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1.
Hum Genet ; 139(4): 545-555, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32020363

RESUMO

Secretory carrier membrane proteins (SCAMPs) play an important role in exocytosis in animals, but the precise function of SCAMPs in human disease is unknown. In this study, we identified a homozygous mutation, SCAMP5 R91W, in a Chinese consanguineous family with pediatric epilepsy and juvenile Parkinson's disease. Scamp5 R91W mutant knock-in mice showed typical early-onset epilepsy similar to that in humans. Single-neuron electrophysiological recordings showed that the R91W mutation significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs) at a resting state and also increased the amplitude of evoked EPSCs. The R91W mutation affected the interaction between SCAMP5 and synaptotagmin 1 and may affect the function of the SNARE complex, the machinery required for vesicular trafficking and neurotransmitter release. Our work shows that dysfunction of SCAMP5 shifted the excitation/inhibition balance of the neuronal network in the brain, and the deficiency of SCAMP5 leads to pediatric epilepsy.


Assuntos
Potenciais de Ação , Encéfalo , Epilepsia , Proteínas de Membrana , Mutação de Sentido Incorreto , Rede Nervosa , Neurotransmissores/metabolismo , Potenciais Sinápticos , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Epilepsia/genética , Epilepsia/metabolismo , Epilepsia/patologia , Técnicas de Introdução de Genes , Células HEK293 , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Rede Nervosa/metabolismo , Rede Nervosa/patologia
2.
J Clin Neurophysiol ; 37(1): 15-27, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31895186

RESUMO

Cannabinoids are compounds that are structurally and/or functionally related to the primary psychoactive constituent of Cannabis sativa, [INCREMENT]-tetrahydrocannabinol (THC). Cannabinoids can be divided into three broad categories: endogenous cannabinoids, plant-derived cannabinoids, and synthetic cannabinoids (SCs). Recently, there has been an unprecedented surge of interest into the pharmacological and medicinal properties of cannabinoids for the treatment of epilepsies. This surge has been stimulated by an ongoing shift in societal opinions about cannabinoid-based medicines and evidence that cannabidiol, a nonintoxicating plant cannabinoid, has demonstrable anticonvulsant activity in children with treatment-refractory epilepsy. The major receptors of the endogenous cannabinoid system (ECS)-the type 1 and 2 cannabinoid receptors (CB1R, CB2R)-have critical roles in the modulation of neurotransmitter release and inflammation, respectively; so, it is not surprising therefore that the ECS is being considered as a target for the treatment of epilepsy. SCs were developed as potential new drug candidates and tool compounds for studying the ECS. Beyond the plant cannabinoids, an extensive research effort is underway to determine whether SCs that directly target CB1R, CB2R, or the enzymes that breakdown endogenous cannabinoids have anticonvulsant effects in preclinical rodent models of epilepsy and seizure. This research demonstrates that many SCs do reduce seizure severity in rodent models and may have both positive and negative pharmacodynamic and pharmacokinetic interactions with clinically used antiepilepsy drugs. Here, we provide a comprehensive review of the preclinical evidence for and against SC modulation of seizure and discuss the important questions that need to be addressed in future studies.


Assuntos
Anticonvulsivantes/farmacologia , Canabinoides/farmacologia , Epilepsia , Receptores de Canabinoides/efeitos dos fármacos , Convulsões , Animais , Modelos Animais de Doenças , Endocanabinoides/fisiologia , Epilepsia/metabolismo , Epilepsia/fisiopatologia , Receptores de Canabinoides/metabolismo , Convulsões/metabolismo , Convulsões/fisiopatologia
3.
Int J Mol Sci ; 20(19)2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31581735

RESUMO

Epilepsy represents one of the most common neurological disorders characterized by abnormal electrical activity in the central nervous system (CNS). Recurrent seizures are the cardinal clinical manifestation. Although it has been reported that the underlying pathological processes include inflammation, changes in synaptic strength, apoptosis, and ion channels dysfunction, currently the pathogenesis of epilepsy is not yet completely understood. Long non-coding RNAs (lncRNAs), a class of long transcripts without protein-coding capacity, have emerged as regulatory molecules that are involved in a wide variety of biological processes. A growing number of studies reported that lncRNAs participate in the regulation of pathological processes of epilepsy and they are dysregulated during epileptogenesis. Moreover, an aberrant expression of lncRNAs linked to epilepsy has been observed both in patients and in animal models. In this review, we summarize latest advances concerning the mechanisms of action and the involvement of the most dysregulated lncRNAs in epilepsy. However, the functional roles of lncRNAs in the disease pathogenesis are still to be explored and we are only at the beginning. Additional studies are needed for the complete understanding of the underlying mechanisms and they would result in the use of lncRNAs as diagnostic biomarkers and novel therapeutic targets.


Assuntos
Epilepsia/etiologia , Epilepsia/metabolismo , Regulação da Expressão Gênica , RNA Longo não Codificante/genética , Transdução de Sinais , Animais , Apoptose/genética , Biomarcadores , Diferenciação Celular/genética , Epigênese Genética , Perfilação da Expressão Gênica , Humanos , Plasticidade Neuronal/genética , Neurônios/citologia , Neurônios/metabolismo , Interferência de RNA
4.
Folia Neuropathol ; 57(2): 146-160, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31556574

RESUMO

INTRODUCTION: Neuronal cell death and glial cell activation are the main pathological findings induced by seizures secondary to oxidative stress. Previous studies have explained neuronal cell death on the basis of cell necrosis and apoptosis. Recent studies have attributed the neuronal loss to autophagy. The proved antioxidant and antifibrotic effect of nilotinib favours its use in the management of epileptic seizures. AIM OF THE STUDY: was to analyse the neuroprotective and antiepileptic effect of nilotinib and explain its mechanism of action. MATERIAL AND METHODS: Forty adult male rats were divided into four groups: control, pentylenetetrazol (PTZ) group (injected with PTZ 60 mg/kg, s.c.), pregabalin (Pregb)-PTZ group (pretreated with pregabalin daily 30 mg/kg; orally for 1 week) and nilotinib (NIL)-PTZ group (pretreated with nilotinib, 25 mg/kg daily for 1 week) prior to PTZ. Seizure latency was evaluated, the hippocampus tissue level of antioxidant enzymes was assessed. The histopathological changes in the hippocampus were studied using hematoxylin and eosin stain and immunohistochemical stain for brain-derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP), beclin-1, nuclear factor kappa-B (NF-κB) and Bcl-2-like protein 4 (BAX). RESULTS: Nilotinib induced an increase in the latency of seizures, enhanced the antioxidant levels of the γ-aminobutyric acid and nuclear factor (erythroid-derived 2)-like 2 activities together with the improvement of the hippocampal histology. A reduction was reported for BDNF, GFAP, beclin-1, NF-κB and BAX expression in nerve cells. CONCLUSIONS: Nilotinib may have promising neuroprotective and antiepileptic effects against pentylenetetrazolinduced seizures through promoting the antioxidant, antifibrotic, anti-inflammatory, antiapoptotic pathways and inhibiting autophagy.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Epilepsia/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Pirimidinas/uso terapêutico , Animais , Epilepsia/induzido quimicamente , Epilepsia/metabolismo , Hipocampo/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Fármacos Neuroprotetores/farmacologia , Pentilenotetrazol , Pirimidinas/farmacologia , Ratos
5.
Neurology ; 93(15): e1485-e1494, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31484709

RESUMO

OBJECTIVE: To determine the relationship between serum serotonin (5-HT) levels, ictal central apnea (ICA), and postconvulsive central apnea (PCCA) in epileptic seizures. METHODS: We prospectively evaluated video EEG, plethysmography, capillary oxygen saturation (SpO2), and ECG for 49 patients (49 seizures) enrolled in a multicenter study of sudden unexpected death in epilepsy (SUDEP). Postictal and interictal venous blood samples were collected after a clinical seizure for measurement of serum 5-HT levels. Seizures were classified according to the International League Against Epilepsy 2017 seizure classification. We analyzed seizures with and without ICA (n = 49) and generalized convulsive seizures (GCS) with and without PCCA (n = 27). RESULTS: Postictal serum 5-HT levels were increased over interictal levels for seizures without ICA (p = 0.01), compared to seizures with ICA (p = 0.21). In patients with GCS without PCCA, serum 5-HT levels were increased postictally compared to interictal levels (p < 0.001), but not in patients with seizures with PCCA (p = 0.22). Postictal minus interictal 5-HT levels also differed between the 2 groups with and without PCCA (p = 0.03). Increased heart rate was accompanied by increased serum 5-HT levels (postictal minus interictal) after seizures without PCCA (p = 0.03) compared to those with PCCA (p = 0.42). CONCLUSIONS: The data suggest that significant seizure-related increases in serum 5-HT levels are associated with a lower incidence of seizure-related breathing dysfunction, and may reflect physiologic changes that confer a protective effect against deleterious phenomena leading to SUDEP. These results need to be confirmed with a larger sample size study.


Assuntos
Apneia/complicações , Apneia/metabolismo , Morte Súbita/etiologia , Epilepsia/complicações , Epilepsia/metabolismo , Serotonina/metabolismo , Adolescente , Adulto , Idoso , Apneia/fisiopatologia , Eletroencefalografia/métodos , Epilepsia/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Convulsões/complicações , Convulsões/fisiopatologia
6.
Redox Biol ; 26: 101278, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31382215

RESUMO

Many epilepsies are acquired conditions following an insult to the brain such as a prolonged seizure, traumatic brain injury or stroke. The generation of reactive oxygen species (ROS) and induction of oxidative stress are common sequelae of such brain insults and have been shown to contribute to neuronal death and the development of epilepsy. Here, we show that combination therapy targeting the generation of ROS through NADPH oxidase inhibition and the endogenous antioxidant system through nuclear factor erythroid 2-related factor 2 (Nrf2) activation prevents excessive ROS accumulation, mitochondrial depolarisation and neuronal death during in vitro seizure-like activity. Moreover, this combination therapy prevented the development of spontaneous seizures in 40% of animals following status epilepticus (70% of animals were seizure free after 8 weeks) and modified the severity of epilepsy when given to chronic epileptic animals.


Assuntos
Antioxidantes/farmacologia , Epilepsia/etiologia , Hansenostáticos/farmacologia , Animais , Antioxidantes/administração & dosagem , Antioxidantes/química , Biomarcadores , Doença Crônica , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Epilepsia/prevenção & controle , Ácido Caínico/metabolismo , Hansenostáticos/administração & dosagem , Hansenostáticos/química , Masculino , NADPH Oxidases/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo
7.
Exp Neurol ; 321: 113029, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31377403

RESUMO

Hyperactivation of the mechanistic target of rapamycin (mTOR) pathway is associated with epilepsy, autism and brain growth abnormalities in humans. mTOR hyperactivation often results from developmental somatic mutations, producing genetic lesions and associated dysfunction in relatively restricted populations of neurons. Disrupted brain regions, such as those observed in focal cortical dysplasia, can contain a mix of normal and mutant cells. Mutant cells exhibit robust anatomical and physiological changes. Less clear, however, is whether adjacent, initially normal cells are affected by the presence of abnormal cells. To explore this question, we used a conditional, inducible mouse model approach to delete the mTOR negative regulator phosphatase and tensin homolog (PTEN) from <1% to >30% of hippocampal dentate granule cells. We then examined the morphology of PTEN-expressing granule cells located in the same dentate gyri as the knockout (KO) cells. Despite the development of spontaneous seizures in higher KO animals, and disease worsening with increasing age, the morphology and physiology of PTEN-expressing cells was only modestly affected. PTEN-expressing cells had smaller somas than cells from control animals, but other parameters were largely unchanged. These findings contrast with the behavior of PTEN KO cells, which show increasing dendritic extent with greater KO cell load. Together, the findings indicate that genetically normal neurons can exhibit relatively stable morphology and intrinsic physiology in the presence of nearby pathological neurons and systemic disease.


Assuntos
Giro Denteado/metabolismo , Giro Denteado/patologia , Neurônios/metabolismo , Neurônios/patologia , PTEN Fosfo-Hidrolase/deficiência , Animais , Epilepsia/genética , Epilepsia/metabolismo , Epilepsia/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Serina-Treonina Quinases TOR/metabolismo
8.
BMC Genomics ; 20(1): 677, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31455240

RESUMO

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a major signaling molecule that the brain uses to control a vast network of intracellular cascades fundamental to properties of learning and memory, and cognition. While much is known about BDNF signaling in the healthy nervous system where it controls the mitogen activated protein kinase (MAPK) and cyclic-AMP pathways, less is known about its role in multiple brain disorders where it contributes to the dysregulated neuroplasticity seen in epilepsy and traumatic brain injury (TBI). We previously found that neurons respond to prolonged BDNF exposure (both in vivo (in models of epilepsy and TBI) and in vitro (in BDNF treated primary neuronal cultures)) by activating the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway. This pathway is best known for its association with inflammatory cytokines in non-neuronal cells. RESULTS: Here, using deep RNA-sequencing of neurons exposed to BDNF in the presence and absence of well characterized JAK/STAT inhibitors, and without non-neuronal cells, we determine the BDNF transcriptome that is specifically regulated by agents that inhibit JAK/STAT signaling. Surprisingly, the BDNF-induced JAK/STAT transcriptome contains ion channels and neurotransmitter receptors coming from all the major classes expressed in the brain, along with key modulators of synaptic plasticity, neurogenesis, and axonal remodeling. Analysis of this dataset has revealed a unique non-canonical mechanism of JAK/STATs in neurons as differential gene expression mediated by STAT3 is not solely dependent upon phosphorylation at residue 705 and may involve a BDNF-induced interaction of STAT3 with Heterochromatin Protein 1 alpha (HP1α). CONCLUSIONS: These findings suggest that the neuronal BDNF-induced JAK/STAT pathway involves more than STAT3 phosphorylation at 705, providing the first evidence for a non-canonical mechanism that may involve HP1α. Our analysis reveals that JAK/STAT signaling regulates many of the genes associated with epilepsy syndromes where BDNF levels are markedly elevated. Uncovering the mechanism of this novel form of BDNF signaling in the brain may provide a new direction for epilepsy therapeutics and open a window into the complex mechanisms of STAT3 transcriptional regulation in neurological disease.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/farmacologia , Encéfalo/metabolismo , Janus Quinases/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Encéfalo/enzimologia , Células Cultivadas , Proteínas Cromossômicas não Histona/metabolismo , Epilepsia/genética , Epilepsia/metabolismo , Regulação da Expressão Gênica , Ontologia Genética , Humanos , Canais Iônicos/biossíntese , Canais Iônicos/genética , Inibidores de Janus Quinases/farmacologia , Janus Quinases/antagonistas & inibidores , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Neurotransmissores/biossíntese , Receptores de Neurotransmissores/genética , Fator de Transcrição STAT3/antagonistas & inibidores , Transdução de Sinais , Transcriptoma
9.
Int J Mol Sci ; 20(17)2019 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-31450553

RESUMO

The correct morphofunctional shaping of the cerebral cortex requires a continuous interaction between intrinsic (genes/molecules expressed within the tissue) and extrinsic (e.g., neural activity) factors at all developmental stages. Forkhead Box G1 (FOXG1) is an evolutionarily conserved transcription factor, essential for the cerebral cortex patterning and layering. FOXG1-related disorders, including the congenital form of Rett syndrome, can be caused by deletions, intragenic mutations or duplications. These genetic alterations are associated with a complex phenotypic spectrum, spanning from intellectual disability, microcephaly, to autistic features, and epilepsy. We investigated the functional correlates of dysregulated gene expression by performing electrophysiological assays on FoxG1+/- mice. Local Field Potential (LFP) recordings on freely moving animals detected cortical hyperexcitability. On the other hand, patch-clamp recordings showed a downregulation of spontaneous glutamatergic transmission. These findings were accompanied by overactivation of Akt/S6 signaling. Furthermore, the expression of vesicular glutamate transporter 2 (vGluT2) was increased, whereas the level of the potassium/chloride cotransporter KCC2 was reduced, thus indicating a higher excitation/inhibition ratio. Our findings provide evidence that altered expression of a key gene for cortical development can result in specific alterations in neural circuit function at the macro- and micro-scale, along with dysregulated intracellular signaling and expression of proteins controlling circuit excitability.


Assuntos
Córtex Cerebral/metabolismo , Córtex Cerebral/fisiopatologia , Epilepsia/genética , Epilepsia/metabolismo , Fatores de Transcrição Forkhead/genética , Proteínas do Tecido Nervoso/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas/metabolismo , Transmissão Sináptica , Animais , Modelos Animais de Doenças , Suscetibilidade a Doenças , Epilepsia/fisiopatologia , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Camundongos , Camundongos Knockout , Fenótipo , Convulsões , Transdução de Sinais , Potenciais Sinápticos
10.
Nat Rev Neurol ; 15(8): 459-472, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31263255

RESUMO

Epilepsy is a chronic neurological disease characterized by an enduring propensity for generation of seizures. The pathogenic processes of seizure generation and recurrence are the subject of intensive preclinical and clinical investigations as their identification would enable development of novel treatments that prevent epileptic seizures and reduce seizure burden. Such treatments are particularly needed for pharmacoresistant epilepsies, which affect ~30% of patients. Neuroinflammation is commonly activated in epileptogenic brain regions in humans and is clearly involved in animal models of epilepsy. An increased understanding of neuroinflammatory mechanisms in epilepsy has identified cellular and molecular targets for new mechanistic therapies or existing anti-inflammatory drugs that could overcome the limitations of current medications, which provide only symptomatic control of seizures. Moreover, inflammatory mediators in the blood and molecular imaging of neuroinflammation could provide diagnostic, prognostic and predictive biomarkers for epilepsy, which will be instrumental for patient stratification in future clinical studies. In this Review, we focus on our understanding of the IL-1 receptor-Toll-like receptor 4 axis, the arachidonic acid-prostaglandin cascade, oxidative stress and transforming growth factor-ß signalling associated with blood-brain barrier dysfunction, all of which are pathways that are activated in pharmacoresistant epilepsy in humans and that can be modulated in animal models to produce therapeutic effects on seizures, neuronal cell loss and neurological comorbidities.


Assuntos
Encefalite/diagnóstico , Encefalite/metabolismo , Epilepsia/diagnóstico , Epilepsia/terapia , Animais , Ácido Araquidônico/metabolismo , Biomarcadores/sangue , Encefalite/complicações , Epilepsia/complicações , Epilepsia/metabolismo , Humanos , Estresse Oxidativo , Prostaglandinas/metabolismo , Receptores de Interleucina-1/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Fator de Crescimento Transformador beta/metabolismo
11.
Int J Mol Sci ; 20(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340538

RESUMO

WW domain-containing oxidoreductase (Wwox) is a putative tumor suppressor. Several germline mutations of Wwox have been associated with infant neurological disorders characterized by epilepsy, growth retardation, and early death. Less is known, however, about the pathological link between Wwox mutations and these disorders or the physiological role of Wwox in brain development. In this study, we examined age-related expression and histological localization of Wwox in forebrains as well as the effects of loss of function mutations in the Wwox gene in the immature cortex of a rat model of lethal dwarfism with epilepsy (lde/lde). Immunostaining revealed that Wwox is expressed in neurons, astrocytes, and oligodendrocytes. lde/lde cortices were characterized by a reduction in neurite growth without a reduced number of neurons, severe reduction in myelination with a reduced number of mature oligodendrocytes, and a reduction in cell populations of astrocytes and microglia. These results indicate that Wwox is essential for normal development of neurons and glial cells in the cerebral cortex.


Assuntos
Sistemas de Transporte de Aminoácidos Acídicos/deficiência , Antiporters/deficiência , Córtex Cerebral/metabolismo , Nanismo/genética , Epilepsia/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Doenças Mitocondriais/genética , Neurogênese/genética , Transtornos Psicomotores/genética , Proteínas Supressoras de Tumor/genética , Oxidorredutase com Domínios WW/genética , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/genética , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/metabolismo , Proteína da Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Sistemas de Transporte de Aminoácidos Acídicos/genética , Sistemas de Transporte de Aminoácidos Acídicos/metabolismo , Animais , Antiporters/genética , Antiporters/metabolismo , Astrócitos/metabolismo , Astrócitos/patologia , Contagem de Células , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/patologia , Modelos Animais de Doenças , Nanismo/metabolismo , Nanismo/patologia , Epilepsia/metabolismo , Epilepsia/patologia , Regulação da Expressão Gênica no Desenvolvimento , Mutação em Linhagem Germinativa , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/metabolismo , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Masculino , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Proteína Básica da Mielina/genética , Proteína Básica da Mielina/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Prosencéfalo/crescimento & desenvolvimento , Prosencéfalo/metabolismo , Prosencéfalo/patologia , Transtornos Psicomotores/metabolismo , Transtornos Psicomotores/patologia , Ratos , Ratos Transgênicos , Transdução de Sinais , Proteínas Supressoras de Tumor/deficiência , Oxidorredutase com Domínios WW/deficiência
12.
Clin Neuropathol ; 38(5): 210-224, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31347492

RESUMO

Epilepsy is one of the most common and serious neurological disorders worldwide. It has no identifiable cause in approximately 50% of patients; in the other 50%, the condition may be due to a variety of etiologies and pathomechanisms. In this review, special focus is put on the prototypes of "mTORpathies": tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) type IIb. We review recent research data on mTORpathies, with emphasis on cortical tubers and FCD-like lesions (neuronal migration lines (NML)). A major pathologic aspect in the network of drug-resistant epilepsy progression is the limited myelination of the white matter observed in these lesions. Recently, an association between the myelin pathology and dysregulation of the mTOR signaling pathway was observed by several studies. The lowered myelin content was shown to correlate not only with an increased mTOR expression but also with the relative duration of epilepsy. Another recently published finding in surgical tissue from patients with drug-resistant epilepsy and malformations of cortical development is inflammation. Accumulating evidence reports persistent and complex activation of inflammatory pathways in both cortical tubers and FCD lesions. Due to the fact that cortical tubers, as well as FCD lesions, are highly epileptogenic, a possible link between chronic seizure activity and the occurrence of an inflammatory response observed within the dysplastic cortex was postulated. Previously, alterations in the levels of classical complement C1q-C3 molecules in experimental and human epilepsy have been reported, suggesting that the classical complement pathway may be a novel candidate mechanism for the underlying epileptogenic circuit mechanism.
.


Assuntos
Encéfalo/metabolismo , Epilepsia/metabolismo , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Humanos
13.
Biomed Res Int ; 2019: 8941046, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31240228

RESUMO

Chloride (Cl-) homeostasis is an essential process involved in neuronal signalling and cell survival. Inadequate regulation of intracellular Cl- interferes with synaptic signalling and is implicated in several neurological diseases. The main inhibitory neurotransmitter of the central nervous system is γ-aminobutyric acid (GABA). GABA hyperpolarises the membrane potential by activating Cl- permeable GABAA receptor channels (GABAAR). This process is reliant on Cl- extruder K+-Cl- cotransporter 2 (KCC2), which generates the neuron's inward, hyperpolarising Cl- gradient. KCC2 is encoded by the fifth member of the solute carrier 12 family (SLC12A5) and has remained a poorly understood component in the development and severity of many neurological diseases for many years. Recent advancements in next-generation sequencing and specific gene targeting, however, have indicated that loss of KCC2 activity is involved in a number of diseases including epilepsy and schizophrenia. It has also been implicated in neuropathic pain following spinal cord injury. Any variant of SLC12A5 that negatively regulates the transporter's expression may, therefore, be implicated in neurological disease. A recent whole exome study has discovered several causative mutations in patients with epilepsy. Here, we discuss the implications of KCC2 in neurological disease and consider the evolving evidence for KCC2's potential as a therapeutic target.


Assuntos
Canais de Cloreto/metabolismo , Neurônios/metabolismo , Simportadores/antagonistas & inibidores , Simportadores/metabolismo , Ácido gama-Aminobutírico/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Cloretos/metabolismo , Epilepsia/metabolismo , Marcação de Genes , Homeostase , Humanos , Potenciais da Membrana , Neuralgia/metabolismo , Neurotransmissores/farmacologia , Fosforilação , Esquizofrenia/metabolismo , Membro 2 da Família 12 de Carreador de Soluto/metabolismo , Traumatismos da Medula Espinal , Simportadores/genética
14.
Cell Mol Life Sci ; 76(16): 3055-3081, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31236626

RESUMO

'A disintegrin and metalloproteases' (ADAMs) are a family of transmembrane proteins with diverse functions in multicellular organisms. About half of the ADAMs are active metalloproteases and cleave numerous cell surface proteins, including growth factors, receptors, cytokines and cell adhesion proteins. The other ADAMs have no catalytic activity and function as adhesion proteins or receptors. Some ADAMs are ubiquitously expressed, others are expressed tissue specifically. This review highlights functions of ADAMs in the mammalian nervous system, including their links to diseases. The non-proteolytic ADAM11, ADAM22 and ADAM23 have key functions in neural development, myelination and synaptic transmission and are linked to epilepsy. Among the proteolytic ADAMs, ADAM10 is the best characterized one due to its substrates Notch and amyloid precursor protein, where cleavage is required for nervous system development or linked to Alzheimer's disease (AD), respectively. Recent work demonstrates that ADAM10 has additional substrates and functions in the nervous system and its substrate selectivity may be regulated by tetraspanins. New roles for other proteolytic ADAMs in the nervous system are also emerging. For example, ADAM8 and ADAM17 are involved in neuroinflammation. ADAM17 additionally regulates neurite outgrowth and myelination and its activity is controlled by iRhoms. ADAM19 and ADAM21 function in regenerative processes upon neuronal injury. Several ADAMs, including ADAM9, ADAM10, ADAM15 and ADAM30, are potential drug targets for AD. Taken together, this review summarizes recent progress concerning substrates and functions of ADAMs in the nervous system and their use as drug targets for neurological and psychiatric diseases.


Assuntos
Proteínas ADAM/metabolismo , Sistema Nervoso/metabolismo , Proteínas ADAM/química , Animais , Transporte Biológico , Epilepsia/metabolismo , Epilepsia/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Bainha de Mielina/fisiologia , Sistema Nervoso/crescimento & desenvolvimento , Canais de Potássio/metabolismo , Proteólise
15.
Cell Mol Life Sci ; 76(16): 3207-3228, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31172215

RESUMO

Matrix metalloproteinases (MMPs) are a group of over twenty proteases, operating chiefly extracellularly to cleave components of the extracellular matrix, cell adhesion molecules as well as cytokines and growth factors. By virtue of their expression and activity patterns in animal models and clinical investigations, as well as functional studies with gene knockouts and enzyme inhibitors, MMPs have been demonstrated to play a paramount role in many physiological and pathological processes in the brain. In particular, they have been shown to influence learning and memory processes, as well as major neuropsychiatric disorders such as schizophrenia, various kinds of addiction, epilepsy, fragile X syndrome, and depression. A possible link connecting all those conditions is either physiological or aberrant synaptic plasticity where some MMPs, e.g., MMP-9, have been demonstrated to contribute to the structural and functional reorganization of excitatory synapses that are located on dendritic spines. Another common theme linking the aforementioned pathological conditions is neuroinflammation and MMPs have also been shown to be important mediators of immune responses.


Assuntos
Aprendizagem , Metaloproteinases da Matriz/metabolismo , Memória/fisiologia , Transtornos Mentais/patologia , Animais , Encéfalo/metabolismo , Epilepsia/metabolismo , Epilepsia/patologia , Humanos , Metaloproteinases da Matriz/genética , Transtornos Mentais/metabolismo , Plasticidade Neuronal , Inibidores Teciduais de Metaloproteinases/genética , Inibidores Teciduais de Metaloproteinases/metabolismo
16.
Int J Mol Med ; 44(2): 694-704, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173166

RESUMO

The present study aimed to examine the functional and molecular effects of miR­128 in epilepsy, in order to investigate its potential protective mechanisms. Firstly, miR­128 expression in rats with lithium chloride­induced epilepsy was demonstrated to be increased compared with the control rats. Subsequently, results from an in vitro epilepsy model demonstrated that overexpression of miR­128 promoted nerve cell apoptosis, increased the protein expression of tumor protein p53, BCL2 associated X (Bax) and Cytochrome c, and enhanced caspase­3/9 activity, whereas it suppressed the protein expression of sirtuin 1 (SIRT1). In addition, these alterations may be reversed by the downregulation of miR­128. Furthermore, treatment with CAY10602, a SIRT1 agonist, reduced the effects of miR­128 on nerve cells in vitro. Treatment with pifithrin­ß hydrobromide, a p53 inhibitor, was additionally able to mitigate the effects of miR­128 in vitro. In conclusion, the present findings indicated that anti­miR­128 may exert neuroprotective effects in epilepsy, through the SIRT1/p53/Bax/Cytochrome c/caspase signaling pathway.


Assuntos
Apoptose , Epilepsia/genética , MicroRNAs/genética , Sirtuína 1/genética , Animais , Regulação para Baixo , Epilepsia/metabolismo , Epilepsia/patologia , Masculino , Neurônios/metabolismo , Neurônios/patologia , Ratos Sprague-Dawley , Transdução de Sinais , Sirtuína 1/metabolismo , Regulação para Cima
17.
J Neurol ; 266(9): 2273-2276, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31168673

RESUMO

OBJECTIVE: The efficacy of levetiracetam (LEV) in controlling seizures in patients with brain tumor-related epilepsy (BTRE) depends on tumoral expression of synaptic vesicle protein 2A (SV2A). Although LEV is generally well tolerated, neuropsychiatric adverse events (NPAEs) might occur, limiting compliance and seizure control. We aimed to assess the influence of tumoral SV2A expression on the occurrence of LEV-related NPAEs in patients with glioma. METHODS: Specimens from patients enrolled in the multicenter COMPO study, with glioma and BTRE treated with LEV, undergoing neurosurgery were retrieved. Immunohistochemistry-based expression of SV2A in tumoral and peritumoral tissue was scored in a four-point scale from absent (score = 0) to strong (score = 3). Low immunoreactivity (IR) corresponded to scores < 2. Staining ratios (tumoral SV2A IR/peritumoral SV2A IR) were grouped into low (≤ 0.5) and high (> 0.5). NPAEs were assessed longitudinally with the Neuropsychiatry Inventory 12 test (NPI-12). RESULTS: Overall, 18 patients were eligible for analysis. All received LEV monotherapy, with 67% developing NPAEs. Patients with NPAEs had significantly lower median SV2A intensity score compared to patients without NPAEs (score 1 vs 0, p = 0.025). Low staining ratio (≤ 0.5) associated with higher NPAE occurrence compared to SR > 0.5 (85.7% vs 0%, p < 0.01). A SR ≤ 0.5 predicted a consistent increase in risk of NPAEs (OR 45.0; 95% CI 1.8-1128; p = 0.02). CONCLUSIONS: Our results suggest that SV2A expression in tumoral and peritumoral tissue correlates with the occurrence of LEV-related NPAEs. Thus, considering that SV2A expression also influences LEV effectiveness, SV2A staining might help in tailoring treatment to patients.


Assuntos
Anticonvulsivantes/uso terapêutico , Neoplasias Encefálicas/metabolismo , Epilepsia/metabolismo , Levetiracetam/uso terapêutico , Glicoproteínas de Membrana/biossíntese , Proteínas do Tecido Nervoso/biossíntese , Adulto , Idoso , Anticonvulsivantes/efeitos adversos , Biomarcadores/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Epilepsia/tratamento farmacológico , Epilepsia/genética , Feminino , Expressão Gênica , Humanos , Levetiracetam/efeitos adversos , Masculino , Glicoproteínas de Membrana/genética , Transtornos Mentais/induzido quimicamente , Transtornos Mentais/genética , Transtornos Mentais/metabolismo , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Valor Preditivo dos Testes , Estudos Prospectivos
18.
Biofactors ; 45(5): 740-749, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31120577

RESUMO

BACKGROUND: Valproic acid (VPA) is a clinical medicine primarily prescribed to control epileptic symptoms. VPA has potential side-effects, such as hepatotoxicity. Fibroblast growth factor 21 (FGF21) is a functional cytokine for metabolic regulation. In this article, we aimed to evaluate the possible clinical application of FGF21 in VPA-treated livers in early undetected liver injury (EULI). METHODS: Methodologically, plasma samples of VPA-treated epileptic patients were isolated for biochemical and high-performance liquid chromatography tests. In addition, VPA-dosed mice were subjected to determinations of serological parameters, key regulatory effectors and FGF21 expressions through biochemical analyses, enzyme-linked immunosorbent assay, immunohistochemistry stain, immunofluorescence stain, and reverse transcription-polymerase chain reaction (RT-PCR) test, respectively. RESULTS: The serological data suggested that VPA-treated epileptic patients showed visibly elevated FGF21 contents in plasma samples. However, other diagnostic parameters showed inconspicuous changes. As revealed in animal study, VPA-dosed mice exhibited undetected morphological alterations and hormonal changes in the liver, pancreas, and kidneys. Furthermore, serological parameters and key regulatory proteins in VPA-dosed livers and controls showed inconspicuous changes. Interestingly, endogenous FGF21 expressions in VPA-dosed mice were increased in sera. In further experiments, the findings showed that intracellular expressions of FGF21 mRNA and protein were upregulated in VPA-dosed livers as revealed in RT-PCR and immunoassay. CONCLUSIONS: Taken together, these preliminary data reveal that functional FGF21 cytokine may serve as a potent predictor in VPA-related EULI.


Assuntos
Anticonvulsivantes/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Epilepsia/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/genética , RNA Mensageiro/genética , Ácido Valproico/efeitos adversos , Adulto , Animais , Anticonvulsivantes/administração & dosagem , Biomarcadores/sangue , Estudos de Casos e Controles , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Preparações de Ação Retardada , Epilepsia/metabolismo , Epilepsia/fisiopatologia , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Metaboloma/efeitos dos fármacos , Camundongos , Pessoa de Meia-Idade , RNA Mensageiro/sangue , Ácido Valproico/administração & dosagem
19.
Seizure ; 69: 186-192, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31075750

RESUMO

PURPOSE: The effects of antiseizure medications (ASMs) on bone metabolism is inconsistent. Most studies are in high income settings and none from sub-Saharan Africa. METHODS: A hospital based cross-sectional study in a paediatric epilepsy service with a comparison group assessed vitamin D metabolism. RESULTS: Seventy-five children with epilepsy and 75 comparison group were recruited. Median age for children with epilepsy was 9 years (range 1-17 years) and controls 3 years (range 1-12 years). Vitamin D deficiency occurred in 11(16.2%) children with epilepsy versus 6 (8.8%) control group (p = 0.29). Vitamin D insufficiency occurred in 30 (44.1%) children with epilepsy compared to 27(39.7%) control group. Children on ASMs had lower mean vitamin D levels than the control group (p = 0.02). Children on enzyme-inducing ASMs had lower mean vitamin D levels (p = 0.08), vitaminD2 (p = 0.0018), vitaminD3 (p = 0.004), serum phosphate levels (p = 0.000), and higher mean parathyroid hormone levels (p = 0.03) compared to controls. There was no difference in dietary intake and ancestry, although the dietary content of both groups was low in vitamin D products. CONCLUSIONS: Low vitamin D levels were common in children from both groups, but statistically lower for the children on ASMs. Children on enzyme-inducing ASMs need screening for vitamin D deficiency. The literature supports extending this for all children on ASMs. This is the first study to report that children on enzyme-inducing ASMs have lower levels of Vitamin D2 and D3 levels, probably as result of increased destruction of vitamin D. Improved vitamin D intake for children in vulnerable settings is important.


Assuntos
Remodelação Óssea , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Vitamina D/metabolismo , Adolescente , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Remodelação Óssea/efeitos dos fármacos , Remodelação Óssea/fisiologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Dieta , Epilepsia/complicações , Epilepsia/epidemiologia , Feminino , Humanos , Lactente , Masculino , África do Sul/epidemiologia , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/epidemiologia , Deficiência de Vitamina D/metabolismo
20.
EBioMedicine ; 43: 641-649, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31078519

RESUMO

Epilepsy remains refractory to medical treatment in ~30% of patients despite decades of new drug development. Neurosurgery to remove or disconnect the seizure focus is often curative but frequently contraindicated by risks of irreversible impairment to brain function. Novel therapies are therefore required that better balance seizure suppression against the risks of side effects. Among experimental gene therapies, chemogenetics has the major advantage that the action on the epileptogenic zone can be modulated on demand. Two broad approaches are to use a designer G-protein-coupled receptor or a modified ligand gated ion channel, targeted to specific neurons in the epileptogenic zone using viral vectors and cell-type selective promoters. The receptor can be activated on demand by either an exogenous compound or by pathological levels of extracellular glutamate that occur in epileptogenic tissue. We review the principal designer receptor technologies and their modes of action. We compare the drawbacks and benefits of each designer receptor with particular focus on the drug activators and the potential for clinical translation in epilepsy.


Assuntos
Desenho de Drogas , Epilepsia/etiologia , Epilepsia/terapia , Receptores Acoplados a Proteínas-G/genética , Animais , Epilepsia/metabolismo , Humanos , Ativação do Canal Iônico , Ligantes , Terapia de Alvo Molecular , Relação Quantitativa Estrutura-Atividade , Receptores Acoplados a Proteínas-G/química , Receptores Acoplados a Proteínas-G/metabolismo
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