Brain Advance Access originally published online on May 4, 2005
Brain 2005 128(7):1649-1666; doi:10.1093/brain/awh516
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Inflammation and primary demyelination induced by the intraspinal injection of lipopolysaccharide
Department of Neuroimmunology and Neuroinflammation Research Group, Guy's, King's and St Thomas' School of Medicine, King's College London, London, UK
Correspondence to: Dr Paul A. Felts, Department of Anatomy and Human Sciences, King's College London, London SE1 1UL, UK E-mail: Paul.Felts{at}kcl.ac.uk
Inflammation is a prominent feature of several disorders characterized by primary demyelination, but it is not clear whether a relationship exists between inflammation and myelin damage. We have found that substantial demyelination results from the focal inflammatory lesion caused by the injection of lipopolysaccharide (LPS; 200 ng) directly into the rat dorsal funiculus. Within 24 h, such injections caused a focal inflammatory response consisting of a substantial number of polymorphonuclear cells and ED1-positive and inducible nitric oxide synthase (iNOS)-positive macrophages/microglia. The number of inflammatory cells was substantially reduced by day 7. OX-52-positive T-cells were less frequently observed but were present in the meninges at 8 h, reached a maximum in the dorsal funiculus at 7 days, and were rare at 14 days. The inflammation was followed by the appearance of a large lesion of primary demyelination that encompassed up to 
75% of the cross-sectional area of the dorsal funiculus. Treatment with dexamethasone significantly reduced the number of cells expressing iNOS, but did not prevent the demyelination. By 28 days the lesions were largely remyelinated, usually by Schwann cells. These changes were not observed in control, saline-injected animals. We conclude that the intraspinal injection of LPS results in inflammation and subsequently in prominent demyelination. The mechanisms underlying the demyelination are not clear, but it is notable that it typically begins with disruption of the adaxonal myelin. Indeed, there is an early loss of myelin-associated glycoprotein within the lesion, despite the persistence of proteolipid protein. This combination is a feature of the pattern III lesion recently described in multiple sclerosis (Lucchinetti et al., 2000), and we therefore suggest that LPS-induced demyelination may serve as the first experimental model available for the study of this type of multiple sclerosis lesion.
Key Words: multiple sclerosis; models; microglia; inflammation; demyelination
Abbreviations: AdPC = adenomatous polyposis coli; GFAP = glial fibrillary acidic protein; ICAM-1 = intercellular adhesion molecule-1; iNOS = inducible form of nitric oxide synthase; LPS = lipopolysaccharide; MAG = myelin-associated glycoprotein; PBS = phosphate-buffered saline; PLP = proteolipid protein; PMN = polymorphonuclear cell
Received June 14, 2004. Revised November 30, 2004. Second revision on March 2, 2005. Accepted March 17, 2005.
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