapses indicating decreased release probability of glutamate. In line with this finding, lack of Col-VI expression in the knock-out mice show paired-pulse depression in these synapses, suggesting increased release probability of glutamate. In addition, we observed dynamic changes in Col-VI blood plasma levels in rats after Kainate-induced SE, and increased levels of Col-VI mRNA and protein in autopsy or postmortem brain of humans suffering from epilepsy. Thus, our data indicate that elevated levels of ColVI following seizures leads to attenuated glutamatergic transmission, ultimately resulting in less overall network excitability. Presumably, increased Col-VI may act as part of endogenous compensatory mechanism against enhanced excitability during epileptogenic processes in the hippocampus, and could be further investigated as a potential functional biomarker of epileptogenesis, and/or a novel target for therapeutic intervention.
Assuntos
Colágeno Tipo VI , Camundongos Knockout , Convulsões , Transmissão Sináptica , Animais , Humanos , Masculino , Camundongos , Ratos , Colágeno Tipo VI/metabolismo , Colágeno Tipo VI/genética , Modelos Animais de Doenças , Potenciais Pós-Sinápticos Excitadores/fisiologia , Hipocampo/metabolismo , Ácido Caínico/toxicidade , Camundongos Endogâmicos C57BL , Ratos Sprague-Dawley , Convulsões/metabolismo , Convulsões/fisiopatologia , Convulsões/induzido quimicamente , Transmissão Sináptica/fisiologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Salvia divinorum (Epling and Játiva) is a psychoactive plant traditionally used by the Latinos for various medicinal purposes. Salvinorin A (Sal A), the main bioactive constituent of S. divinorum, is a natural highly selective kappa opioid receptor (KOR) agonist. Considering the anti-inflammatory effect of S. divinorum and endogenous hippocampal dynorphin/kappa opioid receptor (KOR) system playing an anticonvulsant function, we hypothesis that Sal A can be a potential candidate to treat epilepsy. Here, we identified whether Sal A ameliorated epileptic seizures and neuronal damages in animal model and in vitro model and investigated its underlying mechanisms. MATERIALS AND METHODS: Mice epilepsy model was induced by pilocarpine following seizures assessed by Racine classification. Hippocampus tissues were obtained for genetic, protein, and histological investigation. Furthermore, lipopolysaccharide (LPS)-activated BV2 microglial cells were utilized to validate the anti-inflammatory and microglia polarization regulation effects of Sal A. RESULTS: Sal A treatment significantly prolonged the latency to status epileptics (SE) and shortened the duration of SE in the pilocarpine-induced model. It also alleviated neuronal damages via activation of the AMPK/JNK/p-38 MAPK pathway and inhibition of apoptosis-related protein in hippocampus tissues. Furthermore, Sal A dose-dependently reduced microglia-mediated expression of pro-inflammatory cytokines and increased anti-inflammatory factors levels in SE mice and LPS-activated BV2 microglial cells by regulating microglia polarization. In addition, the effect of Sal A in vitro was totally blocked by KOR antagonist nor-BNI. CONCLUSION: Sal A treatment protects against epileptic seizures and neuronal damages in pilocarpine-induced models by suppressing the inflammation response through regulating microglial M1/M2 polarization. This study might serve as a theoretical basis for clinical applications of Sal A and its analogs and provide a new insight into the development of anti-seizure drugs.
Assuntos
Diterpenos Clerodânicos , Hipocampo , Microglia , Pilocarpina , Convulsões , Animais , Microglia/efeitos dos fármacos , Microglia/metabolismo , Pilocarpina/toxicidade , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Diterpenos Clerodânicos/farmacologia , Diterpenos Clerodânicos/uso terapêutico , Masculino , Camundongos , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamente , Anticonvulsivantes/farmacologia , Linhagem Celular , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/isolamento & purificaçãoRESUMO
Seizures are neurological disorders triggered by an imbalance in the activity of excitatory and inhibitory neurotransmitters in the brain. When triggered chronically, this imbalance can lead to epilepsy. Critically, many of the affected individuals are refractory to treatment. Given this, anti-inflammatory drugs, in particular glucocorticoids, have been considered as a potential antiepileptogenic therapy. Glucocorticoids are currently used in the treatment of refractory patients, although there have been contradictory results in terms of their use in association with antiepileptic drugs, which reinforces the need for a more thorough investigation of their effects. In this context, the present study evaluated the effects of dexamethasone (DEX, 0.6 mg/kg) on the electroencephalographic (EEG) and histopathological parameters of male Wistar rats submitted to acute seizure induced by pentylenetetrazol (PTZ). The EEG monitoring revealed that DEX reduced the total brainwave power, in comparison with PTZ, in 12 h after the convulsive episode, exerting this effect in up to 36 h (p < 0.05 for all comparisons). An increase in the accommodation of the oscillations of the delta, alpha, and gamma frequencies was also observed from the first 12 h onwards, with the accommodation of the theta frequency occurring after 36 h, and that of the beta frequency 24 h after the seizure. The histopathological analyses showed that the CA3 region and hilum of the hippocampus suffered cell loss after the PTZ-induced seizure (control vs. PTZ, p < 0.05), although DEX was not able to protect these regions against cell death (PTZ vs. DEX + PTZ, p > 0.05). While DEX did not reverse the cell damage caused by PTZ, the data indicate that DEX has beneficial properties in the EEG analysis, which makes it a promising candidate for the attenuation of the epileptiform wave patterns that can precipitate refractory seizures.
Assuntos
Ondas Encefálicas , Dexametasona , Eletroencefalografia , Pentilenotetrazol , Ratos Wistar , Convulsões , Animais , Dexametasona/farmacologia , Dexametasona/efeitos adversos , Pentilenotetrazol/toxicidade , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamente , Convulsões/fisiopatologia , Masculino , Ratos , Ondas Encefálicas/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/fisiopatologia , Anticonvulsivantes/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/fisiopatologiaRESUMO
INTRODUCTION: Excessive anxiety is a mental disorder, and its treatment involves the use of benzodiazepines, a class of drugs that enhance the effects of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABAA receptor. Anxiety disorders are frequent comorbidities in patients with epilepsy, and it has been speculated that anxiety disorders and epileptic seizures share common neurobiological mechanisms. However, conflicting results regarding anxiolytic and anxiogenic effects have been reported in animal models of epilepsy induced by pentylenetetrazole (PTZ) injections, and the causes of this discrepancy are unknown. We hypothesized that anxiety-like behaviors would change dynamically according to the changes in epilepsy susceptibility that occur during the PTZ kindling process. Therefore, we attempted to change anxiety-like behaviors bidirectionally depending on the number of PTZ injections. METHODS: Adult male rats were injected with PTZ 20 times every other day, and stages of seizure onset were classified according to the Racine staging system. Anxiety-like behaviors were measured after 10 and 20 injections. The control group was injected with an equal volume of saline solution. Anxiety-like behaviors were investigated using the open-field, light/dark transition, elevated plus maze, and social interaction tests. RESULTS: Bimodal changes in seizure stage were observed in response to PTZ kindling. The increase in the seizure stage was transiently suppressed after 10 injections, and this decrease in epileptic sensitivity disappeared after 20 injections. However, none of the rats reached a fully kindled state after 20 PTZ injections. After 10 PTZ injections, anxiety-like behaviors decreased compared with those of the control group in the open field, light/dark transition, and elevated plus-maze tests. The anxiolytic effects correlated with the seizure stage in individual rats. After 20 PTZ injections, anxiety-like behaviors returned to control levels. CONCLUSION: PTZ kindling induced bimodal changes in the seizure stage. Anxiety-like behaviors decreased with transient decrease in epileptic sensitivity and returned to control levels with the disappearance of these states. These findings suggest a common neurobiological mechanism underlying anxiety disorders and epileptic seizures. In addition, the discrepancy in the previous studies, in which anxiety levels increase or decrease in PTZ-kindled animals, may be due to examination at different phases of the kindling process.
Assuntos
Ansiedade , Convulsivantes , Modelos Animais de Doenças , Excitação Neurológica , Pentilenotetrazol , Convulsões , Animais , Masculino , Excitação Neurológica/efeitos dos fármacos , Ansiedade/etiologia , Ansiedade/induzido quimicamente , Convulsões/induzido quimicamente , Convulsões/psicologia , Convulsivantes/toxicidade , Ratos , Ratos Sprague-Dawley , Aprendizagem em Labirinto/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Teste de Campo Aberto , Interação Social/efeitos dos fármacosRESUMO
ABSTRACT: A 29-year-old Korean woman with chronic aplastic anemia presented with seizures due to cyclosporine-induced posterior reversible encephalopathy syndrome, caused by unpredictable oral cyclosporine (CS) accumulation and prolonged elimination. This case demonstrates the need to monitor CS drug levels with careful dose adjustments.