Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of experimental autoimmune encephalomyelitis (attack and recovery) on levels of six amino acids have been investigated in nine regions of the Lewis rat spinal cord between segments C3 and Co1 and in the brainstem. Amino acids were analyzed by separation of their 4'-dimethylaminoazobenzene-4-sulfonyl chloride derivatives on a reversed-phase column using a ternary gradient. Glutamate and gamma-aminobutyric acid were reduced by 10-30% in all segments during the attack, whereas taurine, lysine, glutamine, and glycine were all greatly increased (up to 300%). Most values except those of taurine, as well as glutamate in certain segments, returned to normal on recovery. Because some of these compounds have neurotransmitter function, these changes may contribute to the neurological symptoms of experimental autoimmune encephalomyelitis.
 ...
PMID:Changes in amino acid contents in the spinal cord and brainstem of rats with experimental autoimmune encephalomyelitis. 278 89

Experimental allergic encephalomyelitis (EAE) was induced in SJL/J mice by adoptive transfer of MBP-reactive T cells in order to investigate the role of astrocytes in pathology. GFAP protein and mRNA expression (analyzed using semiquantitative Western blot and RT-PCR techniques) were upregulated in the spinal cord of mice, which had developed a complete paralysis of hind- and fore-limbs and tail (grade 4 EAE), thus establishing that reactive gliosis occurred under these experimental conditions. Within the same samples and using similar techniques, we found that glutamine synthetase (GS) and glutamate dehydrogenase (GDH) expression were dramatically reduced. These two astrocytic enzymes are responsible for degradation of glutamate, the most abundant excitatory neurotransmitter in the brain. Since elevated levels of glutamate may be neurotoxic, we propose that the decreased capacity of astrocytes to metabolize glutamate may contribute to EAE pathology.
 ...
PMID:Glutamate metabolism is down-regulated in astrocytes during experimental allergic encephalomyelitis. 914 7

Multiple sclerosis is an immune-mediated disorder of the central nervous system leading to progressive decline of motor and sensory functions and permanent disability. The therapy of multiple sclerosis is only partially effective, despite anti-inflammatory, immunosuppresive and immunomodulatory measures. White matter inflammation and loss of myelin, the pathological hallmarks of multiple sclerosis, are thought to determine disease severity. Experimental autoimmune encephalomyelitis reproduces the features of multiple sclerosis in rodents and in nonhuman primates. The dominant early clinical symptom of acute autoimmune encephalomyelitis is progressive ascending muscle weakness. However, demyelination may not be profound and its extent may not correlate with severity of neurological decline, indicating that targets unrelated to myelin or oligodendrocytes may contribute to the pathogenesis of acute autoimmune encephalomyelitis. Here we report that within the spinal cord in the course of autoimmune encephalomyelitis not only myelin but also neurons are subject to lymphocyte attack and may degenerate. Blockade of glutamate AMPA receptors ameliorated the neurological sequelae of autoimmune encephalomyelitis, indicating the potential for AMPA antagonists in the therapy of multiple sclerosis.
 ...
PMID:Autoimmune encephalomyelitis ameliorated by AMPA antagonists. 1061 11

Glutamate excitotoxicity mediated by the AMPA/kainate type of glutamate receptors damages not only neurons but also the myelin-producing cell of the central nervous system, the oligodendrocyte. In multiple sclerosis, myelin, oligodendrocytes and some axons are lost as a result of an inflammatory attack on the central nervous system. Because glutamate is released in large quantities by activated immune cells, we expected that during inflammation in MS, glutamate excitotoxicity might contribute to the lesion. We addressed this by using the AMPA/kainate antagonist NBQX to treat mice sensitized for experimental autoimmune encephalomyelitis, a demyelinating model that mimics many of the clinical and pathologic features of multiple sclerosis. Treatment resulted in substantial amelioration of disease, increased oligodendrocyte survival and reduced dephosphorylation of neurofilament H, an indicator of axonal damage. Despite the clinical differences, treatment with NBQX had no effect on lesion size and did not reduce the degree of central nervous system inflammation. In addition, NBQX did not alter the proliferative activity of antigen-primed T cells in vitro, further indicating a lack of effect on the immune system. Thus, glutamate excitotoxicity seems to be an important mechanism in autoimmune demyelination, and its prevention with AMPA/kainate antagonists may prove to be an effective therapy for multiple sclerosis.
 ...
PMID:Glutamate excitotoxicity in a model of multiple sclerosis. 1061 11

Gene expression monitoring using gene expression microarrays represents an extremely powerful technology for gene discovery in a variety of systems. We describe the results of seven experiments using Incyte GEM technology to compile a proprietary portfolio of data concerning differential gene expression in six different models of neuronal differentiation and regeneration, and recovery from injury or disease. Our first two experiments cataloged genes significantly up- or down-regulated during two phases of the retinoic acid-induced differentiation of the embryonal carcinoma line Ntera-2. To identify genes involved in neuronal regeneration we performed three GEM experiments, which included changes in gene expression in rat dorsal root ganglia during the healing of experimentally injured sciatic nerve, in regenerating neonatal opossum spinal cord, and during lipopolysaccharide stimulation of primary cultures of rat Schwann cells. Finally we have monitored genes involved in the recovery phase of the inflammatory disease of the rat spinal cord, experimental allergic encephalomyelitis, as well as those responsible for protection from oxidative stress in a glutamate-resistant rat hippocampal cell line. Analysis of the results of the approximately 70,000 data points collected is presented.
 ...
PMID:Gene expression monitoring for gene discovery in models of peripheral and central nervous system differentiation, regeneration, and trauma. 1107 84

Glutamate excitotoxicity mediated by the AMPA/kainate-type of glutamate receptors is known not only to damage neurons but also the myelin-producing cell of the central nervous system (CNS), the oligodendrocyte. In Multiple Sclerosis (MS), myelin, oligodendrocytes and axons are lost or damaged as a result of an inflammatory attack on the CNS. Activated immune cells produce glutamate in large quantities by deamidating glutamine via glutaminase. Thus, we hypothesized that during inflammation in MS, glutamate excitotoxicity may contribute to the lesion. This was addressed by treating mice sensitized to develop acute experimental autoimmune encephalomyelitis (EAE) with an AMPA/kainate antagonist, NBQX. Treatment resulted in substantial amelioration of disease, increased oligodendrocyte survival and reduced axonal damage, as indicated by the levels of dephosphorylated neurofilament-H. Despite the clinical differences, NBQX-treatment had no effect on lesion size and did not reduce the degree of CNS inflammation. In addition, NBQX did not alter the proliferative activity of antigen-primed T cells in vitro, further indicating a lack of effect at the level of the immune system. In separate studies, infiltrating immune cells present in perivascular cuffs, commonly the site of entry for invading immune cells, were found to express glutaminase in abundance, supporting the production of glutamate in inflammatory lesions. Thus, glutamate excitotoxicity appears to be an important mechanism in autoimmune demyelination and its prevention with AMPA/kainate antagonists may prove to be an effective therapy for MS.
 ...
PMID:Glutamate excitotoxicity--a mechanism for axonal damage and oligodendrocyte death in Multiple Sclerosis? 1120 56

Our group recently demonstrated that autoimmune T cells directed against central nervous system-associated myelin antigens protect neurons from secondary degeneration. We further showed that the synthetic peptide copolymer 1 (Cop-1), known to suppress experimental autoimmune encephalomyelitis, can be safely substituted for the natural myelin antigen in both passive and active immunization for neuroprotection of the injured optic nerve. Here we attempted to determine whether similar immunizations are protective from retinal ganglion cell loss resulting from a direct biochemical insult caused, for example, by glutamate (a major mediator of degeneration in acute and chronic optic nerve insults) and in a rat model of ocular hypertension. Passive immunization with T cells reactive to myelin basic protein or active immunization with myelin oligodendrocyte glycoprotein-derived peptide, although neuroprotective after optic nerve injury, was ineffective against glutamate toxicity in mice and rats. In contrast, the number of surviving retinal ganglion cells per square millimeter in glutamate-injected retinas was significantly larger in mice immunized 10 days previously with Cop-1 emulsified in complete Freund's adjuvant than in mice injected with PBS in the same adjuvant (2,133 +/- 270 and 1,329 +/- 121, respectively, mean +/- SEM; P < 0.02). A similar pattern was observed when mice were immunized on the day of glutamate injection (1,777 +/- 101 compared with 1,414 +/- 36; P < 0.05), but not when they were immunized 48 h later. These findings suggest that protection from glutamate toxicity requires reinforcement of the immune system by antigens that are different from those associated with myelin. The use of Cop-1 apparently circumvents this antigen specificity barrier. In the rat ocular hypertension model, which simulates glaucoma, immunization with Cop-1 significantly reduced the retinal ganglion cell loss from 27.8% +/- 6.8% to 4.3% +/- 1.6%, without affecting the intraocular pressure. This study may point the way to a therapy for glaucoma, a neurodegenerative disease of the optic nerve often associated with increased intraocular pressure, as well as for acute and chronic degenerative disorders in which glutamate is a prominent participant.
 ...
PMID:Vaccination for protection of retinal ganglion cells against death from glutamate cytotoxicity and ocular hypertension: implications for glaucoma. 1124 90

Oligodendrocytes, the myelinating cells of CNS axons, are highly vulnerable to excitotoxic signals mediated by glutamate receptors of the AMPA and kainate classes. Receptors in these cells are commonly activated by glutamate that is released from axons and glial cells. In addition, oligodendrocytes contribute to the control of extracellular glutamate levels by means of their own transporters. However, acute and chronic alterations in glutamate homeostasis can result in overactivation of AMPA and kainate receptors and subsequent excitotoxic oligodendroglial death. Furthermore, demyelinating lesions caused by excitotoxins can be similar to those observed in multiple sclerosis. This, together with the effect of AMPA and kainate receptor antagonists in ameliorating the neurological score of animals with experimental autoimmune encephalomyelitis (an animal model of multiple sclerosis), indicates that oligodendrocyte excitotoxicity could be involved in the pathogenesis of demyelinating disorders.
 ...
PMID:The link between excitotoxic oligodendroglial death and demyelinating diseases. 1125 7

Injury to the CNS is often followed by a spread of damage (secondary degeneration), resulting in neuronal losses that are substantially greater than might have been predicted from the severity of the primary insult. Studies in our laboratory have shown that injured CNS neurons can benefit from active or passive immunization with CNS myelin-associated antigens. The fact that autoimmune T-cells can be both beneficial and destructive, taken together with the established phenomenon of genetic predisposition to autoimmune diseases, raises the question: will genetic predisposition to autoimmune diseases affect the outcome of traumatic insult to the CNS? Here we show that the survival rate of retinal ganglion cells in adult mice or rats after crush injury of the optic nerve or intravitreal injection of a toxic dosage of glutamate is up to twofold higher in strains that are resistant to the CNS autoimmune disease experimental autoimmune encephalomyelitis (EAE) than in susceptible strains. The difference was found to be attributed, at least in part, to a beneficial T-cell response that was spontaneously evoked after CNS insult in the resistant but not in the susceptible strains. In animals of EAE-resistant but not of EAE-susceptible strains devoid of mature T-cells (as a result of having undergone thymectomy at birth), the numbers of surviving neurons after optic nerve injury were significantly lower (by 60%) than in the corresponding normal animals. Moreover, the rate of retinal ganglion cell survival was higher when the optic nerve injury was preceded by an unrelated CNS (spinal cord) injury in the resistant strains but not in the susceptible strains. It thus seems that, in normal animals of EAE-resistant strains (but not of susceptible strains), the injury evokes an endogenous protective response that is T-cell dependent. These findings imply that a protective T-cell-dependent response and resistance to autoimmune disease are regulated by a common mechanism. The results of this study compel us to modify our understanding of autoimmunity and autoimmune diseases, as well as the role of autoimmunity in non-autoimmune CNS disorders. They also obviously have far-reaching clinical implications in terms of prognosis and individual therapy.
 ...
PMID:Neuronal survival after CNS insult is determined by a genetically encoded autoimmune response. 1142 84

Injuries to the central nervous system (CNS) evoke self-destructive processes, which eventually lead to a much greater loss of tissue than that caused by the trauma itself. The agents of self-destruction include physiological compounds, such as glutamate, which are essential for the proper functioning of the CNS, but become cytotoxic when their normal concentrations are exceeded. The CNS is equipped with buffering mechanisms that are specific for each compound. Here we show, using Balb/c mice (a strain resistant to induction of experimental autoimmune encephalomyelitis), that after intravitreal injection of any concentration of glutamate (a neurotransmitter that becomes toxic when in excess) or ammonium-ferrous sulfate hexahydrate (which increases the formation of toxic oxygen species), the loss of retinal ganglion cells in mice devoid of mature T cells (nude mice) is significantly greater than in matched wild-type controls. We further show that this outcome can be partially reversed by supplying the T cell-defective mice with splenocytes derived from the wild-type mice. The results suggest that potentially toxic physiological compounds, when present in excessive amounts, can recruit and activate a T-cell-dependent self-protective immune mechanism. This may represent a prototype mechanism for the physiological regulation of potentially destructive CNS events by T-cell-mediated immune activity, when the local buffering mechanisms cannot adequately cope with them.
 ...
PMID:T-cell-based immunity counteracts the potential toxicity of glutamate in the central nervous system. 1158 22


1 2 3 4 5 6 7 8 9 10 Next >>