RESUMO
Trilostane is a 3ß-hydroxysteroid dehydrogenase/Δ5-4 isomerase inhibitor able to produce a manyfold increase in brain levels of various neurosteroids, including allopregnanolone. We previously found that treatment with trilostane can slow down epileptogenesis in the kainic acid (KA) model of temporal lobe epilepsy. It is unknown whether trilostane may have a similar effect on the progression of epilepsy severity, as observed in KA-treated rats. Consequently, we investigated the effects of trilostane (50 mg/kg/day, 1 week) in epileptic rats, given 64 days after KA administration. Seizures were monitored by video-electrocorticographic recordings before and during the treatment with trilostane or vehicle (sesame oil), and neurosteroid levels were measured in serum and cerebral tissue using liquid chromatography-electrospray tandem mass spectrometry after treatment. Pregnenolone sulfate, pregnenolone, progesterone, 5α-dihydroprogesterone, and allopregnanolone peripheral levels were massively increased by trilostane. With the only exception of hippocampal pregnenolone sulfate, the other neurosteroids augmented in both the neocortex and hippocampus. Only pregnanolone levels were not upregulated by trilostane. As expected, a significant increase in the seizure occurrence was observed in rats receiving the vehicle, but not in the trilostane group. This suggests that the increased availability of neurosteroids produced a disease-modifying effect in the brain of epileptic rats.
Assuntos
Epilepsia , Neuroesteroides , Ratos , Animais , Neuroesteroides/farmacologia , Pregnanolona/farmacologia , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Encéfalo , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológicoRESUMO
Epilepsy is a chronic brain disease with a global prevalence of 70 million people. According to the World Health Organization, roughly 5 million new cases are diagnosed every year. Anti-seizure drugs are the treatment of choice. However, in roughly one third of the patients, these drugs fail to produce the desired effect. As a result, finding novel treatments for epilepsy becomes inevitable. Recently, angiotensin receptor blockers have been proposed as a treatment to reduce the over-excitation of neurons in epilepsy. For this purpose, we conducted a review using Medline/PubMed and Google Scholar using the relevant search terms and extracted the relevant data in a table. Our review suggests that this novel approach has a very high potential to treat epilepsy, especially in those patients who fail to respond to conventional treatment options. However, more extensive and human-based trials should be conducted to reach a decisive conclusion. Nevertheless, the use of ARBs in patients with epilepsy should be carefully monitored keeping the adverse effects in mind.
Assuntos
Epilepsias Parciais , Epilepsia Generalizada , Epilepsia Tônico-Clônica , Epilepsia , Humanos , Anticonvulsivantes/uso terapêutico , Epilepsia Tônico-Clônica/induzido quimicamente , Epilepsia Tônico-Clônica/tratamento farmacológico , Carbamazepina/efeitos adversos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Epilepsia Generalizada/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Epilepsia/tratamento farmacológicoRESUMO
Acute organophosphate (OP) intoxication can trigger seizures that progress to status epilepticus (SE), and survivors often develop chronic morbidities, including spontaneous recurrent seizures (SRS). The pathogenic mechanisms underlying OP-induced SRS are unknown, but increased BBB permeability is hypothesized to be involved. Previous studies reported BBB leakage following OP-induced SE, but key information regarding time and regional distribution of BBB impairment during the epileptogenic period is missing. To address this data gap, we characterized the spatiotemporal progression of BBB impairment during the first week post-exposure in a rat model of diisopropylfluorophosphate-induced SE, using MRI and albumin immunohistochemistry. Increased BBB permeability, which was detected at 6 h and persisted up to 7 d post-exposure, was most severe and persistent in the piriform cortex and amygdala, moderate but persistent in the thalamus, and less severe and transient in the hippocampus and somatosensory cortex. The extent of BBB leakage was positively correlated with behavioral seizure severity, with the strongest association identified in the piriform cortex and amygdala. These findings provide evidence of the duration, magnitude and spatial breakdown of the BBB during the epileptogenic period following OP-induced SE and support BBB regulation as a viable therapeutic target for preventing SRS following acute OP intoxication.
Assuntos
Barreira Hematoencefálica , Estado Epiléptico , Ratos , Animais , Barreira Hematoencefálica/patologia , Ratos Sprague-Dawley , Organofosfatos/efeitos adversos , Organofosfatos/metabolismo , Estado Epiléptico/metabolismo , Convulsões/metabolismo , Encéfalo/metabolismoRESUMO
Temporal lobe epilepsy is a common, chronic disorder with spontaneous seizures that is often refractory to drug therapy. A potential cause of temporal lobe epilepsy is primary brain injury, making prevention of epileptogenesis after the initial event an optimal method of treatment. Despite this, no preventive therapy for epilepsy is currently available. The purpose of this study was to evaluate the effects of anakinra, lamotrigine, and their combination on epileptogenesis using the rat lithium-pilocarpine model of temporal lobe epilepsy. The study showed that there was no significant difference in the number and duration of seizures between treated and untreated animals. However, the severity of seizures was significantly reduced after treatment. Anakinra and lamotrigine, alone or in combination, significantly reduced neuronal loss in the CA1 hippocampus compared to the control group. However, the drugs administered alone were found to be more effective in preventing neuron loss in the hippocampal CA3 field compared to combination treatment. The treatment alleviated the impairments in activity level, exploratory behavior, and anxiety but had a relatively weak effect on TLE-induced impairments in social behavior and memory. The efficacy of the combination treatment did not differ from that of anakinra and lamotrigine monotherapy. These findings suggest that anakinra and lamotrigine, either alone or in combination, may be clinically useful in preventing the development of histopathological and behavioral abnormalities associated with epilepsy.
Assuntos
Epilepsia do Lobo Temporal , Ratos , Animais , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/tratamento farmacológico , Epilepsia do Lobo Temporal/patologia , Pilocarpina/efeitos adversos , Lamotrigina/efeitos adversos , Lítio/efeitos adversos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Anticonvulsivantes/efeitos adversos , Convulsões/tratamento farmacológico , Hipocampo , Modelos Animais de DoençasRESUMO
Current medical countermeasures for organophosphate (OP)-induced status epilepticus (SE) are not effective in preventing long-term morbidity and there is an urgent need for improved therapies. Rat models of acute intoxication with the OP, diisopropylfluorophosphate (DFP), are increasingly being used to evaluate therapeutic candidates for efficacy in mitigating the long-term neurologic effects associated with OP-induced SE. Many of these therapeutic candidates target neuroinflammation and oxidative stress because of their implication in the pathogenesis of persistent neurologic deficits associated with OP-induced SE. Critical to these efforts is the rigorous characterization of the rat DFP model with respect to outcomes associated with acute OP intoxication in humans, which include long-term electroencephalographic, neurobehavioral, and neuropathologic effects, and their temporal relationship to neuroinflammation and oxidative stress. To address these needs, we examined a range of outcomes at later times post-exposure than have previously been reported for this model. Adult male Sprague-Dawley rats were given pyridostigmine bromide (0.1â¯mg/kg, im) 30â¯min prior to administration of DFP (4â¯mg/kg, sc), which was immediately followed by atropine sulfate (2â¯mg/kg, im) and pralidoxime (25â¯mg/kg, im). This exposure paradigm triggered robust electroencephalographic and behavioral seizures that rapidly progressed to SE lasting several hours in 90% of exposed animals. Animals that survived DFP-induced SE (~70%) exhibited spontaneous recurrent seizures and hyperreactive responses to tactile stimuli over the first 2â¯months post-exposure. Performance in the elevated plus maze, open field, and Pavlovian fear conditioning tests indicated that acute DFP intoxication reduced anxiety-like behavior and impaired learning and memory at 1 and 2â¯months post-exposure in the absence of effects on general locomotor behavior. Immunohistochemical analyses revealed significantly increased expression of biomarkers of reactive astrogliosis, microglial activation and oxidative stress in multiple brain regions at 1 and 2â¯months post-DFP, although there was significant spatiotemporal heterogeneity across these endpoints. Collectively, these data largely support the relevance of the rat model of acute DFP intoxication as a model for acute OP intoxication in the human, and support the hypothesis that neuroinflammation and/or oxidative stress represent potential therapeutic targets for mitigating the long-term neurologic sequelae of acute OP intoxication.
Assuntos
Encéfalo , Modelos Animais de Doenças , Isoflurofato/toxicidade , Síndromes Neurotóxicas , Estresse Oxidativo/efeitos dos fármacos , Animais , Comportamento Animal , Encéfalo/metabolismo , Encéfalo/patologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Masculino , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Intoxicação por Organofosfatos/metabolismo , Intoxicação por Organofosfatos/patologia , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/induzido quimicamenteRESUMO
Microglia are the resident immune cells of the center nervous system and participate in various neurological diseases. Here we determined the function of microglia in epileptogenesis using microglial ablation approaches. Three different microglia-specific genetic tools were used, CX3CR1CreER/+:R26iDTA/+, CX3CR1CreER/+:R26iDTR/+, and CX3CR1CreER/+:Csf1rFlox/Flox mice. We found that microglial depletion led to worse kainic acid (KA)-induced status epilepticus, higher mortality rate, and increased neuronal degeneration in the hippocampus. In KA-induced chronic spontaneous recurrent seizures, microglial depletion increased seizure frequency, interictal spiking, and seizure duration. Therefore, microglial depletion aggravates the severity of KA-induced acute and chronic seizures. Interestingly, microglial repopulation reversed the effects of depletion upon KA-induced status epilepticus. Our results demonstrate a beneficial role of microglia in suppressing both acute and chronic seizures, suggesting that microglia are a potential therapeutic target for the management of epilepsy.
Assuntos
Microglia , Estado Epiléptico , Animais , Modelos Animais de Doenças , Hipocampo , Ácido Caínico , Camundongos , Camundongos Transgênicos , ConvulsõesRESUMO
Aberrant epileptic activity is detectable at early disease stages in Alzheimer's disease (AD) patients and in AD mouse models. Here, we investigated in young ArcticAß mice whether AD-like pathology renders neuronal networks more susceptible to the development of acquired epilepsy induced by unilateral intrahippocampal injection of kainic acid (IHK). In this temporal lobe epilepsy model, IHK induces a status epilepticus followed after two weeks by spontaneous recurrent seizures (SRS). ArcticAß mice exhibited more severe status epilepticus and early onset of SRS. This hyperexcitable phenotype was characterized in CA1 neurons by decreased synaptic strength, increased kainic acid-induced LTP and reduced frequency of spontaneous inhibitory currents. However, no difference in neurodegeneration, neuroinflammation, axonal reorganization or adult neurogenesis was observed in ArcticAß mice compared to wild-type littermates following IHK-induced epileptogenesis. Neuropeptide Y (NPY) expression was reduced at baseline and its IHK-induced elevation in mossy fibres and granule cells was attenuated. However, although this alteration might underlie premature seizure onset, neutralization of soluble Aß species by intracerebroventricular Aß-specific antibody application mitigated the hyperexcitable phenotype of ArcticAß mice and prevented early SRS onset. Therefore, the development of seizures at early stages of AD is mediated primarily by Aß species causing widespread changes in synaptic function.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Epilepsia do Lobo Temporal , Hipocampo , Plasticidade Neuronal , Convulsões , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Animais , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/fisiopatologia , Giro Denteado/metabolismo , Giro Denteado/fisiopatologia , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia do Lobo Temporal/metabolismo , Epilepsia do Lobo Temporal/fisiopatologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Ácido Caínico/farmacologia , Masculino , Camundongos , Camundongos Transgênicos , Plasticidade Neuronal/fisiologia , Convulsões/metabolismo , Convulsões/fisiopatologia , Estado Epiléptico/metabolismo , Estado Epiléptico/fisiopatologiaRESUMO
OBJECTIVE: Exposure to chemical warfare nerve agents (CWNAs), such as soman (GD), can induce status epilepticus (SE) that becomes refractory to benzodiazepines when treatment is delayed, leading to increased risk of epileptogenesis, severe neuropathology, and long-term behavioral and cognitive deficits. Rodent models, widely used to evaluate novel medical countermeasures (MCMs) against CWNA exposure, normally express plasma carboxylesterase, an enzyme involved in the metabolism of certain organophosphorus compounds. To better predict the efficacy of novel MCMs against CWNA exposure in human casualties, it is crucial to use appropriate animal models that mirror the human condition. We present a comprehensive characterization of the seizurogenic, epileptogenic, and neuropathologic effects of GD exposure with delayed anticonvulsant treatment in the plasma carboxylesterase knockout (ES1-/-) mouse. METHODS: Electroencephalography (EEG) electrode-implanted ES1-/- and wild-type (C57BL/6) mice were exposed to various seizure-inducing doses of GD, treated with atropine sulfate and the oxime HI-6 at 1 minute after exposure, and administered midazolam at 15-30 minutes following the onset of seizure activity. The latency of acute seizure onset and spontaneous recurrent seizures (SRS) was assessed, as were changes in EEG power spectra. At 2 weeks after GD exposure, neurodegeneration and neuroinflammation were assessed. RESULTS: GD-exposed ES1-/- mice displayed a dose-dependent response in seizure severity. Only ES1-/- mice exposed to the highest tested dose of GD developed SE, subchronic alterations in EEG power spectra, and SRS. Degree of neuronal cell loss and neuroinflammation were dose-dependent; no significant neuropathology was observed in C57BL/6 mice or ES1-/- mice exposed to lower GD doses. SIGNIFICANCE: The US Food and Drug Administration (FDA) animal rule requires the use of relevant animal models for the advancement of MCMs against CWNAs. We present evidence that argues for the use of the ES1-/- mouse model to screen anticonvulsant, antiepileptic, and/or neuroprotective drugs against GD-induced toxicity, as well as to identify mechanisms of GD-induced epileptogenesis.
Assuntos
Anticonvulsivantes/uso terapêutico , Carboxilesterase/genética , Substâncias para a Guerra Química , Midazolam/uso terapêutico , Soman , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/tratamento farmacológico , Animais , Contagem de Células , Reativadores da Colinesterase/uso terapêutico , Eletroencefalografia , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Degeneração Neural/patologia , Convulsões/fisiopatologia , Estado Epiléptico/genéticaRESUMO
Several studies indicate that sodium cromoglycate (CG) induces neuroprotective effects in acute neurological conditions. The present study focused on investigating if the use of CG in rats during the post-status epilepticus (post-SE) period reduces the acute and long-term consequences of seizure activity. Our results revealed that animals that received a single dose of CG (50â¯mg/kg s.c.: subcutaneously) during the post-SE period showed a lower number of neurons in the process of dying in the dentate gyrus, hilus, cornu ammonis 1 (CA1), and CA3 of the dorsal hippocampus than the rats that received the vehicle. However, this effect was not evident in layers V-VI of the sensorimotor cortex or the lateral-posterior thalamic nucleus. A second experiment showed that animals that received CG subchronically (50â¯mg/kg s.c. every 12â¯h for 5â¯days followed by 24â¯mg/kg/day s.c. for 14â¯days using osmotic minipumps) after SE presented fewer generalized convulsive seizures and less neuronal damage in the lateral-posterior thalamic nucleus but not in the hippocampus or cortex. Our data indicate that CG can be used as a therapeutic strategy to reduce short- and long-term neuronal damage in the hippocampus and thalamus, respectively. The data also indicate that CG can reduce the expression of generalized convulsive spontaneous seizures when it is given during the latent period of epileptogenesis.
Assuntos
Cromolina Sódica/uso terapêutico , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/patologia , Animais , Cromolina Sódica/farmacologia , Giro Denteado/efeitos dos fármacos , Giro Denteado/patologia , Giro Denteado/fisiopatologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/fisiopatologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ratos , Ratos Wistar , Estado Epiléptico/fisiopatologia , Fatores de TempoRESUMO
Brain inflammation is an important factor in the conversion of a healthy brain into an epileptic one, a phenomenon known as epileptogenesis, offering a new entry point for prognostic tools. The development of anti-epileptogenic therapies to treat before or at disease onset is hampered by our inability to predict the severity of the disease outcome. In a rat model of temporal lobe epilepsy we aimed to assess whether in vivo non-invasive imaging of brain inflammation at disease onset was predictive of spontaneous recurrent seizures (SRS) frequency and severity of depression-like and sensorimotor-related comorbidities. To this end, translocator protein, a biomarker of inflammation, was imaged by means of positron emission tomography (PET) 2 and 4weeks post-status epilepticus using [18F]-PBR111. Translocator protein was highly upregulated 2weeks post-status epilepticus in limbic structures (up to 2.1-fold increase compared to controls in temporal lobe, P<0.001), whereas 4weeks post-status epilepticus, upregulation decreased (up to 1.6-fold increase compared to controls in temporal lobe, P<0.01) and was only apparent in a subset of these regions. Animals were monitored with video-electroencephalography during all stages of disease (acute, latent - first seizures appearing around 2weeks post-status epilepticus - and chronic phases), for a total of 12weeks, in order to determine SRS frequency for each subject (range 0.00-0.83SRS/day). We found that regional PET uptake at 2 and 4weeks post-status epilepticus correlated with the severity of depression-like and sensorimotor-related comorbidities during chronic epilepsy (P<0.05 for each test). Regional PET imaging did not correlate with SRS frequency, however, by applying a multivariate data-driven modeling approach based on translocator protein PET imaging at 2weeks post-status epilepticus, we accurately predicted the frequency of SRS (R=0.92; R2=0.86; P<0.0001) at the onset of epilepsy. This study not only demonstrates non-invasive imaging of translocator protein as a prognostic biomarker to ascertain SRS frequency, but also shows its capability to reflect the severity of depression-like and sensorimotor-related comorbidities. Our results are an encouraging step towards the development of anti-epileptogenic treatments by providing early quantitative assessment of SRS frequency and severity of comorbidities with high clinical relevance.
Assuntos
Encéfalo/diagnóstico por imagem , Encefalite/diagnóstico por imagem , Convulsões/diagnóstico por imagem , Estado Epiléptico/diagnóstico por imagem , Animais , Progressão da Doença , Eletroencefalografia , Masculino , Tomografia por Emissão de Pósitrons , Valor Preditivo dos Testes , Ratos , Ratos Wistar , RecidivaRESUMO
Status epilepticus (SE) initiates epileptogenesis to transform normal brain to epileptic state which is characterized by spontaneous recurrent seizures (SRS). Prior to SRS, progressive changes occur in the brain soon after SE, for example, loss of blood-brain barrier (BBB) integrity, neuronal hyper-excitability (epileptiform spiking), neuroinflammation [reactive gliosis, high levels of reactive oxygen/nitrogen species (ROS/RNS)], neurodegeneration and synaptic re-organization. Our hypothesis was that modification of early epileptogenic events will alter the course of disease development and its progression. We tested the hypothesis in the rat kainate model of chronic epilepsy using a novel disease modifying drug, 1400W, a highly selective inhibitor of inducible nitric oxide synthase (iNOS/NOS-II). In an in vitro mouse brain slice model, using a multi-electrode array system, co-application of 1400W with kainate significantly suppressed kainate-induced epileptiform spiking. In the rats, in vivo, 4h after the induction of SE with kainate, 1400W (20mg/kg, i.p.) was administered twice daily for three days to target early events of epileptogenesis. The rats were subjected to continuous (24/7) video-EEG monitoring, remotely, for six months from epidurally implanted cortical electrodes. The 1400W treatment significantly reduced the epileptiform spike rate during the first 12-74h post-SE, which resulted in >90% reduction in SRS in long-term during the six month period when compared to the vehicle-treated control group (257±113 versus 19±10 episodes). Immunohistochemistry (IHC) of brain sections at seven days and six months revealed a significant reduction in; reactive astrogliosis and microgliosis (M1 type), extravascular serum albumin (a marker for BBB leakage) and neurodegeneration in the hippocampus, amygdala and entorhinal cortex in the 1400W-treated rats when compared to the vehicle control. In the seven day group, hippocampal Western blots revealed downregulation of inwardly-rectifying potassium (Kir 4.1) channels and glutamate transporter-1 (GLT-1) levels in the vehicle group, and 1400W treatment partially reversed Kir 4.1 levels, however, GLT-1 levels were unaffected. In the six month group, a significant reduction in mossy fiber staining intensity in the inner molecular layer of the dentate gyrus was observed in the 1400W-treated group. Overall these findings demonstrate that 1400W, by reducing the epileptiform spike rate during the first three days of post-insult, potentially modifies epileptogenesis and the severity of chronic epilepsy in the rat kainate model of TLE.
Assuntos
Amidinas/farmacologia , Benzilaminas/farmacologia , Epilepsia do Lobo Temporal/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Estado Epiléptico/tratamento farmacológico , Animais , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Ratos Sprague-Dawley , Estado Epiléptico/induzido quimicamenteRESUMO
Over the last 10 years, accumulated experimental and clinical evidence has supported the idea that AT1 receptor subtype is involved in epilepsy. Recently, we have shown that the selective AT1 receptor antagonist losartan attenuates epileptogenesis and exerts neuroprotection in the CA1 area of the hippocampus in epileptic Wistar rats. This study aimed to verify the efficacy of long-term treatment with losartan (10 mg/kg) after kainate-induced status epilepticus (SE) on seizure activity, behavioral and biochemical changes, and neuronal damage in a model of co-morbid hypertension and epilepsy. Spontaneous seizures were video- and EEG-monitored in spontaneously hypertensive rats (SHRs) for a 16-week period after SE. The behavior was analyzed by open field, elevated plus maze, sugar preference test, and forced swim test. The levels of serotonin in the hippocampus and neuronal loss were estimated by HPLC and hematoxylin and eosin staining, respectively. The AT1 receptor antagonism delayed the onset of seizures and alleviated their frequency and duration during and after discontinuation of treatment. Losartan showed neuroprotection mostly in the CA3 area of the hippocampus and the septo-temporal hilus of the dentate gyrus in SHRs. However, the AT1 receptor antagonist did not exert a substantial influence on concomitant with epilepsy behavioral changes and decreased 5-HT levels in the hippocampus. Our results suggest that the antihypertensive therapy with an AT1 receptor blocker might be effective against seizure activity and neuronal damage in a co-morbid hypertension and epilepsy.
Assuntos
Comportamento Animal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipertensão/fisiopatologia , Losartan/farmacologia , Neurônios/efeitos dos fármacos , Convulsões/tratamento farmacológico , Animais , Modelos Animais de Doenças , Hipertensão/complicações , Losartan/administração & dosagem , Masculino , Ratos , Ratos Endogâmicos SHR , Convulsões/complicações , Convulsões/fisiopatologia , Estado Epiléptico/induzido quimicamenteRESUMO
OBJECTIVES: During the last decade, experimental evidence has demonstrated an important role of hypoxia, which leads to neuronal cell death and angiogenesis, in the mechanisms of seizure precipitation and recurrence. MicroRNA-199 targets hypoxia-inducible factor-1alpha (HIF-1α), which has recently been implicated in the pathophysiology of the hypoxic state and brain injury. However, little is known about the roles of MicroRNA-199 and HIF-1α in the human epileptogenic process. DESIGN AND METHODS: In this study, we investigated the expression of miR-199a-5p, miR-199b-5p and HIF-1α using real-time PCR, immunohistochemistry and western blots in the temporal neocortex of twenty four patients with intractable epilepsy and twelve control subjects. RESULTS: Compared with the control group, the expression of miR-199a-5p and miR-199b-5p was significantly lower in epileptic brain tissues (p < 0.05). The levels of HIF-1α mRNA and protein were highly up-regulated in epileptic brain tissues compared with those of control subjects (p < 0.05). CONCLUSION: These data suggest that the abnormal expression of miR-199 and HIF-1α in epileptic brain tissue may be involved in the pathophysiology of human epilepsy and that the expression of HIF-1α may be regulated by miR-199. These findings may provide new insights into the treatment of epilepsy.
Assuntos
Epilepsia Resistente a Medicamentos/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , MicroRNAs/biossíntese , Lobo Temporal/metabolismo , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
OBJECTIVES: To determine the risk factors for and outcomes after recurrent seizures (RS) in patients following cardiac surgery. DESIGN: A historical cohort study. SETTING: A single-center university teaching hospital. PARTICIPANTS: Cardiac surgery patients from April 2003 to September 2010 experiencing postoperative seizures. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were divided into an isolated seizure group and an RS group. Risk factors for RS were determined using logistic regression. Intermediate-term follow-up was conducted by phone. Of 7,280 consecutive patients undergoing cardiac surgery, 61 (0.8%) experienced postoperative seizure and 36 (59%) of those experienced at least 1 recurrence. Of these, 32 (89%) experienced RS within 24 hours of the first seizure, and 29 (81%) had grand mal seizures. Preoperative creatinine ≥120 µmol/L (p = 0.02), time until first seizure occurred (≤4 hours; p = 0.01), and procedures involving the thoracic aorta were associated with RS (R(2) = 0.53, p<0.05). Patients with RS had longer intensive care unit stays (5.3 v 2.9 days, p = 0.03) and longer mechanical ventilation duration (53.3 v 15.0 hours, p = 0.01). At a median follow-up of 21 months for the RS group and 16 months for the isolated seizure group, restrictions, anticonvulsant use, morbidity, and mortality were similar between patients with isolated versus recurrent seizures. CONCLUSIONS: Higher preoperative creatinine, thoracic aortic surgery, and early seizure onset were associated with RS after cardiac surgery. When compared to isolated seizures, recurrence per se was not associated with significantly increased long-term morbidity or mortality.
Assuntos
Procedimentos Cirúrgicos Cardíacos , Complicações Pós-Operatórias/epidemiologia , Convulsões/epidemiologia , Idoso , Estudos de Coortes , Creatinina/sangue , Feminino , Seguimentos , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Complicações Pós-Operatórias/sangue , Recidiva , Fatores de Risco , Convulsões/sangueRESUMO
Although epilepsy is a common neurological disorder, its mechanism(s) are still not completely understood. Hypoxia can lead to neuronal cell death and angiogenesis, and the same mechanisms were also found in epilepsy. Hypoxia-inducible factor-1α (HIF-1α) is an important transcription protein that regulates gene expression in the brain and other tissues in response to decreases in oxygen availability. However, little is known regarding the expression of HIF-1α in the epileptic brain and whether HIF-1α interventions affect the epileptic process. The aims of this study are to investigate the expression profile of HIF-1α in rat models and to explore the role of HIF-1α in epilepsy. We performed Western blots and immunofluorescence in a lithium-pilocarpine rat epilepsy model. To determine the role of HIF-1α in epilepsy, we used the HIF-1α agonist DMOG and inhibitor KC7F2 to detect changes in the animal behavior in pentylenetetrazole (PTZ) and lithium-pilocarpine epilepsy models. The expression of HIF-1α was significantly increased after pilocarpine-induced status epilepticus. DMOG significantly prolonged the latent period in the PTZ kindling model and decreased the rate of spontaneous recurrent seizures during the chronic stage in the lithium-pilocarpine model. Conversely, the inhibitor KC7F2 produced an opposite behavioral change. Interestingly, both KC7F2 and DMOG had no effect on the acute stage of pilocarpine model and PTZ convulsive model. Our study suggests that upregulated HIF-1α may be involved in the process of epileptogenesis but not in the acute stage of epilepsy. The modulation of HIF-1α may offer a novel therapeutic target in epilepsy.
Assuntos
Encéfalo/fisiopatologia , Epilepsia/fisiopatologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Doença Aguda , Aminoácidos Dicarboxílicos/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Fármacos do Sistema Nervoso Central/farmacologia , Doença Crônica , Modelos Animais de Doenças , Dissulfetos/farmacologia , Epilepsia/tratamento farmacológico , Subunidade alfa do Fator 1 Induzível por Hipóxia/agonistas , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Compostos de Lítio , Masculino , Pentilenotetrazol , Pilocarpina , Distribuição Aleatória , Ratos Sprague-Dawley , Convulsões/tratamento farmacológico , Convulsões/fisiopatologia , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/fisiopatologia , Sulfonamidas/farmacologiaRESUMO
Damage to the hippocampus can occur through many causes including head trauma, ischemia, stroke, status epilepticus, and Alzheimer's disease. Certain changes such as increased levels of neurogenesis and elevated concentrations of multiple neurotrophic factors that ensue in the acute phase after injury seem beneficial for restraining hippocampal dysfunction. However, many alterations that arise in the intermediate to chronic phase after injury such as abnormal migration of newly born neurons, aberrant synaptic reorganization, progressive loss of inhibitory gamma-amino butyric acid positive interneurons including those expressing reelin, greatly declined neurogenesis, and sustained inflammation are detrimental. Consequently, the net effect of postinjury plasticity in the hippocampus remains inadequate for promoting significant functional recovery. Hence, ideal therapeutic interventions ought to be efficient for restraining these detrimental changes in order to block the propensity of most hippocampal injuries to evolve into learning deficits, memory dysfunction, depression, and temporal lobe epilepsy. Neural stem cell (NSC) grafting into the hippocampus early after injury appears alluring from this perspective because several recent studies have demonstrated the therapeutic value of this intervention, especially for preventing/easing memory dysfunction, depression, and temporal lobe epilepsy development in the chronic phase after injury. These beneficial effects of NSC grafting appeared to be mediated through considerable modulation of aberrant hippocampal postinjury plasticity with additions of new inhibitory gamma-amino butyric acid positive interneurons and astrocytes secreting a variety of neurotrophic factors and anticonvulsant proteins. This review presents advancements made in NSC grafting therapy for treating hippocampal injury in animal models of excitotoxic injury, traumatic brain injury, Alzheimer's disease, and status epilepticus; potential mechanisms of functional recovery mediated by NSC grafts placed early after hippocampal injury; and issues that need to be resolved prior to considering clinical application of NSC grafting for hippocampal injury.
Assuntos
Lesões Encefálicas , Transtornos Cognitivos , Epilepsia , Hipocampo , Transtornos do Humor , Células-Tronco Neurais/transplante , Neurogênese/fisiologia , Animais , Lesões Encefálicas/complicações , Lesões Encefálicas/cirurgia , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/cirurgia , Epilepsia/etiologia , Epilepsia/cirurgia , Hipocampo/lesões , Hipocampo/cirurgia , Humanos , Transtornos do Humor/etiologia , Transtornos do Humor/cirurgia , Proteína ReelinaRESUMO
Melatonin is involved in the control of circadian and seasonal rhythmicity, possesses potent antioxidant activity, and exerts a neuroprotective and anticonvulsant effect. Spontaneously hypertensive rats (SHRs) are widely accepted as an experimental model of essential hypertension with hyperactivity, deficient sustained attention, and alterations in circadian autonomic profiles. The purpose of the present study was to determine whether melatonin treatment during epileptogenesis can prevent the deleterious consequences of status epilepticus (SE) in SHRs in the kainate (KA) model of temporal lobe of epilepsy (TLE). Spontaneous recurrent seizures (SRSs) were EEG- and video-recorded during and after the treatment protocol. Melatonin (10mg/kg diluted in drinking water, 8weeks) increased the seizure-latent period, decreased the frequency of SRSs, and attenuated the circadian rhythm of seizure activity in SHRs. However, melatonin was unable to affect the disturbed diurnal rhythms and behavioral changes associated with epilepsy, including the decreased anxiety level, depression, and impaired spatial memory. Melatonin reduced neuronal damage specifically in the CA1 area of the hippocampus and piriform cortex and decreased hippocampal serotonin (5-HT) levels both in control and epileptic SHRs. Although long-term melatonin treatment after SE shows a potential to attenuate seizure activity and neuronal loss, it is unable to restore epilepsy-associated behavioral abnormalities in SHRs.
Assuntos
Antioxidantes/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Encéfalo/patologia , Epilepsia do Lobo Temporal/tratamento farmacológico , Epilepsia do Lobo Temporal/fisiopatologia , Melatonina/uso terapêutico , Animais , Antioxidantes/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/induzido quimicamente , Comportamento Exploratório/efeitos dos fármacos , Preferências Alimentares/efeitos dos fármacos , Ácido Caínico/toxicidade , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Melatonina/farmacologia , Ratos , Ratos Endogâmicos SHR , Serotonina/metabolismo , Natação/psicologia , Fatores de TempoRESUMO
Autoimmune encephalitis (AE) is a rare immune-mediated disorder comprised of non-infectious neuroinflammatory disease processes. Clinical presentation overlaps with a broad range of neurodegenerative disorders and infectious encephalitis; therefore, AE remains a diagnosis of exclusion. Patients may present with nonspecific symptoms such as psychiatric disturbances, cognitive deficits, seizures, movement disorders, and confusion. Prompt diagnosis and management are necessary for patients with AE to decrease mortality and improve quality of life. First-line therapy includes immunosuppression with corticosteroids, intravenous immunoglobulin, and plasmapheresis. We report the case of an 86-year-old female with a medical history of Parkinson's disease who presented with nonspecific seizure-like activity and was diagnosed with AE.
RESUMO
The lithium-pilocarpine model is commonly used to recapitulate characteristics of human intractable focal epilepsy. In the current study, we explored the impact of topiramate (TPM) alone and in combination with pregabalin and lacosamide administration for 6 weeks on the evolution of spontaneous recurrent seizures (SRS) and disease-modifying potential on associated neuropsychiatric comorbidities. In addition, redox impairments and neurodegeneration in hippocampus regions vulnerable to temporal lobe epilepsy (TLE) were assessed by cresyl violet staining. Results revealed that acute electrophysiological (EEG) profiling of the ASD cocktail markedly halted sharp ictogenic spikes as well as altered dynamics of brain wave oscillations thus validating the need for polytherapy vs. monotherapy. In TLE animals, pharmacological intervention for 6 weeks with topiramate 10 mg/kg in combination with PREG and LAC at the dose of 20 mg/kg exhibited marked protection from SRS incidence, improved body weight, offensive aggression, anxiety-like behavior, cognitive impairments, and depressive-like behavior (p < 0.05). Moreover, combination therapy impeded redox impairments as evidenced by decreased MDA and AchE levels and increased activity of antioxidant SOD, GSH enzymes. Furthermore, polytherapy rescued animals from SE-induced neurodegeneration with increased neuronal density in CA1, CA3c, CA3ab, hilus, and granular cell layer (GCL) of the dentate gyrus. In conclusion, early polytherapy with topiramate in combination with pregabalin and lacosamide prompted synergy and prevented epileptogenesis with associated psychological and neuropathologic alterations.
Assuntos
Modelos Animais de Doenças , Eletroencefalografia , Lacosamida , Fármacos Neuroprotetores , Pregabalina , Topiramato , Animais , Lacosamida/farmacologia , Lacosamida/uso terapêutico , Topiramato/farmacologia , Topiramato/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Masculino , Pregabalina/farmacologia , Pregabalina/uso terapêutico , Ratos , Comportamento Animal/efeitos dos fármacos , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Quimioterapia Combinada , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Hipocampo/patologia , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/fisiopatologia , Ratos Wistar , Epilepsia do Lobo Temporal/tratamento farmacológico , Epilepsia do Lobo Temporal/fisiopatologia , Epilepsia do Lobo Temporal/induzido quimicamenteRESUMO
In old and modern times and across cultures, recurrent seizures have been attributed to the lunar phase. It is unclear whether this relationship should be classified as a myth or whether a true connection exists between moon phases and seizures. We analyzed the worldwide aggregated search queries related to epilepsy health-seeking behavior between 2005 and 2012. Epilepsy-related Internet searches increased in periods with a high moon illumination. The overall association was weak (r=0.11, 95% confidence interval: 0.07 to 0.14) but seems to be higher than most control search queries not related to epilepsy. Increased sleep deprivation during periods of full moon might explain this positive association and warrants further study into epilepsy-related health-seeking behavior on the Internet, the lunar phase, and its contribution to nocturnal luminance.