myelin-basic-protein and Epilepsy

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 (

Topics: 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; Adenomatous Polyposis Coli Protein; Amino Acid Transport Systems, Acidic; Animals; Antiporters; Astrocytes; Cell Count; Cerebral Cortex; Disease Models, Animal; Dwarfism; Epilepsy; Gene Expression Regulation, Developmental; Germ-Line Mutation; Glial Fibrillary Acidic Protein; Hereditary Central Nervous System Demyelinating Diseases; Male; Mitochondrial Diseases; Myelin Basic Protein; Neurogenesis; Neurons; Oligodendroglia; Prosencephalon; Psychomotor Disorders; Rats; Rats, Transgenic; Signal Transduction; Tumor Suppressor Proteins; WW Domain-Containing Oxidoreductase

Focal cortical dysplasias (FCDs) are local malformations of the human neocortex with strong epileptogenic potential. To investigate the underlying pathomechanisms, we performed a whole human transcriptome screening to compare the gene expression pattern of dysplastic versus nondysplastic temporal neocortex. Tissue obtained from FCD IIIa cases (mean age 20.5 years) who had undergone surgical treatment, due to intractable epilepsy, was compared with nondysplastic specimens (mean age 19.9 years) by means of Affymetrix arrays covering 28 869 genes. We found 211 differentially expressed genes (DEX) among which mainly genes important for oligodendrocyte differentiation and myelination were downregulated in FCD IIIa. These findings were confirmed as functionally important by Database for Annotation, Visualization, and Integrated Discovery (DAVID) analysis. The reduced expression of myelin-associated transcripts was confirmed for FCD Ia, IIa, and IIIa by real-time RT-qPCR. In addition, we found that the density of myelin basic protein mRNA-expressing oligodendrocytes and of 2',3'-cyclic nucleotide 3'-phosphodiesterase-positive myelin fibers was significantly reduced in dysplastic cortex. Moreover, high-resolution confocal imaging and 3D reconstruction revealed that the myelin fiber network was severely disorganized in dysplastic neocortex, indicating a disturbance of myelin sheath formation and maintenance in FCD.

Topics: Adolescent; Adult; Child; Child, Preschool; Epilepsy; Female; Humans; Infant; Male; Malformations of Cortical Development; Myelin Basic Protein; Neocortex; Oligodendroglia; Transcriptome; Young Adult

The purpose of research was to determine the level of natural neurotropic autoantibodies in blood serum of patients with idiopathic and symptomatic epilepsies.. 43 epilepsy patients (27 males and 16 females) at the age of from 16 till 70 years (average age 43.1 ± 1.02 years) were studied--11 patients with idiopathic epilepsy (group I) and 32 patients with symptomatic epilepsy (group II). By the method of immunoenzymatic analysis and original idiotype-antiidiotype test-system ELI-N-Test (Russia) in blood serum of the patients the levels of autoantibodies (aAB) to brain proteins-antigens (NF-200, GFAP, MBP and S100β) and to receptors of neuromediators (glutamate, GABA, dopamine, serotonin and choline-receptors) we determined.. All groups of epilepsy patients differed from control group by as individual levels, as degree of deviations of the studied immunological parameters. Serum levels of neurotropic aAB to NF-200, GFAP, MBP and S100β, as well as to receptors of neuromediators (glutamate, GABA, dopamine, serotonin and choline-receptors) were noted to increase. The features of immune disturbances depended on the form and severity of epilepsy.. Autoimmune processes have the certain place in the pathogenesis of epilepsy. The degree and duration of increase in the levels of neurotropic aAB have the prognostic significance for the evaluation severity degree of epilepsy course that could be an additional criterion in the integrated diagnosis and timely correction of treatment for epilepsy.

Topics: Adult; Autoantibodies; Brain; Epilepsy; Female; Humans; Male; Myelin Basic Protein; Nerve Tissue Proteins; Neurofilament Proteins; Prognosis; S100 Calcium Binding Protein beta Subunit; Severity of Illness Index; Statistics as Topic

A diagnostic feature of focal cortical dysplasia (FCD) type II on magnetic resonance imaging (MRI) is increased subcortical white matter (WM) signal on T2 sequences corresponding to hypomyelination, the cause of which is unknown. We aimed to quantify WM pathology in FCD type II and any deficiency in the numbers and differentiation of oligodendroglial (OL) cell types within the dysplasia.. In 19 cases we defined four regions of interests (ROIs): ROI1 = abnormal WM beneath dysplasia, ROI2 =dysplastic cortex, ROI3 = normal WM, and ROI4 = normal cortex. We quantified axonal and myelin density using immunohistochemistry for neurofilament, myelin basic protein and quantified mature OL with NogoA, cyclic nucleotide 3-phosphodiesterase (CNPase) and OL precursor cell (OPC) densities with platelet derived growth factor receptor (PDGFR)α, β and NG-2 in each region.. We observed a significant reduction in myelin and axons in the WM beneath dysplasia relative to normal WM and there was a correlation between relative reduction of myelin and neurofilament in each case. OL and OPC were present in the WM beneath dysplasia and although present in lower numbers with most markers, were not significantly different from normal WM. Neurofilament and myelin labeling highlighted disorganized orientation of fibers in dysplastic cortex but there were no significant quantitative differences compared to normal cortex. Clinical correlations showed an association between the severity of reduction of myelin and axons in the WM of FCD and duration of epilepsy.. These findings indicate a reduction of myelinated axons in the WM of FCD type II rather than dysmyelination as the primary pathologic process underlying WM abnormalities, possibly influenced by duration of seizures. The range of OPC to OL present in FCD type II does not implicate a primary failure of cell recruitment and differentiation of these cell types in this pathology.

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Adolescent; Adult; Aged; Antigens; Brain; Brain Diseases; Child; Epilepsy; Female; Humans; Leukocyte Common Antigens; Magnetic Resonance Imaging; Male; Malformations of Cortical Development; Malformations of Cortical Development, Group I; Middle Aged; Myelin Basic Protein; Myelin Proteins; Nerve Fibers, Myelinated; Nerve Tissue Proteins; Neural Pathways; Nogo Proteins; Oligodendroglia; Proteoglycans; Receptor, Platelet-Derived Growth Factor alpha; Statistics, Nonparametric; Young Adult

Glatiramer acetate (GA) is a clinically prescribed immunomodulator drug used to treat demyelinating disease like multiple sclerosis (MS). Persistent down-regulation in the expression of myelin sheath proteins has been observed in both rats with pentylenetetrazol (PTZ) induced chronic epilepsy and some clinical epilepsy patients. Hypothetically, protection of myelin sheath by pharmaceutical means in the process of epilepsy might, to some extent, be helpful to control epileptic seizures. Therefore, we tried to use GA to treat PTZ-induced epilepsy rats. GA treatment successfully protected rats' myelin sheath from demyelination in the process of PTZ-induced epileptic seizures. Notably, electroencephalogram (EEG) monitoring demonstrated that GA-treated epilepsy rats showed significantly lowered epileptiform discharges. Correspondingly, behavioral recording showed reduced frequency of seizures in GA-treated epilepsy rats. The results indicate that epilepsy associated demyelination may be a contributing factor in seizures behavior, and early intervention with anti-demyelination drugs may be beneficial to reduce the severity of seizures behavior.

Topics: Animals; Anticonvulsants; Cerebral Cortex; Epilepsy; Glatiramer Acetate; Hippocampus; Male; Myelin Basic Protein; Myelin Sheath; Pentylenetetrazole; Peptides; Rats; Rats, Sprague-Dawley

Epilepsy is a chronic neurological disorder characterized by spontaneous recurrent seizures, which also occur in demyelinating diseases of the central nervous system (CNS) with a higher prevalence. Meanwhile, demyelination occurrings have been occasionally observed in CNS of epilepsy patients, indicating an association between demyelination and epileptic seizures by an unknown mechanism. However, no confirmative experimental evidence has yet been given. Thus, by using a rat pentylenetetrazol model, electroencephalogram (EEG), Western blotting, enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, the present study provided direct evidence that myelin sheath damage in rat hippocampus and cerebral cortex started in the early stage of epileptic seizures induction and lasted with no further increase in severity in the development of epileptic seizures. It was illustrated that myelin sheath damage was not the result of oligodendrocyte destruction, but the autoantibodies against myelin basic protein (MBP) produced in peripheral circulation accompanied by increased permeability of blood-brain barrier (BBB) formed in the development of epileptic seizures. This study firstly provided experimental evidence for myelin sheath damage in PTZ-induced rat's epileptic seizures and further demonstrated that its possible cause was autoimmunoreaction.

Topics: Animals; Autoantibodies; Blood-Brain Barrier; Blotting, Western; Cerebral Cortex; Electroencephalography; Enzyme-Linked Immunosorbent Assay; Epilepsy; Hippocampus; Immunohistochemistry; Male; Myelin Basic Protein; Myelin Sheath; Nerve Fibers, Myelinated; Oligodendroglia; Pentylenetetrazole; Rats; Rats, Sprague-Dawley

Inbred strains of mice differ in their susceptibility to excitotoxin-induced cell death, but the genetic basis of individual variation in differential susceptibility is unknown. Previously, we identified a highly significant quantitative trait locus (QTL) on chromosome 18 that influenced susceptibility to kainic acid-induced cell death (Sicd1). Comparison of susceptibility to seizure-induced cell death between reciprocal congenic lines for Sicd1 and parental background mice indicates that genes influencing this trait were captured in both strains. Two positional gene candidates, Galr1 and Mbp, map to 55 cM, where the Sicd1 QTL had been previously mapped. Thus, this study was undertaken to determine if Galr1 and/or Mbp could be considered as candidate genes. Genomic sequence comparison of these two functional candidate genes from the C57BL/6J (resistant at Sicd1) and the FVB/NJ (susceptible at Sicd1) strains showed no single-nucleotide polymorphisms. However, expression studies confirmed that Galr1 shows significant differential expression in the congenic and parental inbred strains. Galr1 expression was downregulated in the hippocampus of C57BL/6J mice and FVB.B6-Sicd1 congenic mice when compared with FVB/NJ or B6.FVB-Sicd1 congenic mice. A survey of Galr1 expression among other inbred strains showed a significant effect such that 'susceptible' strains showed a reduction in Galr1 expression as compared with 'resistant' strains. In contrast, no differences in Mbp expression were observed. In summary, these results suggest that differential expression of Galr1 may contribute to the differences in susceptibility to seizure-induced cell death between cell death-resistant and cell death-susceptible strains.

Topics: Animals; Base Sequence; Cell Death; Epilepsy; Excitatory Amino Acid Agonists; Genetic Predisposition to Disease; Genetic Variation; Genomics; Haplotypes; Hippocampus; Kainic Acid; Male; Mice; Mice, Congenic; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Myelin Basic Protein; Nerve Tissue Proteins; Neurotoxins; Phenotype; Polymorphism, Single Nucleotide; Receptor, Galanin, Type 1; Species Specificity; Transcription Factors

Brain derived neurotrophic factor (BDNF) elevation in newborn sera predicts intellectual/social developmental abnormalities. Other autoantibodies (AAs) to endothelial cells (ECs) and myelin basic protein (MBP) are also elevated in some children. We tested relationships between BDNF, BDNF AAs, and other AAs in children with these disorders.. BDNF levels and IgG/IgM autoantibodies to BDNF, ECs, MBP, and histones were measured in children with autism, childhood disintegrative disorder (CDD), pervasive developmental delay-not otherwise specified (PDD-nos), acquired epilepsy, Landau-Kleffner syndrome (LKS); healthy children (HC), and children with non-neurological illnesses (NNI).. Mean BDNF levels were elevated in children with autism and CDD, (p < or = 0.0002) compared to HC or NNI. Mean IgG and IgM BDNF AAs were elevated in children with autism, CDD and epilepsy (p < or = 0.0005) compared to HC but not to NNI. Mean IgM AA EC titers detected by immunocytochemistry were higher in autism, PDD-NOS, epilepsy, and LKS (p < or = 0.005) compared to HC and NNI. While mean ELISA IgG EC AAs were higher in autism and PPD-NOS (p < 0.005) compared to HC but not NNI, ELISA IgM EC AAs were higher in children with autism, CDD, PDD-NOS, and epilepsy compared to both HC and NNI (p < 0.0005). Mean anti-MBP IgG and IgM titers were higher in all study groups (p < 0.005) except for LKS compared to both HC and NNI.. Children with developmental disorders and epilepsy have higher AAs to several neural antigens compared to controls. The presence of both BDNF AAs and elevated BDNF levels in some children with autism and CDD suggests a previously unrecognized interaction between the immune system and BDNF.

Topics: Antibodies, Antinuclear; Autistic Disorder; Autoantibodies; Brain-Derived Neurotrophic Factor; Cells, Cultured; Cerebral Cortex; Child; Child, Preschool; Cohort Studies; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Epilepsy; Female; Histones; Humans; Immunoglobulin G; Immunoglobulin M; Immunohistochemistry; Landau-Kleffner Syndrome; Male; Myelin Basic Protein; Nervous System; Umbilical Veins

The 18q- deletion syndrome (18qDS) is frequently associated with cardiac anomalies. Patients with this syndrome may also have epilepsy, which presents certain diagnostic difficulties. This case report aims to illustrate these diagnostic problems, document the usefulness of heart rate-based seizure detection algorithms in this setting, and define the epilepsy syndrome associated with 18qDS.. Closed-circuit video electroencephalogram (EEG) monitoring using a heart rate-based seizure detection software was used to identify the event in question and to establish the diagnosis of epilepsy. Chromosomal analysis and magnetic resonance imaging (MRI) were used to further define the epilepsy syndrome.. We report on a patient with an atrial septal defect, enlargement of the right heart, and incomplete right bundle branch block, who developed episodes of tachycardia, loss of consciousness, and pallor, for which he was amnesic. Chromosomal analysis demonstrated karyotype 46,XY,del(18)(q21.3). ish del(18)(wcp18+,D18Z1+) with a loss of the gene for myelin basic protein. MRI revealed multifocal dysmyelination. Video-EEG monitoring using an electrocardiogram (ECG)-triggered seizure detection software proved to be indispensable in detecting an autonomic seizure and establishing the correct diagnosis; the procedure also allowed for the definition of the epilepsy syndrome. The patient was treated with carbamazepine and remained seizure-free.. Video-EEG monitoring using a heart rate-based seizure detection software can be helpful in diagnostically differentiating autonomic seizures from syncope. Dysmyelination due to loss of the myelin basic protein gene on 18q and cortical dysgenesis may be of pathogenic relevance.

Topics: Adult; Autonomic Nervous System Diseases; Chromosome Deletion; Chromosome Mapping; Chromosomes, Human, Pair 18; Demyelinating Diseases; Diagnosis, Differential; Electrocardiography; Electroencephalography; Epilepsy; Heart Defects, Congenital; Humans; Magnetic Resonance Imaging; Male; Monitoring, Physiologic; Myelin Basic Protein; Syncope; Syndrome; Videotape Recording

We detected the level of myelin basic protein (MBP) in the serum of experimental epilepsy rats using simplified MBP ELISA, and the myelin sheaths of their brain with MBP immuno-histochemistry (IHC) and transmitted electronmicroscopy (TEM) in order to explore the relation of brain myelin sheaths and MBP to the pathogenic mechanism of epileptic seizure. The results show that the serum MBP level in the experimental epilepsy group is significantly higher than that in the control groups (P < 0.05), and is similar to that in some patients with generalized myoclonic seizures reported by us previously. The IHC and TEM findings in the brain of epilepsy rats indicate that the lamelliform structure of myelin sheaths in some part of hippocampus region becomes relaxing, disorderly and homogenized. Our studies imply that epileptic seizures are associated with MBP release from the subtle damaged regions of myelin sheaths during epileptic seizures, and the change of MBP component in myelin sheath may play and important role in the pathogenesis of epilepsy.

Topics: Animals; Epilepsy; Hippocampus; Immunohistochemistry; Male; Myelin Basic Protein; Myelin Sheath; Rats; Rats, Sprague-Dawley

Preoligodendrocytes have been described in cultures and tissue prints of adult human white matter (Armstrong et al., 1992). To characterize further these precursors of human oligodendrocytes, we have investigated whether they express genes playing a critical role in oligodendrocyte development. In the intact human brain, platelet-derived growth factor receptor alpha (PDGF alpha R) and myelin transcription factor 1 (MyTI) transcripts are expressed in 1-2% of cells of the oligodendrocyte lineage (OL), and clusters of such cells can be found in the periventricular region. Myelin basic protein transcripts containing exon 2 information (exon 2+ MBP), which are characteristic of the premyelinating stage, are detected in 15-20% of OL cells in vivo. When OL cells are separated from human white matter and allowed to regenerate in vitro, a much larger proportion of these cells express developmentally regulated genes, while exon 2- MBP and proteolipid protein (PLP) transcripts characteristic of mature OL cells appear transiently downregulated. Basic fibroblast growth factor (bFGF), even in the presence of PDGF, does not promote DNA synthesis in these cultured OL cells. Yet bFGF induces human oligodendrocytes to regenerate their processes rapidly in vitro and to express O4 antigens as well as exon 2+ MBP, MyTI, and PLP transcripts. While bFGF accelerates early regenerative processes, it also maintains high expression of exon 2+ MBP transcripts in OL cells for up to 2 weeks in vitro. In contrast, high levels of insulin in the absence of bFGF allow accumulation of exon 2- MBP and PLP transcripts in most OL cells at 2-3 weeks in vitro. We propose that the myelinated human brain harbors a small pool of precursors of oligodendrocytes and that growth factor-regulated phenotypic plasticity rather than mitogenic potential accounts for the regeneration of oligodendrocytes in the initial stages of demyelinating diseases such as multiple sclerosis.

Topics: Adolescent; Adult; Base Sequence; Cells, Cultured; Child, Preschool; DNA; Epilepsy; Gene Expression; Growth Substances; Humans; Immunoenzyme Techniques; In Situ Hybridization; Middle Aged; Molecular Sequence Data; Myelin Basic Protein; Neuronal Plasticity; Oligodendroglia; Oligonucleotide Probes; Proteolipids; Stem Cells

Neuromodulating activity of anti-brain autoantibodies obtained from electroshocked (ECS) rats was tested on the neurons of isolated suboesophageal ganglion of the snail Helix pomatia. In 16 out of 18 spontaneously active (pacemaker) neurons, ECS IgG containing anti-brain autoantibodies induced short-lasting epileptiform discharges and membrane depolarization. Membrane input resistance and time constant decreased, while membrane capacitance increased after addition of ECS IgG. Amplitude of evoked action potential (AP) decreased, whereas AP duration, rise time and fall time slightly increased. Thus, anti-neural autoantibody-positive IgG from rats with experimental epilepsy, but not autoantibody-negative IgG from control rats, significantly affected the bioelectrical properties of the isolated snail neurons. These results suggest that anti-neural autoantibodies present in epileptic animals are capable of influencing in vivo the function of the brain neurons.

Topics: Animals; Autoantibodies; Biomarkers; Brain; Cell Membrane; Electroshock; Epilepsy; Helix, Snails; Immunoglobulin G; Male; Membrane Potentials; Myelin Basic Protein; Neuroimmunomodulation; Neurons; Phosphopyruvate Hydratase; Rats; Rats, Inbred Strains; S100 Proteins

Cerebrospinal fluid (CSF) myelin basic protein (MBP) was measured blind by double antibody competitive inhibition radioimmunoassay (RIA) in 20 children who had seizures and 17 children with hydrocephalus. MBP values correlated with clinical outcome and mean maximum intracranial pressure (ICP) in the hydrocephalic group, and with type of convulsion in the epileptic group. A value of 20ng/ml or more was regarded as significantly raised. A significant rise in MBP levels could be demonstrated in those with ICP alone and in patients with additional problems, whose levels tended to be even higher. Hydrocephalic children with normal ICP and children with seizures had similar normal MBP levels, and in the latter group clinical outcome was not related to MBP levels. For individual patients CSF MBP is of little value as a prognostic indicator, or as a method of quantifying cerebral damage.

Topics: Adolescent; Brain Damage, Chronic; Child; Child, Preschool; Epilepsy; Female; Humans; Hydrocephalus; Infant; Intracranial Pressure; Male; Myelin Basic Protein; Radioimmunoassay

Lymphocyte sensitisation to encephalitogenic factor (EF) was determined in 131 children with the electrophoretic mobility test (EM-test) to find out, whether this test may be helpful in the diagnosis of malignant disease in children. None of 34 healthy controls showed a decrease of electrophoretic mobility of more than 5%, while all 10 children with malignant solid tumors showed a slowing of more than 5%. 3 of 54 patients with non malignant disease showed a slowing of more than 5% in the EM-test. Children with malignant solid tumors during therapy and children with leukemia during different stages of the disease often showed a slowing of less than 5% in the EM-test. The possible diagnostic help of the EM-test is shown in a case history. Finally some technical remarks are made on improving this test, and further studies are suggested.

Topics: Cell Movement; Child; Electrophoresis; Epilepsy; Humans; Infectious Mononucleosis; Leukemia, Lymphoid; Lymphocytes; Myelin Basic Protein; Neoplasms