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)

Amelioration of experimental autoimmune encephalomyelitis (EAE) by blockade of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), has been recently demonstrated [Nat. Med. 6 (2000) 67; Nat. Med. 6 (2000) 62]. However, the mechanisms underlying regulation of the extracellular glutamate concentration in EAE are unclear. To address this, we examined the expression of three distinct Na(+)-dependent glutamate transporters (GLT-1, GLAST and EAAC1) in the spinal cord of the Lewis rat EAE. EAE induced a dramatic increase in EAAC1 protein and mRNA levels, which corresponded closely with the course of neurological symptoms. In contrast, the levels of GLT-1 and GLAST protein were down-regulated in the spinal cord at the peak of disease symptoms, and no recovery was observed after remission. Furthermore, these changes in GLT-1, GLAST and EAAC1 expression were suppressed by treatment with NBQX. These results suggest that AMPA receptor activation precedes the altered expression of glutamate transporters, and that the dysregulation of extracellular glutamate concentration might play a critical role in pathological changes and neuronal dysfunction in EAE.
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PMID:Altered expression of glutamate transporters in experimental autoimmune encephalomyelitis. 1196 Jun 54

Astrocytes remove glutamate from the synaptic cleft via specific transporters, and impaired glutamate reuptake may promote excitotoxic neuronal injury. In a model of viral encephalomyelitis caused by neuroadapted Sindbis virus (NSV), mice develop acute paralysis and spinal motor neuron degeneration inhibited by the AMPA receptor antagonist, NBQX. To investigate disrupted glutamate homeostasis in the spinal cord, expression of the main astroglial glutamate transporter, GLT-1, was examined. GLT-1 levels declined in the spinal cord during acute infection while GFAP expression was preserved. There was simultaneous production of inflammatory cytokines at this site, and susceptible animals treated with drugs that blocked IL-1beta release also limited paralysis and prevented the loss of GLT-1 expression. Conversely, infection of resistant mice that develop mild paralysis following NSV challenge showed higher baseline GLT-1 levels as well as lower production of IL-1beta and relatively preserved GLT-1 expression in the spinal cord compared to susceptible hosts. Finally, spinal cord GLT-1 expression was largely maintained following infection of IL-1beta-deficient animals. Together, these data show that IL-1beta inhibits astrocyte glutamate transport in the spinal cord during viral encephalomyelitis. They provide one of the strongest in vivo links between innate immune responses and the development of excitotoxicity demonstrated to date.
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PMID:The inflammatory cytokine, interleukin-1 beta, mediates loss of astroglial glutamate transport and drives excitotoxic motor neuron injury in the spinal cord during acute viral encephalomyelitis. 1819 40

Demyelination and oligodendroglial cell death accompanied by axonal injury are dominating features of multiple sclerosis (MS) a chronic demyelinating disease of the CNS. Accumulation of extracellular glutamate, observed during MS, is implicated in excitotoxic injury of nerve and oligodendroglial cells as a result of over-activation of glutamate receptors. The appropriate concentration of extracellular glutamate is maintained by glutamate transporters, the most predominant of which is glial transporter GLT-1 (excitatory amino acid transporter (EAAT) 2). The aim of this study is to determine the time-course of GLT-1 and glutamate-aspartate transporter (GLAST) expression in forebrain and cerebellum of rats subjected to experimental autoimmune encephalomyelitis (EAE). Our findings revealed that: (1) GLT-1 mRNA and to a lower extent GLAST mRNA are overexpressed in forebrain and cerebellum of EAE rats (2) expression of GLT-1 transporter mRNA shows a similar temporal pattern throughout the course of EAE in both structures examined, and is closely correlated with the appearance of neurological symptoms; and (3) the expression of GLT-1 and GLAST protein does not mirror mRNA changes during EAE and exhibits a differential spatial pattern. The protein levels of GLT-1 in cerebellum and GLAST in both structures are significantly reduced just before the acute phase and later during the recovery. The results imply that transcriptional up-regulation of the GLT-1 gene occurs early in both the forebrain and the cerebellum of the EAE rat model. This up-regulation is associated with the severity of symptoms but tends to precede the onset of maximal neurological deficits. The observations confirm the involvement of glutamate in the pathogenesis of EAE and provide an indication of the protective role of this glutamate transporter. However, changes in protein expression of both transporters suggest the existence of post-translational disturbances or the influence of regulating factors connecting with EAE conditions that may lead to the insufficient protection against glutamate excitotoxicity.
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PMID:Expression of glutamate transporters GLT-1 and GLAST in different regions of rat brain during the course of experimental autoimmune encephalomyelitis. 1857 25

In multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), impairment of glial "Excitatory Amino Acid Transporters" (EAATs) together with an excess glutamate-release by invading immune cells causes excitotoxic damage of the central nervous system (CNS). In order to identify pathways to dampen excitotoxic inflammatory CNS damage, we assessed the effects of a beta-lactam antibiotic, ceftriaxone, reported to enhance expression of glial EAAT2, in "Myelin Oligodendrocyte Glycoprotein" (MOG)-induced EAE. Ceftriaxone profoundly ameliorated the clinical course of murine MOG-induced EAE both under preventive and therapeutic regimens. However, ceftriaxone had impact neither on EAAT2 protein expression levels in several brain areas, nor on the radioactive glutamate uptake capacity in a mixed primary glial cell-culture and the glutamate-induced uptake currents in a mammalian cell line mediated by EAAT2. Moreover, the clinical effect of ceftriaxone was preserved in the presence of the EAAT2-specific transport inhibitor, dihydrokainate, while dihydrokainate alone caused an aggravated EAE course. This demonstrates the need for sufficient glial glutamate uptake upon an excitotoxic autoimmune inflammatory challenge of the CNS and a molecular target of ceftriaxone other than the glutamate transporter. Ceftriaxone treatment indirectly hampered T cell proliferation and proinflammatory INFgamma and IL17 secretion through modulation of myelin-antigen presentation by antigen-presenting cells (APCs) e.g. dendritic cells (DCs) and reduced T cell migration into the CNS in vivo. Taken together, we demonstrate, that a beta-lactam antibiotic attenuates disease course and severity in a model of autoimmune CNS inflammation. The mechanisms are reduction of T cell activation by modulation of cellular antigen-presentation and impairment of antigen-specific T cell migration into the CNS rather than or modulation of central glutamate homeostasis.
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PMID:A beta-lactam antibiotic dampens excitotoxic inflammatory CNS damage in a mouse model of multiple sclerosis. 1877 80

Neuroadapted Sindbis virus (NSV) is a neuronotropic virus that causes a fulminant encephalomyelitis in susceptible mice due to death of motor neurons in the brain and spinal cord. We and others have found that uninfected motor neurons die in response to NSV infection, at least in part due to disrupted astrocytic glutamate transport, resulting in excitotoxic motor neuron death. Here, we examined the mechanisms of astrocyte dysregulation associated with NSV infection. Treatment of organotypic slice cultures with NSV results in viral replication, cell death, altered astrocyte morphology, and the downregulation of the astrocytic glutamate transporter, GLT-1. We have found that TNF-alpha can mediate GLT-1 downregulation. Furthermore, TNF-alpha deficient mice infected with NSV exhibit neither GLT-1 downregulation nor neuronal death of brainstem and cervical spinal cord motor neurons and have markedly reduced mortality. These findings have implications for disease intervention and therapeutic development for the prevention of CNS damage associated with inflammatory responses.
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PMID:Tumor necrosis factor-alpha modulates glutamate transport in the CNS and is a critical determinant of outcome from viral encephalomyelitis. 1936 27

Glutamate neurotransmission is highly regulated, largely by glutamate transporters. In the spinal cord, the glutamate transporter GLT-1 is primarily responsible for glutamate clearance. Downregulation of GLT-1 can occur in activated astrocytes, and is associated with increased extracellular glutamate and neuroexcitation. Among other conditions, astrocyte activation occurs following repeated opioids and in models of chronic pain. If GLT-1 downregulation occurs in these states, GLT-1 could be a pharmacological target for improving opioid efficacy and controlling chronic pain. The present studies explored whether daily intrathecal treatment of rats with ceftriaxone, a beta-lactam antibiotic that upregulates GLT-1 expression, could prevent development of hyperalgesia and allodynia following repeated morphine, reverse pain arising from central or peripheral neuropathy, and reduce glial activation in these models. Ceftriaxone pre-treatment attenuated the development of hyperalgesia and allodynia in response to repeated morphine, and prevented associated astrocyte activation. In a model of multiple sclerosis (experimental autoimmune encephalomyelitis; EAE), ceftriaxone reversed tactile allodynia and halted the progression of motor weakness and paralysis. Similarly, ceftriaxone reversed tactile allodynia induced by chronic constriction nerve injury (CCI). EAE and CCI each significantly reduced the expression of membrane-bound, dimerized GLT-1 protein in lumbar spinal cord, an effect normalized by ceftriaxone. Lastly, ceftriaxone normalized CCI- and EAE-induced astrocyte activation in lumbar spinal cord. Together, these data indicate that increasing spinal GLT-1 expression attenuates opioid-induced paradoxical pain, alleviates neuropathic pain, and suppresses associated glial activation. GLT-1 therefore may be a therapeutic target that could improve available treatment options for patients with chronic pain.
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PMID:Spinal upregulation of glutamate transporter GLT-1 by ceftriaxone: therapeutic efficacy in a range of experimental nervous system disorders. 2054 13

It is increasingly accepted that glutamate excitotoxicity contributes to the death of nerve cells in multiple sclerosis (MS). Matrine (MAT) is a quinolizidine alkaloid that has long been used in the treatment of hepatitis B without obvious side effects. Previous reports have shown that MAT suppresses central nervous system inflammation and demyelination in experimental autoimmune encephalomyelitis (EAE), an animal model of MS; however whether MAT effectively inhibits excitotoxic molecules, such as glutamate-related factors, is still unclear. In this study, we provide data showing that MAT attenuated EAE disease severity, accompanied by downregulated glutamate and upregulated GABA levels, as well as enhanced expression of two dependent glutamate transporters (GLT-1 and GLAST). In addition, MAT treatment significantly reduced the level of the NMDA- and AMPA-glutamate receptor in EAE rats. Taken together, our data indicate that MAT treatment regulates glutamate-related molecules, and suggests that the neuroprotective role of MAT is a novel mechanism underlying its therapeutic effect in EAE.
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PMID:Matrine regulates glutamate-related excitotoxic factors in experimental autoimmune encephalomyelitis. 2436 16

The contribution of glial transporters to glutamate movement across the membrane has been identified as a potential target for anti-seizure therapies. Two such glutamate transporters, GLT-1 and system xc-, are expressed on glial cells, and modulation of their expression and function have been identified as a means by which seizures, neuronal injury, and gliosis can be reduced in models of brain injury. While GLT-1 is responsible for the majority of glutamate uptake in the brain, system xc- releases glutamate in the extracellular cleft in exchange for cystine and represents as such the major source of hippocampal extracellular glutamate. Using the Theiler's Murine Encephalomyelitis Virus (TMEV) model of viral-induced epilepsy, we have taken two well-studied approaches, one pharmacological, one genetic, to investigate the potential role(s) of GLT-1 and system xc- in TMEV-induced pathology. Our findings suggest that the methods we utilized to modulate these glial transporters, while effective in other models, are not sufficient to reduce the number or severity of behavioral seizures in TMEV-infected mice. However, genetic knockout of xCT, the specific subunit of system xc-, may have cellular effects, as we observed a slight decrease in neuronal injury caused by TMEV and an increase in astrogliosis in the CA1 region of the hippocampus. Furthermore, xCT knockout caused an increase in GLT-1 expression selectively in the cortex. These findings have significant implications for both the characterization of the TMEV model as well as for future efforts to discover novel and effective anti-seizure drugs.
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PMID:Genetic and pharmacological manipulation of glial glutamate transporters does not alter infection-induced seizure activity. 3102 85