Autoimmune encephalomyelitis ameliorated by AMPA antagonists

Smith, Terence; Groom, Anthony J.; Zhu, Bin; Turski, Lechosław

doi:10.1038/71548

Cited by 454 publications

(301 citation statements)

References 17 publications

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“…Although we cannot exclude a possible direct “by‐stander” attack of activated complement factors or an indirect effect by another cell type,39 the timing, lack of associated pathology, and localization of the axonal changes make these unlikely, and suggest that axonal swelling is the consequence of astrocyte loss. Indeed, this is not entirely surprising,40, 41, 42 given that numerous vital interactions between astrocytes and axons have been documented43, 44, 45, 46: For example, astrocytes are known to scavenge glutamate,47 and excitotoxicity has been implicated in axonal pathology during neuroinflammation 48, 49, 50. This, together with the well‐established role of excitotoxicity after hypoxia,43, 51 warrants future investigation in our NMO‐related model using in vivo real‐time optical techniques,52 calcium sensors,22, 53 and selective pharmacological inhibitors.…”

Section: Discussionmentioning

confidence: 99%

In vivo imaging reveals rapid astrocyte depletion and axon damage in a model of neuromyelitis optica‐related pathology

Herwerth

Kalluri

Srivastava

et al. 2016

Annals of Neurology

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ObjectiveNeuromyelitis optica (NMO) is an autoimmune disease of the central nervous system, which resembles multiple sclerosis (MS). NMO differs from MS, however, in the distribution and histology of neuroinflammatory lesions and shows a more aggressive clinical course. Moreover, the majority of NMO patients carry immunoglobulin G autoantibodies against aquaporin‐4 (AQP4), an astrocytic water channel. Antibodies against AQP4 can damage astrocytes by complement, but NMO histopathology also shows demyelination, and — importantly—axon injury, which may determine permanent deficits following NMO relapses. The dynamics of astrocyte injury in NMO and the mechanisms by which toxicity spreads to axons are not understood.MethodsHere, we establish in vivo imaging of the spinal cord, one of the main sites of NMO pathology, as a powerful tool to study the formation of experimental NMO‐related lesions caused by human AQP4 antibodies in mice.ResultsWe found that human AQP4 antibodies caused acute astrocyte depletion with initial oligodendrocyte survival. Within 2 hours of antibody application, we observed secondary axon injury in the form of progressive swellings. Astrocyte toxicity and axon damage were dependent on AQP4 antibody titer and complement, specifically C1q.InterpretationIn vivo imaging of the spinal cord reveals the swift development of NMO‐related acute axon injury after AQP4 antibody‐mediated astrocyte depletion. This approach will be useful in studying the mechanisms underlying the spread of NMO pathology beyond astrocytes, as well as in evaluating potential neuroprotective interventions. Ann Neurol 2016;79:794–805

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Section: Discussionmentioning

confidence: 99%

In vivo imaging reveals rapid astrocyte depletion and axon damage in a model of neuromyelitis optica‐related pathology

Herwerth

Kalluri

Srivastava

et al. 2016

Annals of Neurology

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“…Although glutamate excitotoxicity is implicated in numerous CNS abnormalities, including pathological changes associated with head trauma and stroke, and diseases such as amyotrophic lateral sclerosis, Huntington disease, Alzheimer's disease, epilepsy, HIV-1-associated dementia, and immune-mediated damage in multiple sclerosis (3,(14)(15)(16)(17)(18)(19)(37)(38)(39), the mechanism by which the brain (astrocytes) regulates glutamate transport and prevents glutamate damage to neurons remains to be defined. The present study provides insights into the mechanism by which human astrocytes regulate EAAT2 gene expression and consequently glutamate transport.…”

Section: Discussionmentioning

confidence: 99%

Insights into glutamate transport regulation in human astrocytes: Cloning of the promoter for excitatory amino acid transporter 2 (EAAT2)

Leszczyniecka

Kang

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

175

219

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Glutamate transport is central to neurotransmitter functions in the brain. Impaired glutamate transport induces neurotoxicity associated with numerous pathological processes, including stroke͞ischemia, temporal lobe epilepsy, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, HIV-1-associated dementia, and growth of malignant gliomas. Excitatory amino acid transporter-2 (EAAT2) is a major glutamate transporter in the brain expressed primarily in astrocytes. We presently describe the cloning and characterization of the human EAAT2 promoter, demonstrating elevated expression in astrocytes. Regulators of EAAT2 transport, both positive and negative, alter EAAT2 transcription, promoter activity, mRNA, and protein. These findings imply that transcriptional processes can regulate EAAT2 expression. Moreover, they raise the intriguing possibility that the EAAT2 promoter may be useful for targeting gene expression in the brain and for identifying molecules capable of modulating glutamate transport that could potentially inhibit, ameliorate, or prevent various neurodegenerative diseases.sequential progressive genomic scanning ͉ nuclear run-on assays ͉ promoter reporter assays ͉ mRNA and protein expression

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“…[36][37][38] It is significant, therefore, that antagonists of iGluR ameliorate the symptoms of EAE and attenuate excitotoxic injury. 39,40 The loss of oligodendrocytes and myelin results in secondary axonal damage, 10 although axons may also express iGluR, indicating that glutamate may directly compromise axons. 41 Astrocyte signalling at nodes of Ranvier Astrocytes contact nodes of Ranvier, the only areas of axolemma not covered by myelin in the optic nerve, and therefore the only potential site for axon-astrocyte signalling (Figure 4).…”

Section: Oligodendrocytes Are Essential For Axon Functionmentioning

confidence: 99%

Functions of optic nerve glia: axoglial signalling in physiology and pathology

Butt

Pugh

Hubbard

et al. 2004

Eye

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An early concept of glial function envisaged them as passive and unexcitable structural elements, much like the connective tissues of organs in the periphery. It is now known that glia have a widespread range of physiological roles and react to all forms of pathological insult. This paper reviews the major functions of oligodendrocytes and astrocytes, the main types of glia in the optic nerve, and examines novel NG2-glia, otherwise known as oligodendrocyte progenitor cells (OPCs). The major function of oligodendrocytes is to produce the myelin sheaths that insulate CNS axons, but they also have important roles in the establishment of nodes of Ranvier, the sites of action potential propagation, and axonal integrity. Astrocytes have multiple physiological and pathological functions, including potassium homeostasis and metabolism, and reactive astrogliosis in response to CNS insults. The bulk of NG2-glia are postmitotic complex cells, distinct from OPCs, and respond to any insult to the CNS by a rapid and stereotypic injury response. This may be their primary unction, but NG2-glia, or a subpopulation of NG2-expressing adult OPCs, also provide remyelinating oligodendrocytes following demyelination. Oligodendrocytes, astrocytes, and NG2-glia all contact axons at nodes of Ranvier and respond to glutamate, ATP, and potassium released during axonal electrical activity. Glutamate and ATP evoke calcium signalling in optic nerve glia and have dual roles in physiology and pathology, coupling glial functions to axonal activity during normal activity, but enhanced activation induces an injury response, as seen following injury, demyelination, and ischaemia.

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Autoimmune encephalomyelitis ameliorated by AMPA antagonists

Cited by 454 publications

References 17 publications

In vivo imaging reveals rapid astrocyte depletion and axon damage in a model of neuromyelitis optica‐related pathology

In vivo imaging reveals rapid astrocyte depletion and axon damage in a model of neuromyelitis optica‐related pathology

Insights into glutamate transport regulation in human astrocytes: Cloning of the promoter for excitatory amino acid transporter 2 (EAAT2)

Functions of optic nerve glia: axoglial signalling in physiology and pathology

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