Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A common feature of demyelinating diseases such as multiple sclerosis in humans and experimental autoimmune encephalomyelitis in rodents is the marked elevation in the expression of the major histocompatibility complex (MHC) antigens in the involved sites. By specific targeting of a syngeneic MHC class I gene to oligodendrocytes, we have generated transgenic mice which not only exhibit severe involuntary tremors and develop tonic seizures but also show extensive demyelination in both the brain and the spinal cord. The fact that demyelination in these mice occurs in the absence of immune infiltration dismisses an autoimmune involvement but suggests that the MHC class I antigens play a direct role in inducing disease. Our findings lend support to the possibility that demyelinating diseases are induced by infectious agents such as viruses which can either directly activate MHC gene expression in oligodendroglia or indirectly activate expression through the release by reactive T cells of gamma interferon in the brain.
 ...
PMID:Transgenic mouse model for central nervous system demyelination. 171 29

A mouse model for encephalopathy induced by pertussis immunization has been described; it has features that closely resemble some of the severe reactions, including seizures and a shock-like state leading to death, occasionally seen after administration of Bordetella pertussis (whooping cough) vaccine. Susceptibility to encephalopathy maps to genes of the major histocompatibility complex and correlates as well with the genetic regulation of the level of antibody response to bovine serum albumin. In this study we have investigated which bacterial determinant is responsible for the encephalopathy. Two lines of evidence implicate pertussis toxin as the active bacterial component. Single-site mutants of B. pertussis with single affected virulence factors were tested. A mutant that produces a defective pertussis toxin had greatly diminished capacity to induce encephalopathy, whereas a hemolysin- and adenylate-cyclase-deficient avirulent mutant had the same activity in the mouse model as a virulent strain. Purified pertussis toxin plus bovine serum albumin was tested and found to induce the lethal encephalopathy, demonstrating that the toxin was the critical constituent of B. pertussis responsible for encephalopathy.
 ...
PMID:Pertussis toxin is required for pertussis vaccine encephalopathy. 286 45

Why is it that oligodendrocytes do not normally express major histocompatibility complex (MHC) molecules? To examine the effect of aberrant MHC expression in oligodendrocytes, transgenic mice have been produced which expressed the class I MHC gene, H-2Kb, under direction of the MBP promoter [Turnley et al. (1991b) Nature, 353:566-569; Yoshioka et al. (1991) Mol. Cell. Biol., 11:5479-5486]. A proportion of these mice exhibited a shivering phenotype, with tonic seizures and early death. Oligodendrocyte function and viability was shown to be affected, resulting in severe dysmyelination of the CNS. Is this phenomenon of cell damage due to aberrant expression of MHC molecules restricted to oligodendrocytes, and could other, non-MHC molecules, when aberrantly expressed, result in similar cell damage? This paper discusses these questions and examines possible mechanisms for the oligodendrocyte damage and hypomyelination observed in these transgenic mice. Finally, the implications of aberrant MHC expression in oligodendrocytes for demyelinating diseases such as multiple sclerosis are discussed.
 ...
PMID:Dysmyelination in class I MHC transgenic mice. 857 78

To elucidate molecular mechanisms underlying activity-dependent synaptic remodeling in the developing mammalian visual system, we screened for genes whose expression in the lateral geniculate nucleus (LGN) is regulated by spontaneously generated action potentials present prior to vision. Activity blockade did not alter expression in the LGN of 32 known genes. Differential mRNA display, however, revealed a decrease in mRNAs encoding class I major histocompatibility complex antigens (class I MHC). Postnatally, visually driven activity can regulate class I MHC in the LGN during the final remodeling of retinal ganglion cell axon terminals. Moreover, in the mature hippocampus, class I MHC mRNA levels are increased by kainic acid-induced seizures. Normal expression of class I MHC mRNA is correlated with times and regions of synaptic plasticity, and immunohistochemistry confirms that class I MHC is present in specific subsets of CNS neurons. Finally, beta2-microglobulin, a cosubunit of class I MHC, and CD3zeta, a component of a receptor complex for class I MHC, are also expressed by CNS neurons. These observations indicate that class I MHC molecules, classically thought to mediate cell-cell interactions exclusively in immune function, may play a novel role in neuronal signaling and activity-dependent changes in synaptic connectivity.
 ...
PMID:Regulation of class I MHC gene expression in the developing and mature CNS by neural activity. 976 38

Neurodegeneration and gliosis have been extensively described after long-lasting seizures; evidence for cytokine involvement in neuron-glia interactions does exist. We have therefore studied the hippocampal expression of molecules responsible for immune and inflammatory reactions, at different time-points following either experimental status epilepticus (SE) or direct excitotoxic damage. Experiments consisting of immunohistochemical labeling of glial markers, major histocompatibility complex (MHC) and nuclear factor kappaB (NFkappaB), were performed. NFkappaB nuclear translocation was controlled and measured using the electrophoretic mobility shift assay. One day after SE, neurodegeneration was obvious in CA3 pyramidal layers; NFkappaB staining in neurons and its translocation to the nucleus enhanced. From day 4 to at least day 8 post-SE, MHC-positive microglia, NFkappaB over-expression in thickened astrocytes, and increased levels of its activated form could be observed. The excitotoxic model caused more severe lesions, but NFkappaB and MHC expression were similar in both models. These results suggest that during long-lasting seizures: (i) neuronal firing activates NFkappaB expression and translocation; (ii) microglia expresses MHC; (iii) astrocytes, probably stimulated by microglial cytokines, over-express NFkappaB, the activation of which induces a cascade of reactions, particularly the transcription of cytokines and or neuroprotective molecules. Further clarification of the toxic or protective consequences of delayed inflammatory responses may be interesting in therapy of epilepsy.
 ...
PMID:Sequential expression of surface antigens and transcription factor NFkappaB by hippocampal cells in excitotoxicity and experimental epilepsy. 1094 Jun 15

The family of metabotropic glutamate receptors (mGluRs) consists of eight homologous G-protein coupled receptors. Several of the mGluRs, including the mGluR4 receptor subtype, are localized presynaptically; activation of this receptor induces an inhibition of neurotransmitter release from nerve terminals. Disruption of the mGluR4 gene in mice results in impaired motor and spatial learning, and alterations in seizure susceptibility. In this study, we have determined the structure of the human mGluR4 gene, as well as its chromosomal localization. A comparison of the gene structure of mGluR4 with the highly homologous mGluR6 receptor subtype reveals that both of the genes contain ten exons with similar exon/intron boundaries. A refined localization of mGluR4 was carried out by constructing a bacterial artificial chromosome clone contig of the region surrounding the gene. Thirteen sequence tagged sites (STSs) were identified within this contig. The gene was localized to chromosome 6 band p21.3 by fluorescence in situ hybridization (FISH). The mapping of the mGluR4 gene indicates that it is approximately 1 megabases centromeric of the major histocompatibility complex and 5 megabase from the GABA(B)R1 gene. The mGluR4 gene also falls within a susceptibility locus for juvenile myoclonic epilepsy suggesting a potential link to this form of epilepsy.
 ...
PMID:Localization of the human mGluR4 gene within an epilepsy susceptibility locus(1). 1122 65

Domoic acid (DA), a potent neurotoxin, administered intravenously (0.75 mg/kg body weight) in adult rats evoked seizures accompanied by nerve cell damage in the present study. Neuronal degeneration and microglial reaction in the hippocampus were investigated, and the temporal profile of bcl-2, bax, and caspase-3 genes in cell death or survival was assessed following the administration of DA. Nissl staining showed darkly stained degenerating neurons in the hippocampus following the administration of DA at 1-21 days, the degeneration being most severe at 5 days. Ultrastructural study in CA1 and CA3 regions of hippocampus revealed two types of neuronal degeneration, cells that exhibited swollen morphology and shrunken electron-dense cells. Immunoreactivity of Bcl-2 and Bax was increased considerably at 16 hr and 24 hr in the neurons of the hippocampus following DA administration. No significant change was observed in the immunoreactivity of caspase-3 in the controls and DA-treated rats at any time interval. Microglial cells in the hippocampus showed intense immunoreaction with the antibodies OX-42 and OX-6 at 1-21 days after DA administration, indicating the up-regulation of complement type 3 receptors and major histocompatibility complex type II antigens for increased phagocytic activity and antigen presentation, respectively. Terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling (TUNEL) showed occasional positive neurons in the CA1 and CA3 regions at 5 days after DA administration, with no positive cells in the controls. RT-PCR analysis revealed that bcl-2 and bax mRNA transcripts in the hippocampus were significantly increased at 16 hr and gradually decreased at 24 hr following the administration of DA. Although bax and bcl-2 mRNA expression is rapidly induced at early stages, in situ hybridization analysis revealed complete loss of bcl-2, bax, and caspase-3 mRNA at 24 hr after DA administration in the region of neuronal degeneration in the hippocampus. These results indicate that the pattern of neuronal degeneration observed during DA-induced excitotoxic damage is mostly necrotic.
 ...
PMID:Domoic acid-induced neuronal damage in the rat hippocampus: changes in apoptosis related genes (bcl-2, bax, caspase-3) and microglial response. 1159 13

Muromonab-CD3 is widely used for immunosuppression in patients undergoing solid organ transplant. We report two siblings with oligomeganephronia and end-stage renal disease who developed encephalopathy and seizures from muromonab-CD3 following renal transplant. The first case is a 13-year-old girl who developed encephalopathy, seizure, and triparesis following renal transplant while muromonab-CD3 was used for immunosuppression. The second case was the 6-year-old sister of the first case, who also developed recurrent focal seizures while she was on muromonab-CD3 for renal transplant immunosuppression. In both cases, a sequential brain magnetic resonance image (MRI) showed progression of abnormalities from the cerebral cortex to the white matter. In the first case, the MRI normalized after muromonab-CD3 was discontinued. In the second case, the patient developed a leukoencephalopathy following cyclosporin administration. The pathophysiology of muromonab-CD3 encephalopathy is believed to be a disturbance to the blood-brain barrier mediated by cytokine release from lymphocyte stimulation by muromonab-CD3. Because the major histocompatibility complex genes are known to regulate cytokine responses, it is possible that the excessive production of cytokines that causes encephalopathy may occur in patients who share close major histocompatibility complex genes. Muromonab-CD3 in a patient whose sibling has developed cerebral complications from its use should be administered with caution. The second case suggests that muromonab-CD3 encephalopathy predisposes patients to develop cyclosporin neurotoxicity. Because the pathogenesis of muromonab-CD3 encephalopathy and cyclosporin-related cerebral complications are both potentially mediated through a disturbance of the blood-brain barrier, it is possible that one agent may predispose a patient to the complication of the other.
 ...
PMID:Muromonab-CD3-induced neurotoxicity: report of two siblings, one of whom had subsequent cyclosporin-induced neurotoxicity. 1173 68

Excitotoxicity and neuroinflammation are strongly linked to the progressions of neurodegenerative diseases and acute injuries in the brain. Systematic administration of kainic acid (KA) in rodents causes severe limbic seizures, selective neuronal loss, and neuroinflammation in the hippocampus that are attributed to the excitotoxic process. Our previous report demonstrated the antioxidant and neuroprotective effects of pirfenidone (PFD) after the seizure onset induced by KA intraperitoneal injection. However, the aim of the present study is to analyze whether PFD has anti-inflammatory properties. Thus, pubescent male Wistar rats (30 days old) were exposed to 12 mg/Kg of KA, and the experimental group received KA and a single dose of 325 mg/Kg PFD in an orogastric tube at 90 min after KA exposure. The PFD treatment dramatically reduces the microglial activation observed by isolectin B4 staining and major histocompatibility complex II immunohistochemistry. We also determined that the messenger RNA of inducible nitric oxide synthase was downregulated by PFD treatment as measured 6 h after the KA injection. Our results indicate that the mechanism of neuroprotection after PFD treatment may include a decreased expression of the inducible nitric oxide synthase and reduced microglial activation. These findings suggest that PFD is a potentially useful strategy of the treatment for acute or chronic neurodegenerative diseases.
 ...
PMID:Pirfenidone Attenuates Microglial Reactivity and Reduces Inducible Nitric Oxide Synthase mRNA Expression After Kainic Acid-Mediated Excitotoxicity in Pubescent Rat Hippocampus. 2585 76

The human brain is a tissue of vast complexity in terms of the cell types it comprises. Conventional approaches to classifying cell types in the human brain at single cell resolution have been limited to exploring relatively few markers and therefore have provided a limited molecular characterization of any given cell type. We used single cell RNA sequencing on 466 cells to capture the cellular complexity of the adult and fetal human brain at a whole transcriptome level. Healthy adult temporal lobe tissue was obtained during surgical procedures where otherwise normal tissue was removed to gain access to deeper hippocampal pathology in patients with medical refractory seizures. We were able to classify individual cells into all of the major neuronal, glial, and vascular cell types in the brain. We were able to divide neurons into individual communities and show that these communities preserve the categorization of interneuron subtypes that is typically observed with the use of classic interneuron markers. We then used single cell RNA sequencing on fetal human cortical neurons to identify genes that are differentially expressed between fetal and adult neurons and those genes that display an expression gradient that reflects the transition between replicating and quiescent fetal neuronal populations. Finally, we observed the expression of major histocompatibility complex type I genes in a subset of adult neurons, but not fetal neurons. The work presented here demonstrates the applicability of single cell RNA sequencing on the study of the adult human brain and constitutes a first step toward a comprehensive cellular atlas of the human brain.
...
PMID:A survey of human brain transcriptome diversity at the single cell level. 2606 Mar 1


1 2 Next >>