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1.
Int J Dev Neurosci ; 80(1): 1-12, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31909494

RESUMEN

Febrile seizures are one of the most frequent childhood neurological disorders; they are classified into simple and prolonged, depending on their duration. Prolonged FS lasts more than 15 min and may evoke neurological sequelae in a process in which molecular alterations seem to play an important role. Adenosine is a purine nucleoside that exerts anticonvulsant effects through binding to adenosine A1 receptor (A1 R). This receptor belongs to the GPCR superfamily and is negatively coupled to adenylyl cyclase (AC) activity through Gi proteins. In the present study, we analyzed the functionality of A1 R, measured as the inhibition of forskolin-stimulated AC activity, 48 hr after hyperthermia-induced seizures (HIS). Surprisingly, the results obtained show that the activation of A1 R increased forskolin-stimulated cAMP production instead of decreasing it. This alteration was not accompanied by changes in αG protein levels. The functionality of A1 R remained altered two months after HIS. However, this alteration was abolished when AC assays were carried out in the presence of anti αGs subunit-specific antibody, suggesting that HIS can switch A1 R coupling from Gi to Gs proteins. Finally, radioligand binding assays revealed that density and affinity of A1 R were not significantly altered by HIS. In summary, the results obtained show that HIS induces long-term changes in the A1 R/AC signaling pathway in rat brain cortex.


Asunto(s)
Corteza Cerebral/metabolismo , Receptor de Adenosina A1/metabolismo , Convulsiones Febriles/metabolismo , Animales , Hipertermia Inducida , Ratas
2.
Brain Dev ; 42(2): 103-112, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31677915

RESUMEN

BACKGROUND: Several studies have investigated the potential effects of antihistamines on febrile seizure. However, these findings are inconsistent across the studies. METHOD: A retrospective observational study was conducted on a total of 434 consecutive patients aged between 6 months and 5 years with the diagnosis of febrile seizure. Patients with chronic medical conditions were excluded. Multivariable generalized linear models were conducted to ascertain the effects of antihistamine use on duration of febrile seizure. Also, we conducted a systematic review and meta-analyses of the medical literatures to calculate the pooled estimates using random effects models. RESULTS: The adjusted mean duration of febrile seizure in the antihistamine group was 4.9 min shorter than that in the non-user group (95% confidence interval (CI), 0.4-9.5). The risk of duration in febrile seizure >5 min among antihistamine users was also 0.83 times that among the non-users (95%CI, 0.58-1.19), whereas the risk of duration in febrile seizure >10 min among first-generation antihistamine users was 1.21 times that among non-users (95%CI, 0.69-2.13). According to the systematic review of the literature, 8 observational studies were included in the meta-analyses. Comparing to non-users, the antihistamine users had prolonged duration of febrile seizure by 1.07 min (95%CI, -1.13 to 3.27), elevated risk of duration in febrile seizure >5 min (Risk ratio, 1.16; 95%CI, 0.90-1.49), and similar duration from fever to febrile seizure onset (pooled mean difference, -0.01 h; -1.43 to 1.41), but these estimates were imprecise. Similar results were obtained when we stratified the data by types of antihistamine (first vs. second generation). CONCLUSIONS: Our study may indicate the effects of antihistamine on prolonging febrile seizure duration, but they are still controversial given the limited evidence, highly heterogeneous results, and concerns of the internal and external validities.


Asunto(s)
Antagonistas de los Receptores Histamínicos/uso terapéutico , Convulsiones Febriles/tratamiento farmacológico , Carbamazepina , Preescolar , Epilepsias Parciales/tratamiento farmacológico , Epilepsia Tónico-Clónica/tratamiento farmacológico , Femenino , Antagonistas de los Receptores Histamínicos/metabolismo , Humanos , Lactante , Masculino , Estudios Retrospectivos , Convulsiones Febriles/metabolismo , Convulsiones Febriles/fisiopatología , Factores de Tiempo , Insuficiencia del Tratamiento
3.
eNeuro ; 6(6)2019.
Artículo en Inglés | MEDLINE | ID: mdl-31685676

RESUMEN

The role of neuroinflammation in the mechanisms of epilepsy development is important because inflammatory mediators provide tractable targets for intervention. Inflammation is intrinsically involved in the generation of childhood febrile seizures (FSs), and prolonged FS [febrile status epilepticus (FSE)] precedes a large proportion of adult cases of temporal lobe epilepsy (TLE). As TLE is often refractory to therapy and is associated with serious cognitive and emotional problems, we investigated whether its development can be prevented using anti-inflammatory strategies. Using an immature rat model of FSE [experimental FSE (eFSE)], we administered dexamethasone (DEX), a broad anti-inflammatory agent, over 3 d following eFSE. We assessed eFSE-provoked hippocampal network hyperexcitability by quantifying the presence, frequency, and duration of hippocampal spike series, as these precede and herald the development of TLE-like epilepsy. We tested whether eFSE provoked hippocampal microgliosis, astrocytosis, and proinflammatory cytokine production in male and female rats and investigated blood-brain barrier (BBB) breaches as a potential contributor. We then evaluated whether DEX attenuated these eFSE sequelae. Spike series were not observed in control rats given vehicle or DEX, but occurred in 41.6% of eFSE-vehicle rats, associated with BBB leakage and elevated hippocampal cytokines. eFSE did not induce astrocytosis or microgliosis but provoked BBB disruption in 60% of animals. DEX significantly reduced spike series prevalence (to 7.6%) and frequency, and abrogated eFSE-induced cytokine production and BBB leakage (to 20%). These findings suggest that a short, postinsult intervention with a clinically available anti-inflammatory agent potently attenuates epilepsy-predicting hippocampal hyperexcitability, potentially by minimizing BBB disruption and related neuroinflammation.


Asunto(s)
Antiinflamatorios/farmacología , Dexametasona/farmacología , Hipocampo/efectos de los fármacos , Convulsiones Febriles/tratamiento farmacológico , Estado Epiléptico/tratamiento farmacológico , Animales , Antiinflamatorios/uso terapéutico , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/fisiopatología , Citocinas/metabolismo , Dexametasona/uso terapéutico , Modelos Animales de Enfermedad , Femenino , Hipocampo/metabolismo , Hipocampo/fisiopatología , Masculino , Ratas , Convulsiones Febriles/metabolismo , Convulsiones Febriles/fisiopatología , Estado Epiléptico/metabolismo , Estado Epiléptico/fisiopatología
4.
J Mol Neurosci ; 69(4): 636-642, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31418115

RESUMEN

Melatonin is a neurohormone that has anticonvulsant activity in different experimental seizure models including hyperthermic febrile seizure. However, the mechanisms of this effect are not clear at the receptor level. The aim of the study was to determine which melatonin receptors involve in the hyperthermic febrile seizure model. 22-30 days Wistar male rats were used, and in children, it corresponds to 1.5-2 years. Groups were performed as (1) control, (2) ethanol/saline, (3) DMSO, (4) melatonin (MT), (5) MT + luzindole (LUZ), (6) MT + K-185, (7) MT + prazosin (PRZ), (8) MT + LUZ + K-185, (9) MT + LUZ + PRZ, (10) MT + K-185 + PRZ, and (11) MT + LUZ + PRZ + K-185. The hyperthermic febrile seizure pattern was established by keeping the rats in 45 °C hot water, and the latency, duration, and severity of seizures were determined in all groups. MT, LUZ, K-185, and PRZ were given 15, 45, 15, and 30 min before the induction of seizure, respectively. It was observed that melatonin shortened the duration of seizure, reduced the severity, and did not affect latency and that these effects were not completely blocked by receptor antagonists when compared with control, ethanol/saline, and DMSO groups. In conclusion, the fact that the anticonvulsant effect of melatonin is not completely blocked by all melatonin receptor antagonists. We can conclude that a multimodal mechanism may be responsible for the effect of melatonin receptors alone on the anticonvulsant effect of melatonin. It will be useful to design new pharmacological studies to make the subject clear.


Asunto(s)
Fiebre/complicaciones , Melatonina/farmacología , Receptores de Melatonina/agonistas , Convulsiones Febriles/metabolismo , Animales , Anticonvulsivantes/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Depresores del Sistema Nervioso Central/farmacología , Masculino , Prazosina/farmacología , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Receptores de Melatonina/antagonistas & inhibidores , Convulsiones Febriles/etiología , Convulsiones Febriles/fisiopatología , Triptaminas/farmacología
5.
J Integr Neurosci ; 18(2): 173-179, 2019 06 30.
Artículo en Inglés | MEDLINE | ID: mdl-31321958

RESUMEN

This study aimed to understand the role of Interleukin-1ß in mouse febrile seizures. To investigate the chronic effects of raised Interleukin-1ß on seizures, the sodium currents of hippocampal neurons were recorded by whole-cell voltage clamp. Interleukin-1ß inhibited sodium currents in mouse hippocampal neurons and verified that protein kinase C epsilon contributed to the effect of Interleukin-1ß exposure. The inhibitory effect was also identified in neurons from a protein kinase C epsilon null mutant mouse. Action potentials were recorded using a ramp depolarizing current. Peak spike depolarization was significantly reduced by Interleukin-1ß treatment, and was abolished following the administration of a protein kinase C epsilon inhibitor, εV1-2. However, neither Interleukin-1ß nor εV1-2 had any significant effect on spike threshold. Interleukin-1ß reduced the amplitude of action potentials due to its inhibitory effect on sodium channels. This is hypothesised to decrease the release of presynaptic transmitters of neuroexcitability, thus exerting a neuroprotective role in excitotoxicity. To ascertain the role of protein kinase C epsilon on febrile seizures in vivo, a heated water-bath model was used to identify susceptible mice. It was found that protein kinase C epsilon reduced susceptibility to, and frequency of, febrile seizure onset. This may be related to the neuroprotective effect of Interleukin-1ß on hippocampal neurons.


Asunto(s)
Interleucina-1beta/metabolismo , Neuronas/metabolismo , Proteína Quinasa C-epsilon/metabolismo , Convulsiones Febriles/metabolismo , Canales de Sodio Activados por Voltaje/metabolismo , Animales , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Interleucina-1beta/administración & dosificación , Masculino , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos
6.
Pediatr Neurol ; 98: 61-67, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31248670

RESUMEN

BACKGROUND: Acute encephalitis and encephalopathy are life-threatening diseases in children. However, no laboratory examinations are performed for their early diagnosis and treatment. Alpha 2-macroglobulin (α2M) is a blood glycoprotein that increases during the early stages of inflammation. In the present study, we investigated the role of α2M levels in acute encephalitis and encephalopathy. METHODS: We analyzed the cerebrospinal fluid and serum samples from patients with acute disseminated encephalomyelitis, infection-related acute encephalopathy, febrile status epilepticus, and febrile seizure simplex type. Samples were collected from the pediatric department of hospitals throughout the Fukushima Prefecture between January 1, 1999, and May 31, 2012. RESULTS: α2M levels in the cerebrospinal fluid were 4.7 (3.8-8.4) µg/mL for acute disseminated encephalomyelitis, 2.1 (1.1-2.3) µg/mL for infection-related acute encephalopathy, 1.1 (0.9-6.4) µg/mL for febrile status epilepticus, and 1.0 (0.8-1.1) µg/mL for febrile seizure simplex type. α2M levels in patients with acute disseminated encephalomyelitis were significantly higher than those in patients with infection-related acute encephalopathy and febrile seizure simplex type (P = 0.019 and P = 0.002, respectively). The ratio of α2M level in the cerebrospinal fluid to that in the serum in patients with acute disseminated encephalomyelitis was significantly higher than the ratio in patients with febrile status epilepticus (P = 0.04). In patients with acute disseminated encephalomyelitis, α2M levels in the cerebrospinal fluid decreased with treatment. CONCLUSIONS: Our results suggest that α2M levels in the cerebrospinal fluid reflect the neuroinflammatory status of patients with acute disseminated encephalomyelitis.


Asunto(s)
Encefalomielitis Aguda Diseminada/metabolismo , Encefalitis Infecciosa/metabolismo , Inflamación/metabolismo , alfa 2-Macroglobulinas Asociadas al Embarazo/metabolismo , Convulsiones Febriles/metabolismo , Niño , Preescolar , Encefalomielitis Aguda Diseminada/sangre , Encefalomielitis Aguda Diseminada/líquido cefalorraquídeo , Femenino , Humanos , Lactante , Encefalitis Infecciosa/sangre , Encefalitis Infecciosa/líquido cefalorraquídeo , Inflamación/sangre , Inflamación/líquido cefalorraquídeo , Masculino , alfa 2-Macroglobulinas Asociadas al Embarazo/líquido cefalorraquídeo , Convulsiones Febriles/sangre , Convulsiones Febriles/líquido cefalorraquídeo
7.
J Food Sci ; 84(7): 1703-1711, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31218711

RESUMEN

We evaluated the effect of krill oil (KO) supplement on seizures induced by pentylenetetrazole (PTZ) in animals with previous febrile seizures (FSs) induced by hyperthermia to determine its effectiveness in seizure susceptibility and as an anticonvulsant. Male Wistar rats with FS separated into water (W, 1 mL), palm oil (PO, 300 mg/kg, total volume 1 mL), or KO (300 mg/kg, total volume 1 mL) groups. All drugs were administered chronically via the intragastric route. Electrical activity was recorded by intracranial EEG simultaneously with convulsive behavior. All animals' brains were processed by immunofluorescence against GFAP, NeuN, and connexins (Cx); cellular quantification was performed in hippocampus and pyramidal or granular layer thickness was evaluated with cresyl violet (CV) staining. The results showed a significant delay in convulsive behavior and a slight increased survival time after PTZ administration in the group treated with KO compared with PO and W groups. The epileptiform activity showed high amplitude and frequency, with no significant differences between groups, nor were there differences in the number and duration of discharge trains. KO and PO increased the number of astrocytes and the number of neurons compared with the W group. KO and PO decreased the expression of Cx36 without affecting Cx43 expression or the thickness of layers. Based on these data, we consider it important to perform more experiments to determine the anticonvulsant role of KO, taking into account the partial effect found in this study. KO could be used as a coadjuvant of traditional anticonvulsive treatments. PRACTICAL APPLICATION: In this study was evaluated the anticonvulsive effect of a chronic krill oil (KO) supplement in animals with seizures. Results showed that KO had partial anticonvulsive effects measured by EEG activity and convulsive behavior analysis. These data justify further research that looks at KO supplementation as a prospective coadjuvant of pharmacologic management of seizure disorder.


Asunto(s)
Anticonvulsivantes/administración & dosificación , Euphausiacea/química , Hipocampo/efectos de los fármacos , Aceites Vegetales/administración & dosificación , Convulsiones Febriles/tratamiento farmacológico , Animales , Conexina 43/genética , Conexina 43/metabolismo , Conexinas/genética , Conexinas/metabolismo , Proteínas de Unión al ADN , Suplementos Dietéticos/análisis , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Hipocampo/metabolismo , Humanos , Masculino , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Pentilenotetrazol/efectos adversos , Ratas , Ratas Wistar , Convulsiones Febriles/inducido químicamente , Convulsiones Febriles/genética , Convulsiones Febriles/metabolismo
8.
Ann Neurol ; 85(4): 526-537, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30779222

RESUMEN

OBJECTIVE: We recently reported successful treatment of a child with febrile infection-related epilepsy syndrome (FIRES), a subtype of new onset refractory status epilepticus, with the recombinant interleukin-1 (IL1) receptor antagonist (IL1RA) anakinra. On this basis, we tested whether endogenous IL1RA production or function is deficient in FIRES patients. METHODS: Levels of IL1ß and IL1RA were measured in serum and cerebrospinal fluid (CSF). The inhibitory activity of endogenous IL1RA was assessed using a cell-based reporter assay. IL1RN gene variants were identified by sequencing. Expression levels for the secreted and intracellular isoforms of IL1RA were measured in patient and control cells by real-time polymerase chain reaction. RESULTS: Levels of endogenous IL1RA and IL1ß were elevated in the serum and CSF of patients with FIRES (n = 7) relative to healthy controls (n = 10). Serum from FIRES patients drove IL1R signaling activity and potentiated IL1R signaling in response to exogenous IL1ß in a cell-based reporter assay. Functional assessment of endogenous IL1RA activity in 3 FIRES patients revealed attenuated inhibition of IL1R signaling. Sequencing of IL1RN in our index patient revealed multiple variants. This was accompanied by reduced expression of intracellular but not secreted isoforms of IL1RA in the patient's peripheral blood mononuclear cells. INTERPRETATION: Our findings suggest that FIRES is associated with reduced expression of intracellular IL1RA isoforms and a functional deficiency in IL1RA inhibitory activity. These observations may provide insight into disease pathogenesis for FIRES and other inflammatory seizure disorders and may provide a valuable biomarker for therapeutic decision-making. Ann Neurol 2019;85:526-537.


Asunto(s)
Epilepsia Refractaria/metabolismo , Síndromes Epilépticos/metabolismo , Infecciones/metabolismo , Proteína Antagonista del Receptor de Interleucina 1/sangre , Proteína Antagonista del Receptor de Interleucina 1/líquido cefalorraquídeo , Convulsiones Febriles/metabolismo , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Epilepsia Refractaria/diagnóstico , Epilepsia Refractaria/tratamiento farmacológico , Síndromes Epilépticos/diagnóstico , Síndromes Epilépticos/tratamiento farmacológico , Femenino , Células HEK293 , Humanos , Infecciones/diagnóstico , Infecciones/tratamiento farmacológico , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Masculino , Convulsiones Febriles/diagnóstico , Convulsiones Febriles/tratamiento farmacológico
9.
CNS Neurosci Ther ; 25(5): 601-611, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30666786

RESUMEN

AIMS: Febrile seizures (FSs) are the most common types of seizures in young children. However, little is known whether the memory deficits induced by early-life FSs could transmit across generations or not. METHODS: The memory functions of different generations of FS rats were behaviorally evaluated by morris water maze, inhibitory avoidance task, and contextual fear conditioning task. Meanwhile, molecular biology and pharmacological methods were used to investigate the role of DNA methylation in transgenerational transmission of memory defects. RESULTS: Prolonged FSs in infant rats resulted in memory deficits in adult and transgenerationally transmitted to next generation, which was mainly through mothers. For these two generations, DNA methyltransferase (DNMT) 1 was upregulated, leading to transcriptional inhibition of the synaptic plasticity protein reelin but not the memory suppressor protein phosphatase 1. DNMT inhibitors prevented the high expression of DNMT1 and hypermethylation of reelin gene and reversed the transgenerationally memory deficits. In addition, enriched environment in juvenile rats rescued memory deficits induced by prolonged FSs. CONCLUSIONS: Our study demonstrated early experience of prolonged FSs led to memory deficits in adult rats and their unaffected offspring, which involved epigenetic mechanisms, suggesting early environmental experiences had a significant impact on the transgenerational transmission of neurological diseases.


Asunto(s)
Metilación de ADN , Trastornos de la Memoria/genética , Trastornos de la Memoria/metabolismo , Convulsiones Febriles/genética , Convulsiones Febriles/metabolismo , Animales , Reacción de Prevención , Moléculas de Adhesión Celular Neuronal/genética , Moléculas de Adhesión Celular Neuronal/metabolismo , Condicionamiento Psicológico , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Miedo , Femenino , Hipocampo/metabolismo , Vivienda para Animales , Masculino , Aprendizaje por Laberinto , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Distribución Aleatoria , Ratas Sprague-Dawley , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo
10.
Anal Chem ; 90(24): 14514-14520, 2018 12 18.
Artículo en Inglés | MEDLINE | ID: mdl-30474971

RESUMEN

Febrile seizure (FS), a frequently encountered seizure disorder in pediatric populations, can cause hippocampus damage. It has been elucidated that sulfur dioxide (SO2) content is overproduced during the development of FS and related brain injury. Thus, monitoring in situ the level of endogenous SO2 in FS-related models is helpful to estimate the pathogenesis of FS-induced brain injury, but the effect detection method remains to be explored. Herein, we developed a two-photon energy transfer cassette based on an acedan-anthocyanidin scaffold, TP-Ratio-SO2, allowing us to achieve this purpose. TP-Ratio-SO2 specifically responds to SO2 derivatives (HSO3-/SO32-) in an ultrafast fashion (less than 3 s), and HSO3-/SO32- can be sensitively determined with a detection limit of 26 nM. Moreover, it exhibits significant changes in two well-resolved fluorescence emissions (Δλ = 140 nm) by reacting with HSO3-/SO32-, behaving as a ratiometric fluorescent sensor. Importantly, ratiometric imaging of endogenous SO2 derivatives generation in hyperpyretic U251 cells and in a rat model of FS-treated hippocampus damage was successfully carried out by TP-Ratio-SO2, demonstrating that it may be a promising tool for studying the role of SO2 in FS-associated neurological diseases.


Asunto(s)
Transferencia Resonante de Energía de Fluorescencia , Hipocampo/metabolismo , Microscopía de Fluorescencia por Excitación Multifotónica/métodos , Dióxido de Azufre/análisis , Animales , Antocianinas/química , Línea Celular Tumoral , Modelos Animales de Enfermedad , Colorantes Fluorescentes/química , Hipocampo/química , Humanos , Límite de Detección , Hígado/metabolismo , Hígado/patología , Ratas , Convulsiones Febriles/metabolismo , Convulsiones Febriles/patología , Espectrofotometría , Dióxido de Azufre/química , Dióxido de Azufre/metabolismo
11.
Clin Neurol Neurosurg ; 175: 61-67, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30384118

RESUMEN

OBJECTIVE: The objective of this feasibility study was to investigate whether myelin water fraction (MWF) patterns can differentiate children presenting with febrile seizures who will go on to develop nonfebrile epilepsy from those who will not. PATIENTS AND METHODS: As part of a prospective study of myelination patterns in pediatric epilepsy, seven subjects with febrile seizures underwent magnetic resonance imaging (MRI) including the following standard sequences-T1-weighted, T2-weighted, fluid-attenuated inversion recovery (FLAIR)-and an additional experimental sequence, multicomponent-derived equilibrium single-pulse observation of T1 and T2 (mcDESPOT) to quantify MWF. For each of these subjects, MWF maps were derived and compared with an age-matched population-averaged MWF atlas. RESULTS: All seven subjects (<5 years old) initially presented with febrile seizures. Of the seven, four had complex seizures and three had simple seizures. All of the children with simple febrile seizures had higher MWF compared with model-derived controls and did not develop epilepsy. All of the children with complex febrile seizures had lower MWF than their model-derived control, and two of these subjects later developed epilepsy. CONCLUSION: This is the first study in which MWF maps were used to study children with febrile *seizures. This data suggests that relatively higher or stable MWF compared with normative data indicates a lower risk of nonfebrile epilepsy while relatively lower MWF may indicate a pathological condition that could lead to nonfebrile epilepsy.


Asunto(s)
Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Vaina de Mielina/metabolismo , Convulsiones Febriles/diagnóstico por imagen , Convulsiones Febriles/metabolismo , Agua/metabolismo , Preescolar , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Vaina de Mielina/patología , Estudios Prospectivos
12.
Biosci Rep ; 38(5)2018 10 31.
Artículo en Inglés | MEDLINE | ID: mdl-30287501

RESUMEN

Background: Fangjing decoction is a Traditional Chinese Medicine that exhibits anticonvulsive effects in treating febrile seizures (FS). Its action mechanism and the regulation on Akt/mammalian target of rapamycin (mTOR) pathway were revealed in the present study.Methods: FS model was established in Sprague-Dawley rats with or without Fangjing decoction treatment. On day 5, following initiation of drug treatment, seizures were monitored. Hippocampal neuron apoptosis was assessed using terminal dUTP nick end-labeling method. The levels of Bax, protein kinase B (Akt), phospho-Akt (p-Akt), mTOR, and p-mTOR proteins were analyzed using Western blotting. The content of hippocampal γ-aminobutyric acid (GABA) was measured by using ELISA assay.Results: Compared with the control group (n=8), Fangjing decoction effectively prolonged the latency but shortened the duration of FS in rats (n=8). Concomitantly, the apoptosis of hippocampal neurons, as well as Bax protein levels were also decreased in FS rats which were treated with Fangjing decoction. In addition, the Akt/mTOR signaling was found to be activated in rat hippocampus following FS, as evidenced by increased p-Akt and p-mTOR, while Fangjing decoction could inhibit the activation of Akt/mTOR signaling. Furthermore, the low GABA content in rat hippocampus following FS was significantly elevated by Fangjing decoction treatment. More importantly, SC79, a specific activator for Akt, apparently attenuated the protective effects of Fangjing decoction on FS rats.Conclusion: These results suggest that Fangjing decoction protects the hippocampal neurons from apoptosis by inactivating Akt/mTOR pathway, which may contribute to mitigating FS-induced brain injury.


Asunto(s)
Anticonvulsivantes/farmacología , Medicamentos Herbarios Chinos/farmacología , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Proteínas Proto-Oncogénicas c-akt/genética , Convulsiones Febriles/tratamiento farmacológico , Serina-Treonina Quinasas TOR/genética , Acetatos/farmacología , Animales , Apoptosis/efectos de los fármacos , Benzopiranos/farmacología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Masculino , Neuronas/metabolismo , Neuronas/patología , Extractos Vegetales/química , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Convulsiones Febriles/genética , Convulsiones Febriles/metabolismo , Convulsiones Febriles/patología , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo , Ácido gamma-Aminobutírico/metabolismo
13.
Biochem Pharmacol ; 156: 78-85, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30086287

RESUMEN

Dipeptidyl peptidase-IV (DPP4) is a cell surface serine peptidase widely expressed in the brain. Recent studies suggest that DPP4 contributes to the development of febrile seizures (FS); however, the underlying mechanism is still unclear. Thus, we investigated the role of DPP4 in the progression of FS at the molecular and electrophysiological levels using FS models in vivo and in vitro. Herein, we found that both the mRNA and protein levels of DPP4 were upregulated in the FS model. Administration of the pharmacological DPP4 inhibitor sitagliptin suppressed the hyperthermia-induced neuronal excitability as determined via whole-cell patch-clamp recordings in vitro. Interestingly, sitagliptin administration activated the glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) pathway by increasing the expression of GLP-1 and GLP-1R in a rat model of FS. Moreover, administration of the GLP-1R inhibitor exendin9-39 increased seizure severity, and sitagliptin reversed the effect, as shown in the electroencephalogram (EEG) and patch-clamp results in a rat model of FS. Furthermore, the GLP-1R-mediated reduction in GABAergic transmission was enhanced by sitagliptin and DPP4 knockdown through increasing miniature inhibitory post-synaptic currents (mIPSCs) in vitro accompanied by increased synaptic release of GABA in vivo. Taken together, our results demonstrate a role of DPP4 in regulating GABAergic transmission via the GLP-1/GLP-1R pathway. These findings indicated that DPP4 may represent a novel therapeutic strategy and target for FS.


Asunto(s)
Dipeptidil Peptidasa 4/metabolismo , Péptido 1 Similar al Glucagón/fisiología , Receptor del Péptido 1 Similar al Glucagón/fisiología , Convulsiones Febriles/metabolismo , Animales , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/citología , Masculino , Neurturina/efectos de los fármacos , Neurturina/fisiología , Interferencia de ARN , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Fosfato de Sitagliptina/farmacología
14.
Neurobiol Dis ; 119: 172-189, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30121230

RESUMEN

Thermal hyperpnea, a pattern of breathing during hyperthermia that is characterized by an increase in tidal volume as well as breathing frequency, is known to lead to respiratory alkalosis. Thermal hyperpnea-induced respiratory alkalosis is linked to febrile seizures (FS). The heat-sensitive transient receptor potential vanilloid-1 (TRPV1) receptors are localized in, and implicated in the heat sensitivity of peripheral and central structures involved in the respiratory response to hyperthermia. We, therefore, hypothesize that TRPV1 activation increases susceptibility to experimental FS (EFS) in immature rats due to an exacerbated thermal hyperpnea. We found that peripheral, but not central TRPV1 activation had pro-convulsant effects. These pro-convulsant effects were associated with an increased rate of expired CO2 due to an exaggerated ventilatory response to hyperthermia. The TRPV1 antagonist, AMG-9810, and TRPV1 deletion abolished the pro-convulsant effects, while exposure to 5% CO2, bilateral vagotomy and DREADD (designer receptor exclusively activated by designer drugs)-mediated inhibition of TRPV1-containing cells in the vagal nodose ganglia significantly attenuated these effects. These findings suggest that vagal TRPV1-driven thermal hyperpnea likely increases susceptibility to FS in immature rodents. This identifies a novel peripheral anatomical and molecular target that should be considered when developing therapeutics for FS.


Asunto(s)
Fiebre/metabolismo , Convulsiones Febriles/metabolismo , Canales Catiónicos TRPV/metabolismo , Nervio Vago/metabolismo , Factores de Edad , Animales , Susceptibilidad a Enfermedades , Femenino , Fiebre/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratas , Ratas Sprague-Dawley , Convulsiones Febriles/fisiopatología , Nervio Vago/fisiopatología
15.
Epilepsy Behav ; 86: 173-178, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-30017837

RESUMEN

Febrile seizures (FS) represent one of the most frequent convulsive disorders in children which can be classified into simple and prolonged depending on the duration. Although simple FS are generally considered as benign, there is controversy about the outcome of prolonged FS. Here, we have used an animal model of prolonged FS to investigate persistent neurochemical and behavioral alterations in adult rats. Hyperthermic seizures were induced in 12-day-old rats using a warmed air stream from a hair dryer. Neonates exhibited arrest of heat-induced hyperkinesis followed by body flexion and rearing and falling over associated with hindlimb clonus seizures (stage 5 on Racine scale criteria) after hyperthermic induction. After 48 days, the animals were assayed on dark-light box and forced swim tests in order to detect if rats will show signs of anxiety or depression. Finally, animals were sacrificed 56 days after hyperthermia-induced seizures (HIS), and their effects on adenosine A2A receptor signaling and 5'-nucleotidase activity were studied in plasma membranes from the cerebral cortex by using radioligand-binding assay and by measuring the activities of adenylate cyclase and 5'-nucleotidase. Results obtained have shown that adult rats submitted to HIS during the neonatal period showed depressive-like behavior. Furthermore, animals exposed to hyperthermic insult showed an increase in A2A receptor level which was also accompanied by an increase in A2A receptor functionality.


Asunto(s)
Corteza Cerebral/metabolismo , Depresión/metabolismo , Receptor de Adenosina A2A/biosíntesis , Convulsiones Febriles/metabolismo , Regulación hacia Arriba/fisiología , Factores de Edad , Animales , Depresión/etiología , Depresión/psicología , Fiebre/complicaciones , Fiebre/metabolismo , Fiebre/psicología , Hipertermia Inducida/efectos adversos , Hipertermia Inducida/tendencias , Masculino , Ratas , Convulsiones Febriles/etiología , Convulsiones Febriles/psicología
16.
Metab Brain Dis ; 33(5): 1509-1515, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-29946956

RESUMEN

Febrile seizures (FS) are frequent convulsive disorders, occurring in infants and young children. The present study aims to assess and compare the serum levels of oxidative stress markers and some essential trace minerals in FS with normal or abnormal EEG and evaluate the effect of antioxidant therapy on the clinical outcome. This study has been carried out on 80 children with FS (40 with simple FS and 40 with complex FS) and 40 febrile children without seizures. Clinical and EEG findings were recorded for the included patients. Biochemical assays of serum nitric oxide (NO), malondialdehyde (MDA), superoxide dismutase (SOD), copper (Cu), zinc (Zn) and selenium (Se), using colorimetric methods, were measured in the studied groups. The overall results showed an increased values of NO, MDA and Cu with decreased values of SOD, Zn and Se in patients with FS (simple and complex) in comparison with febrile children without seizures (p < 0.05 for all). Additionally, NO and MDA was increased in complex FS patients with EEG abnormalities in comparison with complex FS with normal EEG findings (p < 0.05); NO and MDA were also significantly decreased after valproate therapy in complex FS patients (p < 0.05 for all). In conclusions, oxidative stress, decreased Zn and Se with increased Cu may play a role in FS. Valproate improves the oxidative stress status in complex FS.


Asunto(s)
Metaboloma , Estrés Oxidativo/fisiología , Convulsiones Febriles/metabolismo , Oligoelementos/sangre , Estudios de Casos y Controles , Niño , Preescolar , Cobre/sangre , Femenino , Humanos , Lactante , Masculino , Malondialdehído/sangre , Óxido Nítrico/sangre , Estudios Prospectivos , Convulsiones Febriles/sangre , Selenio/sangre , Superóxido Dismutasa/sangre , Zinc/sangre
17.
Cell Mol Neurobiol ; 38(6): 1215-1226, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29748835

RESUMEN

Febrile seizure (FS) counts as the most common seizures symptom in children undergoing recurrent seizures, posing a high risk to developing subsequent temporal lobe epilepsy. Canonical transient receptor potential channel (TRPC) members are identified as the FS-related genes in hyperthermia prone rats. However, the role of TRPC3 in hyperthermia-induced FS rats remains unclear. In the present study, we investigated whether TRPC3 functionally contributes to the development of FSs. Elevated TRPC3 mRNA and protein levels was detected in hyperthermia-induced FS rats and rat hippocampal neuron cells. The specific inhibitor of TRPC3, Pyr3, remarkably attenuated the susceptibility and severity of seizures, neuronal cell death, and neuroinflammation in FS rats. Conversely, NCX3 activation was apparently suppressed in rats subjected to recurrent FS and rat hippocampal neuron cells. The expression of NCX3 was up-regulated after TRPC3 inhibition in vivo and in vitro. Furthermore, an interaction between TRPC3 and NCX3 was detected by co-immunoprecipitation. Inhibition of TRPC3 suppressed intracellular Ca2+ levels in hyperthermia-treated hippocampal neuronal cells. In conclusion, our findings supported that TRPC3 functions as a critical regulator of seizure susceptibility and targeting TRPC3 may be a new therapeutic strategy for FS.


Asunto(s)
Convulsiones Febriles/metabolismo , Canales Catiónicos TRPC/metabolismo , Animales , Muerte Celular , Modelos Animales de Enfermedad , Femenino , Hipocampo/metabolismo , Neuronas/metabolismo , Ratas Sprague-Dawley , Canales Catiónicos TRPC/genética , Activación Transcripcional/fisiología , Regulación hacia Arriba
18.
J Child Neurol ; 33(6): 417-421, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29618277

RESUMEN

In this study, the authors assessed cerebrospinal fluid cytokine levels and single-photon emission computed tomography (SPECT) findings in complex febrile seizures. This study included 23 Japanese patients with complex febrile seizures. Twenty patients underwent SPECT and 12 underwent analysis of cerebrospinal fluid cytokine levels (interleukin [IL]-6, interleukin-10, interleukin-17, interleukin-1ß, tumor necrosis factor-α, and interferon-γ); 9 patients underwent both studies. Cerebrospinal fluid cytokine levels were compared between the current complex febrile seizure patients and 30 patients with acute encephalopathy. In 17 of 20 patients, SPECT findings revealed areas of hypoperfusion, including the frontal (5), occipital (4), and lobular (4) regions, overlapping with other areas. Relative to patients with acute encephalopathy, those with complex febrile seizures exhibited significantly lower cerebrospinal fluid interleukin-6, interleukin-1ß, tumor necrosis factor-α, and interleukin-10 levels and significantly higher interleukin-17 levels. As patients with complex febrile seizures frequently exhibit abnormal SPECT findings, cerebrospinal fluid interleukin-17 levels might provide a valid biomarker to discriminate complex febrile seizures and acute encephalopathy, regardless of SPECT findings.


Asunto(s)
Encéfalo/diagnóstico por imagen , Citocinas/líquido cefalorraquídeo , Convulsiones Febriles/diagnóstico por imagen , Convulsiones Febriles/metabolismo , Tomografía Computarizada de Emisión de Fotón Único , Biomarcadores/metabolismo , Encéfalo/metabolismo , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino
19.
Brain Dev ; 40(7): 552-557, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29567266

RESUMEN

BACKGROUND: Children who present with seizure and/or impaired consciousness accompanied by fever without known etiology (SICF) may be diagnosed with either acute encephalopathy (AE) or febrile seizure (FS). Although approximately 5% of AE cases are fatal, it is difficult to identify fatal cases among children with SICF, which are often critical by the time of diagnosis. Thus, early prediction of outcomes for children with SICF, prior to diagnosis, may help to reduce mortality associated with AE. The aim of the present study was to identify clinical and laboratory risk factors for mortality acquired within 6 h of onset among children with SICF. METHODS: We retrospectively reviewed the medical records of children who had been admitted to Kobe Children's Hospital (Kobe, Japan) with SICF between October 2002 and September 2015. We compared clinical and laboratory characteristics acquired within 6 h of onset and outcomes between survivors and non-survivors using univariate and multivariate analyses. RESULTS: The survivor and non-survivor groups included 659 and nine patients, respectively. All patients in the non-survivor group received a final diagnosis of AE. Univariate analysis revealed significant differences between the groups with regard to seizure duration and the following laboratory parameters: aspartate transaminase (AST), alanine aminotransferase, lactate dehydrogenase, sodium, and lactate. The multivariate analysis identified AST as a significant independent factor associated with mortality. CONCLUSIONS: Elevation of AST within 6 h of onset is independently correlated with mortality in children with SICF. Our result may elucidate earlier intervention for patients with high risk of mortality.


Asunto(s)
Trastornos de la Conciencia/complicaciones , Trastornos de la Conciencia/mortalidad , Fiebre/complicaciones , Fiebre/mortalidad , Convulsiones Febriles/complicaciones , Convulsiones Febriles/mortalidad , Adolescente , Biomarcadores/metabolismo , Niño , Preescolar , Trastornos de la Conciencia/metabolismo , Femenino , Fiebre/metabolismo , Humanos , Lactante , Masculino , Análisis Multivariante , Estudios Retrospectivos , Factores de Riesgo , Convulsiones Febriles/metabolismo , Factores de Tiempo
20.
Semin Pediatr Neurol ; 24(3): 152-160, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-29103422

RESUMEN

Though the term "inflammation" is traditionally defined as proliferation or infiltration of lymphatic cells of the lymphatic immune system and macrophages or as immunoreactive proteins including cytokines, interleukins and major histocompatibility complexes, recently recognized reactions to tissue injury also are inflammation, often occurring in the central nervous system in conditions where they previously were not anticipated and where they may play a role in both pathogenesis and repair. We highlight 4 such novel inflammatory conditions revealed by neuropathologic studies: (1) inflammatory markers and cells in the brain of human fetuses with tuberous sclerosis complex and perhaps other disorders of the mechanistic target of rapamycin genetic or metabolic pathway, (2) inflammatory markers in the brain related to febrile seizures of infancy and early childhood, (3) heat-shock protein upregulation in glial cells and neurons at sites of chronic epileptic foci, and (4) the emerging role of astrocytes in the presence of and participation in inflammation. Novel evidence shows that cerebral inflammation plays a role in some genetic diseases as early as midgestation and thus is not always acquired postnatally or in adult life.


Asunto(s)
Astrocitos/fisiología , Encéfalo , Esclerosis Tuberosa , Cadena B de alfa-Cristalina/metabolismo , Animales , Astrocitos/patología , Encéfalo/inmunología , Encéfalo/metabolismo , Encéfalo/patología , Humanos , Convulsiones Febriles/inmunología , Convulsiones Febriles/metabolismo , Convulsiones Febriles/patología , Esclerosis Tuberosa/inmunología , Esclerosis Tuberosa/metabolismo , Esclerosis Tuberosa/patología
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