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1.
Braz. J. Biol. ; 83: 1-10, 2023. ilus, graf, tab
Artigo em Inglês | VETINDEX | ID: vti-765596

RESUMO

Only few studies have focus on animals that received Pilocarpine (Pilo) and did not develop behavioral status epilepticus (SE) and, whether they may become epileptic in the model's chronic phase. Previews works observed mossy fiber sprouting in the hippocampus of Non-SE (NSE) rats, while others observed spontaneous and recurrent seizures (SRS) 6 - 8 months after animals received Pilo. It is known that neuronal excitability is influenced by female hormones, as well as, the occurrence of SE in castrated and non-castrated female rats. However, it is not known whether females that received Pilo and did not show SE, may have SRS. The aim of this work was to investigate whether castrated and non-castrated female rats that did not show behavioral SE after Pilo, will develop SRS in the following one-year. For that, animals received 360 mg/kg of Pilo and were video monitored for 12 months. SE females from castrated and non-castrated groups became epileptic since the first month after drug injection. Epileptic behaviors were identified watching video monitoring recordings in the fast speed. Castrated and Non castrated NSE animals showed behaviors resembling seizures described by Racine Scale stages 1 - 3. Motor alterations showed by NSE groups could be observed only when recordings were analyzed in slow speed. In addition, behavioral manifestations as, rhythmic head movements, sudden head movements, whole body movements and immobility were also observed in both, SE and NSE groups. We concluded that NSE female rats may have become epileptic. Adding to it, slow speed analysis of motor alterations was essential for the observation of NSE findings, which suggests that possibly many motor alterations have been underestimated in epilepsy experimental research.(AU)


Poucos são os estudos com foco em animais que receberam Pilocarpina (Pilo) e não desenvolveram status epilepticus (SE) comportamental e, se os mesmos se tornarão epilépticos na fase crônica do modelo. Autores observaram o brotamento das fibras musgosas no hipocampo de ratos Não-SE (NSE), enquanto outros observaram crises espontâneas e recorrentes (CER) 6 - 8 meses após receberam a droga. A excitabilidade neuronal é influenciada pelos hormônios femininos e, da mesma forma, a ocorrência de SE em ratas castradas e não-castradas. Entretanto, não é sabido se as fêmeas que não apresentam SE terão CER. O objetivo deste trabalho foi investigar se fêmeas castradas e não castradas que não tiveram SE comportamental após a injeção de Pilo desenvolverão CER dentro de um ano. Para isto, os animais receberam 360 mg/kg de Pilo e foram videomonitorados por 12 meses. As fêmeas SE castradas e não-castradas se tornaram epilépticas desde o primeiro mês pós Pilo. O comportamento epiléptico foi identificado assistindo as gravações na velocidade rápida. As fêmeas NSE castradas e não-castradas apresentaram comportamentos similares aos estágios 1 - 3 da Escala de Racine. As alterações motoras nestes grupos (NSE) foram observadas apenas quando as videomonitoração foi analisada na velocidade lenta. Além destas, manifestações comportamentais como movimentos rítmicos da cabeça, movimentos súbitos da cabeça, movimentos de todo o corpo e imobilidade também foram observadas em ambos grupos, SE e NSE. Concluímos que as fêmeas NE podem ter se tornado epilépticas. Adicionado a isto, a análise das alterações motoras na velocidade lenta foi essencial para a observação dos achados das fêmeas NSE, o que sugere que possivelmente muitas alterações motoras têm sido subestimados na pesquisa em epilepsia experimental.(AU)


Assuntos
Animais , Feminino , Ratos , Epilepsia/induzido quimicamente , Epilepsia/veterinária , Pilocarpina/farmacologia , Pilocarpina/administração & dosagem , Pilocarpina/efeitos adversos , Modelos Animais
2.
Int J Mol Sci ; 23(21)2022 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-36361978

RESUMO

Epilepsy is a brain disorder characterized by recurrent epileptic seizures and neurobiological, physiological, mood, and cognitive consequences. In the last decade, the beneficial effects of regular physical exercise have been investigated in patients with neurodegenerative diseases such as epilepsy. However, data on its beneficial effects and underlying mechanisms are still insufficient. The objective of the current study was to investigate the effects of endurance training, applied before and after pilocarpine (Pilo) administration, on status epilepticus (SE) severity, and its relation to epileptogenesis deleterious consequences during the chronic epileptic phase. Long-term aerobic training, applied four weeks before SE and eight weeks after SE, elevated the threshold to induce SE and reduced spontaneous motor seizures. The protective effect of this alternative approach on seizure susceptibility resulted in improved memory responses, and alleviated comorbid depression in epileptic rats. The exercised epileptic rats had improved markers of oxidative stress by decreasing lipid peroxidation and increasing the levels of glutathione and activity of superoxide dismutase in the rat hippocampus. Aerobic training managed to ameliorate the neuroinflammation by decreasing the levels of TNF-α and IL-1ß in the hippocampus. Our results suggest that regular physical training predisposes the subjects to crucial plastic changes, leading to increased resistance to SE and the development of epileptogenesis.


Assuntos
Treino Aeróbico , Epilepsia , Estado Epiléptico , Animais , Ratos , Humanos , Pilocarpina/efeitos adversos , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/terapia , Convulsões , Epilepsia/induzido quimicamente , Hipocampo , Modelos Animais de Doenças
3.
Epilepsy Behav ; 137(Pt A): 108961, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36327645

RESUMO

OBJECTIVE: The main aim of this study was to assess the efficacy, safety, and tolerability of adjunctive perampanel (PER) in the treatment of children and adolescents with epilepsy. METHODS: Pediatric patients who visited the pediatric epilepsy clinic of Henan Provincial People's Hospital between May 2020 and December 2021 were recruited. All participants were treated with PER as adjunctive therapy and were seen routinely (minimum: a baseline and 12-week visit). The efficacy and tolerability of adjunctive PER for the treatment of epilepsy were investigated. RESULTS: One hundred and fourteen patients were enrolled, among whom 7 (6.1%) were lost to follow-up. At 12 weeks, the responder rate and the seizure-free rate were 56.1% (60/107) and 32.7% (35/107), respectively. The responder rate increased with the duration of PER administration and was significantly higher when PER was used as an early add-on (after ≤2 prior antiseizure medications (ASMs)) than a late add-on (after >2 prior ASMs). However, there was no significant difference in the treatment efficacy of adjunctive PER in patients with different epilepsy etiologies or types. Adverse events, including irritability, dizziness, somnolence, ataxic gait, weight gain, and tinnitus, were reported in thirty-two patients (29.9%). CONCLUSIONS: In a routine clinical setting of pediatric patients with epilepsy, good effectiveness and tolerability of adjunctive PER were demonstrated. Notably, patients initiating PER as an early add-on showed a better seizure outcome than those initiating PER as a late add-on.


Assuntos
Anticonvulsivantes , Epilepsia , Adolescente , Humanos , Criança , Anticonvulsivantes/efeitos adversos , Estudos Retrospectivos , Epilepsia/tratamento farmacológico , Epilepsia/induzido quimicamente , Piridonas/efeitos adversos , Resultado do Tratamento , Quimioterapia Combinada
4.
Epilepsy Behav ; 137(Pt A): 108958, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36327646

RESUMO

AIM: To evaluate the effectiveness and tolerability of cannabidiol (CBD) in patients with developmental and epileptic encephalopathies, including Dravet syndrome (DS), and Lennox-Gastaut syndrome (LGS), in a Spanish Expanded Access Program (EAP). METHODS: This was a multicenter, retrospective, observational study of patients treated with purified CBD in 14 hospitals across Spain. Patients with (1) written informed consent and (2) at least 6 months follow-up before the closure of the database were included. Primary effectiveness endpoints included reductions (100 %, ≥75 %, ≥50 %, ≥25 %, or 0 %) or worsening in seizure frequency (all seizure types and most disabling seizures) at 1-, 3-, 6-, and 12-month visits and at the last visit, and median relative seizure reduction between baseline and last visit. Secondary effectiveness endpoints included retention rate, reduction in seizure severity, status epilepticus, healthcare utilization, and quality of life. Primary safety endpoints included rates of adverse events (AEs) and AEs leading to discontinuation. RESULTS: One hundred and two patients (DS 12 %; LGS 59 %; other epilepsy syndromes 29 %) with a mean age of 15.9 years were enrolled. Patients were highly refractory to antiseizure medications (ASMs); mean number of prior failed ASMs was 7.5 (SD 3.7). The mean CBD dose was 13.0 mg/kg/day at the last visit. The proportion of patients with ≥50 % reduction in the total number of seizures from baseline was 44.9 % at 6 months and 38.9 % at 12 months. The median number of total seizures per month reduced by 47.6 % from baseline to the last visit. At 12 months, seizure severity was lower in 33/54 patients (61.1 %) and unchanged in 17/54 patients (31.5 %). Quality of life, based on the CAVE scale, increased from a mean score of 17.9 ± 4.7 (n = 54) at baseline to 21.7 ± 5.5 (n = 51) at the last patient visit (21.2 % improvement). The mean treatment retention time was 10.3 months. There were no statistically significant changes in the number of status epilepticus episodes, but lower healthcare utilization was observed. Adverse events occurred in sixty-eight patients (66.7 %), and the most common were somnolence (34.3 %) and diarrhea (12.7 %). Cannabidiol was discontinued exclusively due to AEs in 7.8 % of patients, increasing to 25.5 % when both lack of efficacy and AEs were considered together. CONCLUSIONS: Cannabidiol demonstrated promising effectiveness and tolerability in patients with developmental and epileptic encephalopathies taking part in a Spanish EAP.


Assuntos
Canabidiol , Epilepsias Mioclônicas , Epilepsia , Síndrome de Lennox-Gastaut , Estado Epiléptico , Adulto , Criança , Humanos , Adolescente , Canabidiol/uso terapêutico , Anticonvulsivantes/uso terapêutico , Estudos Retrospectivos , Qualidade de Vida , Epilepsia/tratamento farmacológico , Epilepsia/induzido quimicamente , Síndrome de Lennox-Gastaut/tratamento farmacológico , Convulsões/tratamento farmacológico , Epilepsias Mioclônicas/tratamento farmacológico , Estado Epiléptico/tratamento farmacológico , Resultado do Tratamento
5.
Int J Mol Sci ; 23(20)2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36293175

RESUMO

Abnormal energy expenditure during seizures and metabolic regulation through post-translational protein acylation suggest acylation as a therapeutic target in epilepsy. Our goal is to characterize an interplay between the brain acylation system components and their changes after seizures. In a rat model of pentylenetetrazole (PTZ)-induced epilepsy, we quantify 43 acylations in 29 cerebral cortex proteins; levels of NAD+; expression of NAD+-dependent deacylases (SIRT2, SIRT3, SIRT5); activities of the acyl-CoA-producing/NAD+-utilizing complexes of 2-oxoacid dehydrogenases. Compared to the control group, acylations of 14 sites in 11 proteins are found to differ significantly after seizures, with six of the proteins involved in glycolysis and energy metabolism. Comparing the single and chronic seizures does not reveal significant differences in the acylations, pyruvate dehydrogenase activity, SIRT2 expression or NAD+. On the contrary, expression of SIRT3, SIRT5 and activity of 2-oxoglutarate dehydrogenase (OGDH) decrease in chronic seizures vs. a single seizure. Negative correlations between the protein succinylation/glutarylation and SIRT5 expression, and positive correlations between the protein acetylation and SIRT2 expression are shown. Our findings unravel involvement of SIRT5 and OGDH in metabolic adaptation to seizures through protein acylation, consistent with the known neuroprotective role of SIRT5 and contribution of OGDH to the Glu/GABA balance perturbed in epilepsy.


Assuntos
Epilepsia , Sirtuína 3 , Animais , Ratos , Sirtuína 3/metabolismo , Pentilenotetrazol , Sirtuína 2/metabolismo , NAD/metabolismo , Acilação , Acil Coenzima A/metabolismo , Convulsões/induzido quimicamente , Epilepsia/induzido quimicamente , Encéfalo/metabolismo , Complexo Cetoglutarato Desidrogenase/metabolismo , Cetoácidos , Oxirredutases/metabolismo , Piruvatos , Ácido gama-Aminobutírico/metabolismo
6.
Epilepsy Behav ; 136: 108918, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36202052

RESUMO

OBJECTIVE: To investigate carotid body (CB) mechanisms related to sudden death during seizure. Ictal activation of oxygen-conserving reflexes (OCRs) can trigger fatal cardiorespiratory collapse in seizing rats, which presents like human sudden unexpected death in epilepsy (SUDEP). The CB is strongly implicated in OCR pathways; we hypothesize that modulating CB activity will provide insight into these mechanisms of death. METHODS: Long-Evans rats were anesthetized with urethane. Recordings included: electrocorticography, electrocardiography, respiration via nasal thermocouple, and blood pressure (BP). The mammalian diving reflex (MDR) was activated by cold water delivered through a nasal cannula. Reflex and stimulation trials were repeated up to 16 times (4 pre-intervention, 12 post-intervention) or until death. In some animals, one or both carotid bodies were denervated. In some animals, the CB was electrically stimulated, both with and without MDR. Seizures were induced with kainic acid (KA). RESULTS: Animals without seizure and with no CB modulation survived all reflexes. Non-seizing animals with CB denervation survived 7.1 ± 5.4 reflexes before death, and only 1 of 7 survived past the 12-trial threshold. Electrical CB stimulation without seizure and without reflex caused significant tachypnea and hypotension. Electrical CB stimulation with seizure and without reflex required higher amplitudes to replicate the physiological responses seen outside seizure. Seizing animals without CB intervention survived 3.2 ± 3.6 trials (per-reflex survival rate 42.0% ± 44.4%), and 0 of 7 survived past the 12-trial threshold. Seizing animals with electrical CB stimulation survived 10.5 ± 4.7 ictal trials (per-reflex survival rate 86.3% ± 35.0%), and 6 of 8 survived past the 12-trial threshold. SIGNIFICANCE: These results suggest that, during seizure, the ability of the CB to stimulate a restart of respiration is impaired. The CB and its afferents may be relevant to fatal ictal apnea and SUDEP in humans, and CB stimulation may be a relevant intervention technique in these deaths.


Assuntos
Corpo Carotídeo , Epilepsia , Morte Súbita Inesperada na Epilepsia , Humanos , Animais , Ratos , Ratos Long-Evans , Morte Súbita/etiologia , Epilepsia/induzido quimicamente , Epilepsia/complicações , Epilepsia/terapia , Convulsões , Mamíferos
7.
Seizure ; 102: 54-60, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36206645

RESUMO

BACKGROUND: Perampanel a third-generation antiseizure medication, belongs to a new promising class of drugs called AMPA receptor antagonists, approved to treat focal-onset seizures with or without focal to bilateral tonic clonic seizures and primary generalized tonic-clonic seizures. METHODS: This review included RCTs on patients with epilepsy exposed to perampanel compared with placebo, or one or more pre-existing antiseizure medications. Four databases and two clinical trial registries were searched from inception to July 2021. Included outcomes were 50% responder rate, seizure-free rate, discontinuation due to treatment-emergent adverse events (TEAE)s, having any TEAEs, and most reported TEAEs. Cochrane risk of bias tool was used to assess the internal validity of the included RCTs. RESULTS: From 2211 retrieved citations, eight RCTs were included in the meta-analysis. Fifty-percent responder and seizure freedom rates were significantly higher in patients receiving perampanel when compared to placebo (RR 1.57, 95 % CI 1.35 to 1.82, I2 15% and RR 2.79, 95% CI 1.58 to 4.93, I2 7%, respectively). The 50% responder rates for 8mg and 12 mg, when compared to placebo, were similar. The most-reported TEAEs were dizziness and somnolence with <1% reporting serious psychological outcomes. CONCLUSION: This systematic review reports significant reduction in seizures and a potential dose-based increase in discontinuations due to TEAE. The most-reported TEAEs were non-threatening, with the possibility of rare but serious adverse psychological outcomes. Further independent RCTs studying the most efficient dose for efficacy and safety are needed.


Assuntos
Anticonvulsivantes , Epilepsia , Humanos , Anticonvulsivantes/efeitos adversos , Resultado do Tratamento , Piridonas/efeitos adversos , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamente , Epilepsia/tratamento farmacológico , Epilepsia/induzido quimicamente , Quimioterapia Combinada , Ensaios Clínicos Controlados Aleatórios como Assunto
8.
Brain Res Bull ; 191: 20-29, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36209957

RESUMO

OBJECTIVES: This study aimed to explore the effect of concomitant use of Furosemide (FRS) and Valproic acid (VPA), demonstrating anti-inflammation efficacy, on epilepsy, and its underlying mechanism. METHODS: Twenty-five adult male Wistar rats were divided into five groups including, Group 1: (Normal) rats received no drugs, Group 2: (E): rats were administered with a single dose of kainic acid (stereotaxic surgery), Group 3: (E + VPA): rats received Valproic acid (200 mg/kg/day/orally), Group 4: (E + FRS): rats received a single dose of Furosemide (100 mg/kg/I.P.) 30 min before epilepsy induction, Group 5: (E + VPA (200 mg/Kg)+FRS (100 mg/Kg, combination treatment). The treatment group received VPA for 14 days. We assessed seizures based on modified Racine΄s scores and conducted the electroencephalographic (EEG) recording. NLRP1 and NLRP3 mRNA levels, Apoptosis-associated Speck-like protein containing a caspase recruitment domain (ASC), absence in melanoma2 (AIM2) protein expression levels, and apoptosis rate of the brain cells were analyzed utilizing real-time PCR, immunohistochemistry, and tunnel assay, respectively. RESULTS: The results revealed that FRS and VPA treatment, alone or in combination, improved behavioral outcome and reduced seizure intensity in epileptic rats. The combination therapy significantly decreased the apoptosis rate NLRP1 and NLRP3 gene as well as ASC and AIM2 protein expression levels. CONCLUSION: Combination therapy protected the brain against neuronal damages in rats, and decreased the severity of epilepsy in K.A. induced rats. Reducing inflammation and apoptosis and improving the performance of behavioral testing in the K.A. induced epilepsy model increased the likelihood of success of combination therapy compared with VPA and FRS treatment alone.


Assuntos
Epilepsia , Ácido Valproico , Animais , Masculino , Ratos , Encéfalo/metabolismo , Modelos Animais de Doenças , Proteínas de Ligação a DNA/metabolismo , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Epilepsia/genética , Furosemida , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos Wistar , RNA Mensageiro , Ácido Valproico/farmacologia , Ácido Valproico/uso terapêutico
9.
Epilepsy Behav ; 136: 108938, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36228485

RESUMO

BACKGROUND: Levetiracetam is a broad-spectrum antiseizure medication with known behavioral side effects. The possible beneficial effect of pyridoxine on improvement of these psychiatric problems has been suggested in few previous studies. This clinical trial aimed to investigate the effect of pyridoxine on behavioral side effects of levetiracetam in adult patients with epilepsy. METHODS: This study was a randomized double-blind placebo-controlled clinical trial on 53 adult patients with epilepsy with behavioral side effects after treatment by levetiracetam. Patients who met the study criteria were randomized to receive 40 mg/day pyridoxine or placebo. Their psychiatric state was surveyed by SCL-90-R questionnaire before and three weeks after initiation of treatment. RESULTS: There were no statistically significant differences in the behavioral adverse effects between the pyridoxine-treated group and the placebo group. CONCLUSION: Although this study showed no statistically significant beneficial effects of pyridoxine on the behavioral adverse effects of levetiracetam, placebo-controlled trials with a larger size and higher doses are needed to determine whether it is effective or not.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Epilepsia , Piracetam , Adulto , Humanos , Levetiracetam/uso terapêutico , Piracetam/efeitos adversos , Piridoxina/uso terapêutico , Anticonvulsivantes/efeitos adversos , Epilepsia/tratamento farmacológico , Epilepsia/induzido quimicamente , Método Duplo-Cego , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Resultado do Tratamento
10.
Biomed Res Int ; 2022: 5940372, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36093409

RESUMO

Ganoderic acid A (GAA) exhibited neuron protection in in vitro epilepsy study, but no study has been done in vivo. Rats were administered (i.p.) pentylenetetrazole daily for 28 days to induce seizure. Rats with grade II or above of epileptic score were divided into three groups and given placebo, sodium valproate, or GAA treatment, respectively, for 7 days. The electrical signals of brain were monitored with electroencephalography (EGG); epileptic behavior was assessed using the Racine scale; morphological changes and apoptosis rate of cortical neurons were assessed with H&E staining and TUNEL staining, respectively. Protein expression of calcium-sensing receptor, p-ERK, p-JNK, and p-p38 in hippocampal tissue and Bcl-2, cleaved caspase-3, and Bax in cortical tissues was observed by Western blot and immunohistochemistry assay, respectively. After GAA treatment, apparent seizure-like EEG with significant arrhythmic disorder and spike waves was reduced or disappeared, and wave amplitude of EEG was reduced significantly. GAA showed similar effect with sodium valproate treatments on epilepsy. There were an apparent improvement of the epileptic behavior and a significant increase in the epileptic latency and shortening of the epileptic duration in the treatment group compared to control. GAA treatment ameliorated the nuclear pyknosis of neurons which appeared seriously in the epilepsy group. GAA treatment significantly reduced the cortical neuron apoptosis of epilepsy and the expression of calcium-sensing receptor, p-P38, p-JNK, cleaved caspase-3, and Bax but increased the expression of both p-ERK and Bcl-2. In conclusion, GAA treatment showed strong antiepileptic effect by decreasing apoptosis in cortical neuron and the expression of calcium-sensing receptor and stimulating the MAPK pathway.


Assuntos
Epilepsia , Pentilenotetrazol , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Caspase 3/metabolismo , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Ácidos Heptanoicos , Lanosterol/análogos & derivados , Pentilenotetrazol/efeitos adversos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Receptores de Detecção de Cálcio , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Ácido Valproico/efeitos adversos , Proteína X Associada a bcl-2/metabolismo
11.
J Neuroinflammation ; 19(1): 226, 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36104755

RESUMO

Evidence from experimental and clinical studies implicates immuno-inflammatory responses as playing an important role in epilepsy-induced brain injury. Captopril, an angiotensin-converting enzyme inhibitor (ACEi), has previously been shown to suppress immuno-inflammatory responses in a variety of neurological diseases. However, the therapeutic potential of captopril on epilepsy remains unclear. In the present study, Sprague Dawley (SD) rats were intraperitoneally subjected to kainic acid (KA) to establish a status epilepticus. Captopril (50 mg/kg, i.p.) was administered daily following the KA administration from day 3 to 49. We found that captopril efficiently suppressed the KA-induced epilepsy, as measured by electroencephalography. Moreover, captopril ameliorated the epilepsy-induced cognitive deficits, with improved performance in the Morris water maze, Y-maze and novel objective test. RNA sequencing (RNA-seq) analysis indicated that captopril reversed a wide range of epilepsy-related biological processes, particularly the glial activation, complement system-mediated phagocytosis and the production of inflammatory factors. Interestingly, captopril suppressed the epilepsy-induced activation and abnormal contact between astrocytes and microglia. Immunohistochemical experiments demonstrated that captopril attenuated microglia-dependent synaptic remodeling presumably through C3-C3ar-mediated phagocytosis in the hippocampus. Finally, the above effects of captopril were partially blocked by an intranasal application of recombinant C3a (1.3 µg/kg/day). Our findings demonstrated that captopril reduced the occurrence of epilepsy and cognitive impairment by attenuation of inflammation and C3-mediated synaptic phagocytosis. This approach can easily be adapted to long-term efficacy and safety in clinical practice.


Assuntos
Disfunção Cognitiva , Epilepsia , Animais , Captopril/farmacologia , Captopril/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Inflamação/tratamento farmacológico , Ácido Caínico/toxicidade , Fagocitose , Ratos , Ratos Sprague-Dawley
12.
Yakugaku Zasshi ; 142(9): 1031-1035, 2022.
Artigo em Japonês | MEDLINE | ID: mdl-36047215

RESUMO

Lacosamide is a novel antiepileptic drug. Although many antiepileptic drugs reportedly pose a risk to fetuses, patients with epilepsy are advised to continue their medications during pregnancy. There have been few reports on lacosamide use during pregnancy, and its effects on the fetus remain unclear. Here, we report a case of lacosamide use during pregnancy. The 33-year-old patient was treated with oral lacosamide (400 mg/d) for symptomatic partial epilepsy. She was concomitantly treated with folic acid (5 mg/d) beginning 4 days before her last menstrual cycle. She was also concomitantly treated with oral perampanel (2 mg/d) at 5-7 weeks' gestation for seizure control but discontinued perampanel after the pregnancy was discovered. She progressed through her pregnancy with only mild seizures. Fetal growth was normal and ultrasonography revealed no external malformations. The patient had an elective cesarean section at 37 weeks and 2 days owing to a previous post-cesarean pregnancy. Her baby boy weighed 3025 g; his Apgar score was 8 and 9, 1 and 5 min, respectively, and his umbilical artery blood pH was 7.348. He had no congenital anomalies and no neonatal drug withdrawal symptoms. This suggests that lacosamide may have a low risk of teratogenicity and fetal toxicity. Thus, this case is valuable for clinicians who are considering the administration of antiepileptic drugs during pregnancy. In the future, more reports on the use of lacosamide during pregnancy should be collected.


Assuntos
Anticonvulsivantes , Epilepsia , Adulto , Anticonvulsivantes/efeitos adversos , Cesárea , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Feminino , Humanos , Lactente , Lacosamida/efeitos adversos , Masculino , Gravidez , Convulsões/induzido quimicamente , Resultado do Tratamento
13.
Epilepsy Behav ; 135: 108904, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36095876

RESUMO

OBJECTIVE: The management of pregnant women with epilepsy (WWE) treated with antiepileptic drugs (AEDs) polytherapy poses a great challenge. The purpose of this study was to evaluate the major congenital malformations (MCMs) associated with AED polytherapy, to assess the impacts of polytherapy regimens on seizure control and breastfeeding, and to determine the potential predictors for pregnancy outcomes. METHODS: This study was based on prospectively acquired data from a registry enrolling WWE in early pregnancy from Feb 2010 to July 2019, in which 123 pregnancies in 110 WWE were exposed to 27 different AED combinations. RESULTS: There were 123 pregnancies in 110 WWE analyzed in our study. The live birth rate was 86.2 % and the risk of MCMs was 10.4 %. Multivariate analysis indicated that prenatal exposure to phenobarbital (odds ratio [OR], 17.424; 95 %CI, 1.510-201.067; P = 0.022) and topiramate (OR, 9.469; 95 %CI, 1.149-62.402; P = 0.036) was associated with increased risk of MCMs. Valproate (OR, 4.441; 95 %CI, 1.165-16.934; P = 0.029), phenobarbital (OR, 13.636; 95 %CI, 2.146-86.660; P = 0.006) and topiramate (OR, 7.527; 95 %CI, 1.764-32.118; P = 0.006) were significantly correlated with adverse pregnancy outcomes. Among 67 pregnancies in four combinations over 10 patients, 15 (22.4 %) remained seizure free through pregnancy, seizure frequency increased in 17 (25.4 %), decreased in 24 (35.8 %) women, in 26 (38.8 %) remained unchanged. Only 23.6 % of mothers undertook exclusive breastfeeding. Planned pregnancy was the only independent factor significantly associated with decreased risk of adverse pregnancy outcomes (OR, 0.139; 95 % CI, 0.051-0.382; P < 0.001). Notably, no adverse pregnancy outcome was recorded in pregnancies exposed to the combination of lamotrigine plus levetiracetam. CONCLUSION: Prenatal exposure to the combinations containing valproate, phenobarbital, or topiramate was associated with increased risk of adverse pregnant outcomes. AED-related teratogenicity may be reduced by planned pregnancy in WWE exposed to polytherapy. Our findings also suggest the combination of lamotrigine and levetiracetam seems to be most desirable to balance seizure control and fetal safety.


Assuntos
Epilepsia , Complicações na Gravidez , Efeitos Tardios da Exposição Pré-Natal , Anticonvulsivantes/efeitos adversos , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Feminino , Humanos , Lamotrigina/uso terapêutico , Levetiracetam/uso terapêutico , Masculino , Fenobarbital/efeitos adversos , Gravidez , Complicações na Gravidez/induzido quimicamente , Complicações na Gravidez/tratamento farmacológico , Resultado da Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Sistema de Registros , Topiramato/uso terapêutico , Ácido Valproico/efeitos adversos
14.
Neuroscience ; 504: 1-9, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36122882

RESUMO

Epilepsy is a neurological disorder caused by abnormally elevated neuronal firing and excitability. Spire2, also known as the nucleating factor of F-actin, plays an important role in long-range vesicle transport. This study showed that Spire2 was highly expressed in neurons in the cortex and hippocampus. Its knockdown significantly reduced the initiation current of the evoked action potential and the frequency of action potential, suggesting that Spire2 knockdown inhibits the threshold current of the neuron. In the cortex of patients with refractory temporal lobe epilepsy (TLE), Spire2 expression was significantly reduced. Decreased expression levels of Spire2 were also observed in kainic acid (KA) and pentylenetetrazole (PTZ) animal models. In the KA and PTZ models, Spire2-knockdown mice showed significantly increased seizures and shortened intervals between seizures, with a tendency to increase seizure duration. In contrast, Spire2-overexpressing mice showed reduced numbers of spontaneous seizures. In conclusion, this study revealed a significantly decreased expression of Spire2 in the brain tissues of epileptic individuals and an inhibitory role for this protein in the development of epilepsy. In addition, knockdown of Spire2 aggravated abnormal firing in epileptic mice, while its overexpression had the opposite effect. These findings provide new insights into the mechanism of epileptogenesis.


Assuntos
Epilepsia do Lobo Temporal , Epilepsia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Epilepsia/metabolismo , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/metabolismo , Pentilenotetrazol/farmacologia , Convulsões/metabolismo , Ácido Caínico , Hipocampo/metabolismo
15.
Epilepsy Behav ; 136: 108885, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36150304

RESUMO

Perampanel, a selective, non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, is a once-daily oral anti-seizure medication (ASM) for focal-onset seizures (FOS) and generalized tonic-clonic seizures (GTCS). In the US, perampanel is approved for the treatment of FOS (adjunctive and monotherapy), with or without focal to bilateral tonic-clonic seizures (FBTCS), in patients aged ≥4 years, and as adjunctive treatment of GTCS in patients aged ≥12 years. The monotherapy approvals in the US were based on the Food and Drug Administration's (FDA's) policy allowing extrapolation of adjunctive data to the monotherapy setting in the absence of randomized controlled monotherapy trials; since then, perampanel monotherapy has received approvals in approximately 48 countries. As there are key differences in clinical evidence of perampanel as adjunctive therapy vs monotherapy, we review the clinical outcomes of perampanel when administered as primary or secondary monotherapy. Eight publications reporting the efficacy and safety outcomes of perampanel monotherapy in clinical trial and real-world settings were selected during our literature search and are included; these comprise three Eisai-sponsored studies in patients with epilepsy: one prospective, open-label, Phase III clinical trial of patients with newly diagnosed epilepsy (Study 342 [FREEDOM]) and two retrospective, real-world Phase IV studies of patients with epilepsy who received perampanel during routine clinical care (Studies 504 and 506 [PROVE]); and five retrospective, real-world studies in patients with epilepsy who were prescribed perampanel during routine clinical care. Results from these studies demonstrated that seizure freedom may be achieved following treatment with perampanel monotherapy (either primary or secondary), with favorable retention rates and safety profiles. Overall, the clinical evidence supports the use of perampanel monotherapy both in newly diagnosed patients and in those who have been unable to control their seizures with other ASMs.


Assuntos
Anticonvulsivantes , Epilepsia , Humanos , Anticonvulsivantes/efeitos adversos , Estudos Retrospectivos , Estudos Prospectivos , Resultado do Tratamento , Piridonas/efeitos adversos , Epilepsia/tratamento farmacológico , Epilepsia/induzido quimicamente , Quimioterapia Combinada
16.
Bratisl Lek Listy ; 123(9): 648-652, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36039883

RESUMO

Epilepsy is a widespread and mainly severe neurological condition portrayed by recurring spontaneous seizures caused by the brain's abnormal electrical activity. According to new research, inflammation may be both a result and the cause of epileptic seizures. The highest zinc levels in the brain have been found in the hippocampus which is one of the most studied regions of the brain regarding epilepsy. Zinc may have an anti-inflammatory potential as zinc co-factors affect numerous biochemical and physiological reactions. In this study, we evaluated the effects of intraperitoneal zinc administration on seizure activity in murine PTZ model. Rats received either intraperitoneal (IP) zinc sulfate at two different dosages (50-100 mg/kg) or a placebo followed by pentylenetetrazole (IP), a strong seizure-inducing drug. The spike percentages were considerably lower in the PTZ (35 mg/kg) and 50 or 100 mg/kg zinc-treated groups (A3 and A4) than in the PTZ (35 mg/kg) and saline-treated group (A2; p may be used as an adjuvant therapy in combination with other antiepileptic drugs in the future (Tab. 3, Fig. 1, Ref. 27) Keywords: anti-seizure effect of zinc, epilepsy, abnormal electrical activity, antiepileptic drugs, rat model.


Assuntos
Anticonvulsivantes , Epilepsia , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Hipocampo , Camundongos , Pentilenotetrazol/efeitos adversos , Ratos , Zinco/uso terapêutico
17.
J Neuroinflammation ; 19(1): 202, 2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35941644

RESUMO

BACKGROUND: Apoptosis signal-regulating kinase 1 (ASK1) not only causes neuronal programmed cell death via the mitochondrial pathway but also is an essential component of the signalling cascade during microglial activation. We hypothesize that ASK1 selective deletion modulates inflammatory responses in microglia/macrophages(Mi/Mϕ) and attenuates seizure severity and long-term cognitive impairments in an epileptic mouse model. METHODS: Mi/Mϕ-specific ASK1 conditional knockout (ASK1 cKO) mice were obtained for experiments by mating ASK1flox/flox mice with CX3CR1creER mice with tamoxifen induction. Epileptic seizures were induced by intrahippocampal injection of kainic acid (KA). ASK1 expression and distribution were detected by western blotting and immunofluorescence staining. Seizures were monitored for 24 h per day with video recordings. Cognition, social and stress related activities were assessed with the Y maze test and the three-chamber social novelty preference test. The heterogeneous Mi/Mϕ status and inflammatory profiles were assessed with immunofluorescence staining and real-time polymerase chain reaction (q-PCR). Immunofluorescence staining was used to detect the proportion of Mi/Mϕ in contact with apoptotic neurons, as well as neuronal damage. RESULTS: ASK1 was highly expressed in Mi/Mϕ during the acute phase of epilepsy. Conditional knockout of ASK1 in Mi/Mϕ markedly reduced the frequency of seizures in the acute phase and the frequency of spontaneous recurrent seizures (SRSs) in the chronic phase. In addition, ASK1 conditional knockout mice displayed long-term neurobehavioral improvements during the Y maze test and the three-chamber social novelty preference test. ASK1 selective knockout mitigated neuroinflammation, as evidenced by lower levels of Iba1+/CD16+ proinflammatory Mi/Mϕ. Conditional knockout of ASK1 increased Mi/Mϕ proportion in contact with apoptotic neurons. Neuronal loss was partially restored by ASK1 selective knockout. CONCLUSION: Conditional knockout of ASK1 in Mi/Mϕ reduced seizure severity, neurobehavioral impairments, and histological damage, at least via inhibiting proinflammatory microglia/macrophages responses. ASK1 in microglia/macrophages is a potential therapeutic target for inflammatory responses in epilepsy.


Assuntos
Epilepsia , Microglia , Animais , Epilepsia/induzido quimicamente , Epilepsia/genética , Epilepsia/metabolismo , Ácido Caínico/toxicidade , Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , Convulsões/induzido quimicamente , Convulsões/genética , Convulsões/metabolismo
18.
Prog Neurobiol ; 218: 102337, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35934131

RESUMO

Decreased expression of the δ subunit of the GABAA receptor (GABAAR) has been found in the dentate gyrus in several animal models of epilepsy and other disorders with increased excitability and is associated with altered modulation of tonic inhibition in dentate granule cells (GCs). In contrast, other GABAAR subunits, including α4 and γ2 subunits, are increased, but the relationship between these changes is unclear. The goals of this study were to determine if viral transfection of δ subunits in dentate GCs could increase δ subunit expression, alter expression of potentially-related GABAAR subunits, and restore more normal network excitability in the dentate gyrus in a mouse model of epilepsy. Pilocarpine-induced seizures were elicited in DOCK10-Cre mice that express Cre selectively in dentate GCs, and two weeks later the mice were injected unilaterally with a Cre-dependent δ-GABAAR viral vector. At 4-6 weeks following transfection, δ subunit immunolabeling was substantially increased in dentate GCs on the transfected side compared to the nontransfected side. Importantly, α4 and γ2 subunit labeling was downregulated on the transfected side. Electrophysiological studies revealed enhanced tonic inhibition, decreased network excitability, and increased neurosteroid sensitivity in slices from the δ subunit-transfected side compared to those from the nontransfected side of the same pilocarpine-treated animal, consistent with the formation of δ subunit-containing GABAARs. No differences were observed between sides of eYFP-transfected animals. These findings are consistent with the idea that altering expression of key subunits, such as the δ subunit, regulates GABAAR subunit assemblies, resulting in substantial effects on network excitability.


Assuntos
Epilepsia , Neuroesteroides , Animais , Giro Denteado/metabolismo , Epilepsia/induzido quimicamente , Epilepsia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pilocarpina/metabolismo , Pilocarpina/farmacologia , Receptores de GABA-A/metabolismo , Ácido gama-Aminobutírico/metabolismo
19.
Cell Biol Int ; 46(11): 1814-1824, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35989483

RESUMO

In previous studies, we found that dynorphin exerts antiepileptic effect by activating the kappa opioid receptor (KOR). However, the role of neuronal autophagy in dynorphin/KOR-mediated antiepileptic is still unclear. This study aimed to investigate the molecular mechanism of dynorphin's antiepileptic effect by inhibiting autophagy and reducing neuronal apoptosis. Here, a pilocarpine-induced rat model of epilepsy was established and hippocampal neurons were treated with Mg2+ -free exposed for epileptiform activity induction. The real-time polymerase chain reaction and Western blot analysis were used to evaluate messenger RNA and protein expression. The TdT-mediated dUTP-biotin nick end labeling staining and flow cytometry were used to analyze cell apoptosis in vivo and in vitro. Neuron cells viability was detected by Cell Counting Kit-8 assay. Immunofluorescent staining and green fluorescent protein-light chain 3 immunofluorescence were used to measure autophagy in vivo and in vitro. Results showed that overexpression of prodynorphin alleviated neuronal apoptosis, activated the mammalian target of rapamycin (mTOR) signaling pathway, and inhibited neuronal autophagy in epileptic rats. Dynorphin inhibited Mg2+ -free-induced seizure-like neuron apoptosis, partially reversing the effect of Mg2+ -free on the mTOR signaling pathway and seizure-like neuron autophagy. Further, using rapamycin, we found that dynorphin inhibited Mg2+ -free-induced seizure-like neuron autophagy and apoptosis by activating the mTOR signaling pathway. In conclusion, dynorphin inhibits autophagy by activating the mTOR signaling pathway and has a protective effect on epilepsy acute seizure and epilepsy-induced brain injury.


Assuntos
Dinorfinas , Epilepsia , Animais , Anticonvulsivantes/farmacologia , Apoptose , Autofagia , Biotina/metabolismo , Biotina/farmacologia , Biotina/uso terapêutico , Epilepsia/induzido quimicamente , Epilepsia/metabolismo , Proteínas de Fluorescência Verde , Mamíferos/metabolismo , Pilocarpina , RNA Mensageiro , Ratos , Ratos Sprague-Dawley , Receptores Opioides kappa/uso terapêutico , Convulsões/induzido quimicamente , Transdução de Sinais , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo
20.
Eur J Pharmacol ; 931: 175213, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35981604

RESUMO

Morin is a bioactive flavonoid with prominent neuroprotective potentials, however, its impact on epilepsy-provoked cognitive dysregulations has not been revealed. Hence, the present investigation aims to divulge the potential anticonvulsant/neuroprotective effects of morin in rats using a pentylenetetrazole (PTZ)-induced kindling model with an emphasis on the possible signaling trajectories involved. Kindling was induced using a sub-convulsive dose of PTZ (35 mg/kg, i.p.), once every other day for 25 days (12 injections). The expression of targeted biomarkers and molecular signals were examined in hippocampal tissues by ELISA, Western blotting, immunohistochemistry, and histopathology. Contrary to PTZ effects, administration of morin (10 mg/kg, i.p., from day 15 of PTZ injection to the end of the experiment) significantly reduced the severity of seizures coupled with a delay in kindling acquisition. It also preserved hippocampal neurons, and diminished astrogliosis to counteract cognitive deficits, exhibited by the enhanced performance in MWM and PA tests. These favorable impacts of morin were mediated via the abrogation of the PTZ-induced necroptotic changes and mitochondrial fragmentation proven by the suppression of p-RIPK-1/p-RIPK-3/p-MLKL and PGAM5/Drp-1 cues alongside the enhancement of caspase-8. Besides, morin inhibited the inflammatory cascade documented by the attenuation of the pro-convulsant receptor/cytokines TNFR-1, TNF-α, I L-1ß, and IL-6 and the marked reduction of hippocampal IL-6/p-JAK2/p-STAT3/GFAP cue. In tandem, morin signified its anti-oxidant capacity by lowering the hippocampal contents of MDA, NOX-1, and Keap-1 with the restoration of the impaired Nrf-2/HO-1 pathway. Together, these versatile neuro-modulatory effects highlight the promising role of morin in the management of epilepsy.


Assuntos
Epilepsia , Excitação Neurológica , Animais , Cognição , Epilepsia/induzido quimicamente , Flavonoides , Hipocampo , Interleucina-6/metabolismo , Janus Quinase 2/metabolismo , Pentilenotetrazol , Proteínas Quinases/metabolismo , Ratos , Convulsões/induzido quimicamente , Fator de Necrose Tumoral alfa/metabolismo
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