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1.
Epilepsy Behav ; 60: 187-196, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27208924

RESUMO

Binding of the extracellular matrix proteinase urokinase-type plasminogen activator (uPA) to its receptor, uPAR, regulates tissue remodeling during development and after injury in different organs, including the brain. Accordingly, mutations in the Plaur gene, which encodes uPAR, have been linked to language deficits, autism, and epilepsy, both in mouse and human. Whether uPAR deficiency modulates epileptogenesis and comorbidogenesis after brain injury, however, is unknown. To address this question, we induced traumatic brain injury (TBI) by controlled cortical impact (CCI) in 10 wild-type (Wt-CCI) and 16 Plaur-deficient (uPAR-CCI) mice. Sham-operated mice served as controls (10 Wt-sham, 10 uPAR-sham). During the 4-month follow-up, the mice were neurophenotyped by assessing the somatomotor performance with the composite neuroscore test, emotional learning and memory with fear conditioning to tone and context, and epileptogenesis with videoelectroencephalography monitoring and the pentylenetetrazol (PTZ) seizure susceptibility test. At the end of the testing, the mice were perfused for histology to analyze cortical and hippocampal neurodegeneration and mossy fiber sprouting. Fourteen percent (1/7) of the mice in the Wt-CCI and 0% in the uPAR-CCI groups developed spontaneous seizures (p>0.05; chi-square). Both the Wt-CCI and uPAR-CCI groups showed increased seizure susceptibility in the PTZ test (p<0.05), impaired recovery of motor function (p<0.001), and neurodegeneration in the hippocampus and cortex (p<0.05) compared with the corresponding sham-operated controls. Motor recovery and emotional learning showed a genotype effect, being more impaired in uPAR-CCI than in Wt-CCI mice (p<0.05). The findings of the present study indicate that uPAR deficiency does not increase susceptibility to epileptogenesis after CCI injury but has an unfavorable comorbidity-modifying effect after TBI.


Assuntos
Lesões Encefálicas Traumáticas/metabolismo , Epilepsia/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase/deficiência , Animais , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/patologia , Suscetibilidade a Doenças , Epilepsia/genética , Epilepsia/patologia , Hipocampo/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Convulsões/genética , Convulsões/metabolismo , Convulsões/patologia
2.
Epilepsy Behav ; 51: 19-27, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26253597

RESUMO

Several components of the urokinase-type plasminogen activator receptor (uPAR)-interactome, including uPAR and its ligand sushi-repeat protein 2, X-linked (SRPX2), are linked to susceptibility to epileptogenesis in animal models and/or humans. Recent evidence indicates that urokinase-type plasminogen activator (uPA), a uPAR ligand with focal proteinase activity in the extracellular matrix, contributes to recovery-enhancing brain plasticity after various epileptogenic insults such as traumatic brain injury (TBI) and status epilepticus. Here, we examined whether deficiency of the uPA-encoding gene Plau augments epileptogenesis after TBI. Traumatic brain injury was induced by controlled cortical impact in the somatosensory cortex of adult male wild-type and Plau-deficient mice. Development of epilepsy and seizure susceptibility were assessed with a 3-week continuous video-electroencephalography monitoring and a pentylenetetrazol test, respectively. Traumatic brain injury-induced cortical or hippocampal pathology did not differ between genotypes. The pentylenetetrazol test revealed increased seizure susceptibility after TBI (p<0.05) in injured mice. Epileptogenesis was not exacerbated, however, in Plau-deficient mice. Taken together, Plau deficiency did not worsen controlled cortical impact-induced brain pathology or epileptogenesis caused by TBI when assessed at chronic timepoints. These data expand previous observations on Plau deficiency in models of status epilepticus and suggest that inhibition of focal extracellular proteinase activity resulting from uPA-uPAR interactions does not modify epileptogenesis after TBI.


Assuntos
Lesões Encefálicas/enzimologia , Epilepsia/enzimologia , Ativador de Plasminogênio Tipo Uroquinase/deficiência , Ativador de Plasminogênio Tipo Uroquinase/fisiologia , Animais , Lesões Encefálicas/complicações , Modelos Animais de Doenças , Suscetibilidade a Doenças , Epilepsia/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
3.
Epilepsy Behav ; 42: 117-28, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25506794

RESUMO

Urokinase-type plasminogen activator (uPA), a serine protease, converts plasminogen to plasmin. Activation of plasmin leads to degradation of the extracellular matrix, which is critical for tissue recovery, angiogenesis, cell migration, and axonal and synaptic plasticity. We hypothesized that uPA deficiency would cause an abnormal neurophenotype and would lead to exacerbated epileptogenesis after brain injury. Wild-type (Wt) and uPA-/- mice underwent a battery of neurologic behavioral tests evaluating general reactivity, spontaneous exploratory activity, motor coordination, pain threshold, fear and anxiety, and memory. We placed particular emphasis on the effect of uPA deficiency on seizure susceptibility, including the response to convulsants (pentylenetetrazol, kainate, or pilocarpine) and kainate-induced epileptogenesis and epilepsy. The uPA-/- mice showed no motor or sensory impairment compared with the Wt mice. Hippocampus-dependent spatial memory also remained intact. The uPA-/- mice, however, exhibited reduced exploratory activity and an enhanced response to a tone stimulus (p<0.05 compared with the Wt mice). The urokinase-type plasminogen activator deficient mice showed no increase in spontaneous or evoked epileptiform electrographic activity. Rather, the response to pilocarpine administration was reduced compared with the Wt mice (p<0.05). Also, the epileptogenesis and the epilepsy phenotype after intrahippocampal kainate injection were similar to those in the Wt mice. Taken together, uPA deficiency led to diminished interest in the environmental surroundings and enhanced emotional reactivity to unexpected aversive stimuli. Urokinase-type plasminogen activator deficiency was not associated with enhanced seizure susceptibility or worsened poststatus epilepticus epilepsy phenotype.


Assuntos
Comportamento Animal/fisiologia , Suscetibilidade a Doenças , Receptores de Ativador de Plasminogênio Tipo Uroquinase/deficiência , Convulsões/fisiopatologia , Ativador de Plasminogênio Tipo Uroquinase/deficiência , Animais , Eletroencefalografia , Potenciais Evocados Auditivos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Receptores de Ativador de Plasminogênio Tipo Uroquinase/fisiologia , Ativador de Plasminogênio Tipo Uroquinase/genética , Ativador de Plasminogênio Tipo Uroquinase/fisiologia
4.
Neurobiol Dis ; 72 Pt B: 224-32, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24912075

RESUMO

Disease modification of epilepsy refers to the alleviation of epileptogenesis or comorbidities after genetic or acquired epileptogenic brain insults. There are currently 30 proof-of-concept experimental pharmacologic studies that have demonstrated some beneficial disease-modifying effects. None of these studies, however, has yet passed from the laboratory to the clinic. The International League Against Epilepsy and American Epilepsy Society working groups on antiepileptogenic (AEG) therapies recently released recommendations for conducting preclinical AEG studies, taking into account many of the critiques raised by previous study designs. One of the issues relates to the lack of analysis of AEG efficacy in both sexes. A review of the literature reveals that most of the preclinical studies have been performed using male rodents, whereas clinical study cohorts include both males and females. Therefore, it is important to determine whether sex differences should be taken into account to a greater extent than they have been historically at different phases of experimental studies. Here we address the following questions based on analysis of available experimental AEG studies: (a) whether sex differences should be considered when searching for novel AEG targets, (b) how sex differences can affect the preclinical AEG study designs and analysis of outcome measures, and (c) what factors should be considered when examining the effect of sex on outcome of clinical AEG trials or the clinical use of AEGs.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Caracteres Sexuais , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/farmacocinética , Epilepsia/metabolismo , Feminino , Hormônios Esteroides Gonadais/metabolismo , Humanos , Masculino , Gravidez , Complicações na Gravidez/induzido quimicamente
5.
Epilepsy Behav ; 38: 19-24, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24529830

RESUMO

Traumatic brain injury (TBI) can cause a myriad of sequelae depending on its type, severity, and location of injured structures. These can include mood disorders, posttraumatic stress disorder and other anxiety disorders, personality disorders, aggressive disorders, cognitive changes, chronic pain, sleep problems, motor or sensory impairments, endocrine dysfunction, gastrointestinal disturbances, increased risk of infections, pulmonary disturbances, parkinsonism, posttraumatic epilepsy, or their combinations. The progression of individual pathologies leading to a given phenotype is variable, and some progress for months. Consequently, the different post-TBI phenotypes appear within different time windows. In parallel with morbidogenesis, spontaneous recovery occurs both in experimental models and in human TBI. A great challenge remains; how can we dissect the specific mechanisms that lead to the different endophenotypes, such as posttraumatic epileptogenesis, in order to identify treatment approaches that would not compromise recovery?


Assuntos
Epilepsia Pós-Traumática/fisiopatologia , Animais , Epilepsia Pós-Traumática/classificação , Humanos
6.
J Med Chem ; 66(18): 13205-13246, 2023 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-37712656

RESUMO

Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. We report the design of a series of HTT pre-mRNA splicing modulators that lower huntingtin (HTT) protein, including the toxic mutant huntingtin (mHTT), by promoting insertion of a pseudoexon containing a premature termination codon at the exon 49-50 junction. The resulting transcript undergoes nonsense-mediated decay, leading to a reduction of HTT mRNA transcripts and protein levels. The starting benzamide core was modified to pyrazine amide and further optimized to give a potent, CNS-penetrant, and orally bioavailable HTT-splicing modulator 27. This compound reduced canonical splicing of the HTT RNA exon 49-50 and demonstrated significant HTT-lowering in both human HD stem cells and mouse BACHD models. Compound 27 is a structurally diverse HTT-splicing modulator that may help understand the mechanism of adverse effects such as peripheral neuropathy associated with branaplam.

7.
Neuroscience ; 415: 184-200, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31362033

RESUMO

Sushi repeat-containing protein X-linked 2 (SRPX2) is a novel hypothalamic protein and a ligand of the urokinase-type plasminogen activator receptor (uPAR), which is essential for proteolysis of extracellular matrix and tissue remodeling after an insult to the brain. However, little is known about regulation of SRPX2. Our objective was to investigate if SRPX2 expression is altered by (i) the deficiency of uPAR or uPA (urokinase-type plasminogen activator), and (ii) traumatic brain injury (TBI). SRPX2 expression was assessed in wild type (Wt), Plaur-/- (uPAR-deficient), and Plau-/- (uPA-deficient) mice, with and without controlled cortical impact injury (CCI). The number of SRPX2+ neurons in hypothalamus was comparable to that in Wt littermates in Plaur-/- (2985 ±â€¯138 vs. 2890 ±â€¯92, p > 0.05) and Plau-/- mice (2180 ±â€¯232 vs. 2027 ±â€¯77, p > 0.05). The number of hypothalamic SRPX2+ neurons in the Wt-CCI group was comparable to that in controls (3645 ±â€¯288 vs. 3385 ±â€¯192, p > 0.05). Hypothalamic, hippocampal and thalamic Srpx2 gene expression was unaltered after TBI. However, at 4 days post-TBI Srpx2 gene expression was upregulated in the perilesional cortex of Plau-/--CCI mice up to 123% of that in the sham group (p < 0.05). Unsupervised hierarchical clustering using SRPX2 expression did not identify genotype or injury-specific clusters. Our data demonstrate that SRPX2 expression in the hypothalamus is resistant to genetic deficiencies in the urokinase-system or to the hypothalamus-affecting TBI. The contribution of elevated Srpx2 gene expression in perilesional cortex to post-TBI recovery process, however, requires further exploration.


Assuntos
Lesões Encefálicas Traumáticas/metabolismo , Hipotálamo/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase/biossíntese , Animais , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/patologia , Expressão Gênica , Genótipo , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Neurônios/patologia , Receptores de Ativador de Plasminogênio Tipo Uroquinase/deficiência , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Transdução de Sinais
8.
Epilepsy Res ; 151: 67-74, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30836238

RESUMO

Extracellular proteolysis initiated by the binding of urokinase-type plasminogen activator (uPA) to its receptor (uPAR) regulates the development of inhibitory neuronal circuits in the cerebral cortex and tissue remodeling after epileptogenic brain injury. To study the function of different components of the uPA-uPAR system on behavior and epileptogenesis, and to complement our previous studies on naïve and injured mice deficient in the uPA-encoding gene Plau or the uPAR-encoding gene Plaur, we analyzed the behavioral phenotype, seizure susceptibility, and perineuronal nets surrounding parvalbumin-positive inhibitory interneurons in Plau and Plaur (double knockout dKO) mice. In a climbing test, dKO mice showed reduced interest towards the environment as compared with Wt mice (p < 0.01). In a social approach test, however, dKO mice spent more time than Wt mice exploring the compartment containing a stranger mouse than the empty compartment (p < 0.05). Moreover, in a social interaction test, dKO mice exhibited increased contact time (p < 0.01). Compared with Wt mice, the dKO mice also had a longer single contact duration (p < 0.001) with the stranger mouse. In the elevated plus-maze, grooming, and marble burying tests, the anxiety level of dKO mice did not differ from that of Wt mice. Rearing time in an exploratory activity test, and spatial learning and memory in the Morris swim navigation task were also comparable between dKO and Wt mice. In the pentylenetetrazol (PTZ) seizure-susceptibility test, dKO mice had a shorter latency to the first epileptiform spike (p = 0.0001) and a greater total number of spikes (p < 0.001) than Wt mice. The dKO genotype did not affect the number of cortical perineuronal nets. Our findings indicate that Plau/Plaur-deficiency leads to a more social phenotype toward other mice with diminished interest in the surrounding environment, and increased seizure susceptibility.


Assuntos
Regulação da Expressão Gênica/genética , Receptores de Ativador de Plasminogênio Tipo Uroquinase/deficiência , Convulsões/metabolismo , Comportamento Social , Ativador de Plasminogênio Tipo Uroquinase/deficiência , Animais , Ansiedade/etiologia , Ansiedade/genética , Aprendizagem da Esquiva/fisiologia , Ondas Encefálicas/efeitos dos fármacos , Ondas Encefálicas/genética , Convulsivantes/toxicidade , Modelos Animais de Doenças , Suscetibilidade a Doenças/induzido quimicamente , Suscetibilidade a Doenças/fisiopatologia , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Asseio Animal/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pentilenotetrazol/toxicidade , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Convulsões/induzido quimicamente , Convulsões/patologia , Ativador de Plasminogênio Tipo Uroquinase/genética
9.
J Comp Neurol ; 526(11): 1806-1819, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29663392

RESUMO

Sushi repeat-containing protein X-linked 2 (SRPX2) is a novel protein associated with language development, synaptic plasticity, tissue remodeling, and angiogenesis. We investigated the expression and spatial localization of SRPX2 in normal mouse, rat, monkey, and human brain using in situ hybridization and immunohistochemistry. Antibody specificity was determined using in vitro siRNA based silencing of SRPX2. Cell type-specific expression was verified by double-labeling with oxytocin or vasopressin. Western blot was used to detect SRPX2 protein in rat and human plasma and cerebrospinal fluid. Unexpectedly, SRPX2 mRNA expression levels were strikingly higher in the hypothalamus as compared to the cortex. All SRPX2 immunoreactive (ir) neurons were localized in the hypothalamic paraventricular, periventricular, and supraoptic nuclei in mouse, rat, monkey, and human brain. SRPX2 colocalized with vasopressin or oxytocin in paraventricular and supraoptic neurons. Hypothalamic SRPX2-ir positive neurons gave origin to dense projections traveling ventrally and caudally toward the hypophysis. Intense axonal varicosities and terminal arborizations were identified in the rat and human neurohypophysis. SRPX2-ir cells were also found in the adenohypophysis. Light SRPX2-ir projections were observed in the dorsal and ventral raphe, locus coeruleus, and the nucleus of the solitary tract in mouse, rat and monkey. SRPX2 protein was also detected in plasma and CSF. Our data revealed intense phylogenetically conserved expression of SRPX2 protein in distinct hypothalamic nuclei and the hypophysis, suggesting its active role in the hypothalamo-pituitary axis. The presence of SRPX2 protein in the plasma and CSF suggests that some of its functions depend on secretion into body fluids.


Assuntos
Sequência Conservada , Sistema Hipotálamo-Hipofisário/metabolismo , Proteínas de Membrana/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Química Encefálica , Linhagem Celular , Córtex Cerebral/metabolismo , Humanos , Hipotálamo/metabolismo , Macaca , Masculino , Proteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Proteínas de Neoplasias , Proteínas do Tecido Nervoso , Filogenia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Interferente Pequeno , Ratos , Ratos Sprague-Dawley
10.
Front Neurosci ; 9: 128, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25954146

RESUMO

Traumatic brain injury (TBI) is a major cause of disability and death in people of all ages worldwide. An initial brain injury caused by external mechanical forces triggers a cascade of tissue changes that lead to a wide spectrum of symptoms and disabilities, such as cognitive deficits, mood or anxiety disorders, motor impairments, chronic pain, and epilepsy. We investigated the detectability of secondary injury at a chronic time-point using ex vivo diffusion tensor imaging (DTI) in a rat model of TBI, lateral fluid percussion (LFP) injury. Our analysis of ex vivo DTI data revealed persistent microstructural tissue changes in white matter tracts, such as the splenium of the corpus callosum, angular bundle, and internal capsule. Histologic examination revealed mainly loss of myelinated axons and/or iron accumulation. Gray matter areas in the thalamus exhibited an increase in fractional anisotropy associated with neurodegeneration, myelinated fiber loss, and/or calcifications at the chronic phase. In addition, we examined whether these changes could also be detected with in vivo settings at the same chronic time-point. Our results provide insight into DTI detection of microstructural changes in the chronic phase of TBI, and elucidate how these changes correlate with cellular level alterations.

11.
J Neurotrauma ; 29(5): 789-812, 2012 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-22023672

RESUMO

The present study investigated the development of hyperexcitability and epilepsy in mice with traumatic brain injury (TBI) induced by controlled cortical impact (CCI) or lateral fluid-percussion injury (FPI), which are the two most commonly used experimental models of human TBI in rodents. TBI was induced with CCI to 50 (14 controls) and with lateral FPI to 45 (15 controls) C57BL/6S adult male mice. The animals were followed-up for 9 months, including three 2-week periods of continuous video-electroencephalographic (EEG) monitoring, and a seizure susceptibility test with pentylenetetrazol (PTZ). In the end, the animals were perfusion-fixed for histology. The experiment included two independent cohorts of animals. Late post-traumatic spontaneous electrographic seizures were detected in 9% of mice after CCI and 3% after lateral FPI. Eighty-two percent of mice after CCI and 71% after lateral FPI had spontaneous epileptiform spiking on EEG. In addition, 58% of mice with lateral FPI showed spontaneous epileptiform discharges. A PTZ test demonstrated increased seizure susceptibility in the majority of mice in both models, compared to control mice. There was no further progression in the occurrence of epilepsy or epileptiform spiking when follow-up was extended from 6 to 9 months. The severity of cortical or hippocampal damage did not differentiate mice with or without epileptiform activity in either model. Finally, two independent series of experiments in both injury models provided comparable data demonstrating reproducibility of the modeling. These data show that different types of impact can trigger epileptogenesis in mice. Even though the frequency of spontaneous seizures in C57BL/6S mice is low, a large majority of animals develop hyperexcitability.


Assuntos
Lesões Encefálicas/complicações , Lesões Encefálicas/fisiopatologia , Epilepsia Pós-Traumática/etiologia , Epilepsia Pós-Traumática/fisiopatologia , Animais , Modelos Animais de Doenças , Eletroencefalografia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
12.
Neurosci Lett ; 497(3): 163-71, 2011 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-21402123

RESUMO

Post-traumatic epilepsy (PTE) accounts for 10-20% of symptomatic epilepsies. The urgency to understand the process of post-traumatic epileptogenesis and search for antiepileptogenic treatments is emphasized by a recent increase in traumatic brain injury (TBI) related to military combat or accidents in the aging population. Recent developments in modeling of PTE in rodents have provided tools for identification of novel drug targets for antiepileptogenesis and biomarkers for predicting the risk of epileptogenesis and treatment efficacy after TBI. Here we review the available data on endophenotypes of humans and rodents with TBI associated with epilepsy. Also, current understanding of the mechanisms and biomarkers for PTE as well as factors associated with preclinical study designs are discussed. Finally, we summarize the attempts to prevent PTE in experimental models.


Assuntos
Anticonvulsivantes/uso terapêutico , Lesões Encefálicas/fisiopatologia , Lesões Encefálicas/terapia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Epilepsia/prevenção & controle , Epilepsia/fisiopatologia , Animais , Encéfalo/efeitos dos fármacos , Lesões Encefálicas/complicações , Epilepsia/etiologia , Humanos , Ratos
13.
Epilepsy Res ; 94(1-2): 75-85, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21300523

RESUMO

Previous studies have demonstrated an increased risk of epilepsy in patients with Alzheimer's disease (AD). Also, in many mouse models of AD, animals have spontaneous seizures and frequent epileptiform discharges (EDs). Abnormal function of sodium channels has been proposed to contribute to hyperexcitability in a manner suggesting that drugs that block sodium channels might exacerbate the condition. Here we addressed this question by investigating whether common antiepileptic drugs (AEDs) that block sodium channels, including carbamazepine (CBZ), phenytoin (DPH), or valproic acid (VPA) have any effect on spontaneous seizures or EDs in APdE9 mice. Mice were successively treated with vehicle, followed by CBZ (10mg/kg, t.i.d.), DPH (10mg/kg, t.i.d.), or VPA (260 mg/kg, b.i.d.) for 3d. After wash-out and new vehicle treatment, higher doses of CBZ (40 mg/kg, t.i.d.), DPH (40 mg/kg, t.i.d.), or VPA (400mg/kg, b.i.d.) were administered for 3d (DPH) or 5d (CBZ, VPA). During the entire experiment, mice were under continuous (24/7) video-EEG monitoring. Our data show that each treatment reduced the number of spontaneous electrographic EDs. VPA was the most effective by reducing the ED frequency below 50% of that at baseline in 75% of mice. Western blot analysis of the Na(v)1.1 protein levels in the ventral temporal cortex and the hippocampus did not reveal any differences between the genotypes. Under the conditions tested, sodium channel blocking AEDs suppressed epileptiform activity in APdE9 mice with increased amyloid pathology. Whether this applies to other mouse models of AD with different APP mutations and/or genetic background remains to be explored.


Assuntos
Anticonvulsivantes/uso terapêutico , Encéfalo/metabolismo , Epilepsia/tratamento farmacológico , Epilepsia/patologia , Canais de Sódio/metabolismo , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Doença de Alzheimer/mortalidade , Precursor de Proteína beta-Amiloide/genética , Animais , Anticonvulsivantes/farmacologia , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Eletroencefalografia/métodos , Epilepsia/etiologia , Epilepsia/mortalidade , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas In Vitro , Masculino , Camundongos , Camundongos Transgênicos , Bloqueadores dos Canais de Sódio/farmacologia , Bloqueadores dos Canais de Sódio/uso terapêutico , Análise Espectral , Gravação em Vídeo/métodos
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