Simultaneous neuroprotection and blockade of inflammation reverses autoimmune encephalomyelitis

Kanwar, Jagat R., Kanwar, Rupinder K. and Krissansen, Geoffrey W. 2004, Simultaneous neuroprotection and blockade of inflammation reverses autoimmune encephalomyelitis, Brain : a journal of neurology, vol. 127, no. 6, pp. 1313-1331, doi: 10.1093/brain/awh156.

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Title Simultaneous neuroprotection and blockade of inflammation reverses autoimmune encephalomyelitis
Author(s) Kanwar, Jagat R.ORCID iD for Kanwar, Jagat R.
Kanwar, Rupinder K.
Krissansen, Geoffrey W.
Journal name Brain : a journal of neurology
Volume number 127
Issue number 6
Start page 1313
End page 1331
Publisher Oxford University Press
Place of publication Oxford, England
Publication date 2004
ISSN 0006-8950
Summary In multiple sclerosis, the immune system attacks the white matter of the brain and spinal cord, leading to disability and/or paralysis. Myelin, oligodendrocytes and neurons are lost due to the release by immune cells of cytotoxic cytokines, autoantibodies and toxic amounts of the excitatory neurotransmitter glutamate. Experimental autoimmune encephalomyelitis (EAE) is an animal model that exhibits the clinical and pathological features of multiple sclerosis. Current therapies that suppress either the inflammation or glutamate excitotoxicity are partially effective when administered at an early stage of EAE, but cannot block advanced disease. In a multi-faceted approach to combat EAE, we blocked inflammation with an anti-MAdCAM-1 (mucosal addressin cell adhesion molecule-1) monoclonal antibody and simultaneously protected oligodendrocytes and neurons against glutamate-mediated damage with the -amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate antagonist 2,3-dihydroxy-6-nitro-7- sulfamoylbenzo(f)quinoxaline (NBQX) and the neuroprotector glycine–proline–glutamic acid (GPE; N-terminal tripeptide of insulin-like growth factor). Remarkably, administration at an advanced stage of unremitting EAE of either a combination of NBQX and GPE, or preferably all three latter reagents, resulted in amelioration of disease and repair of the CNS, as assessed by increased oligodendrocyte survival and remyelination, and corresponding decreased paralysis, inflammation, CNS apoptosis and axonal damage. Each treatment reduced the expression of nitric oxide and a large panel of proinflammatory and immunoregulatory cytokines, in particular IL-6 which plays a critical role in mediating EAE. Mice displayed discernible improvements in all physical features examined. Disease was suppressed for 5 weeks, but relapsed when treatment was suspended, suggesting treatment must be maintained to be effective. The above approaches, which allow CNS repair by inhibiting inflammation and/or simultaneously protect neurons and oligodendrocytes from damage, could thus be effective therapies for multiple sclerosis.
Language eng
DOI 10.1093/brain/awh156
Field of Research 110904 Neurology and Neuromuscular Diseases
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2004, Oxford University Press
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Created: Fri, 26 Mar 2010, 15:41:49 EST by Rupinder Kanwar

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