Inflammation and primary demyelination induced by the intraspinal injection of lipopolysaccharide

Abstract

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 approximately 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.

Cause and prevention of demyelination in a model multiple sclerosis lesion

“…By 14 days postinjection, lesions were comprised of many demyelinated axons and debris‐filled macrophages, but no evidence of edema was observed. The lesion in this study closely resembled that described in more detail previously 26, 27, 28, 30…”

“…The findings show that iNOS is prominent in the early LPS lesion,26, 27 and nitric oxide is strongly implicated in neurodegeneration34; many of the mechanisms thought responsible for neuronal loss will also apply to oligodendrocytes. Nitric oxide competes with oxygen for the same binding site on mitochondrial cytochrome c oxidase, raising the Michaelis constant for oxygen, so the combination of raised nitric oxide with reduced oxygen can be lethal to cells such as oligodendrocytes, even if either complication can be tolerated alone 35…”

“…The inflammatory reaction is followed by the appearance of a demyelinating lesion in which the demyelination is achieved by the distinctive pattern III mechanism 4, 6, 26. The experimental lesion is achieved by the same mechanisms as implicated in the human MS lesion,27, 28 and notably it does not seem to result from autoimmune mechanisms.…”

Glia Disease and Repair—Remyelination

“…This occurs in several experimental animal models of demyelination as well as in human demyelinating disease (Snyder et al 1975;Itoyama et al 1983Itoyama et al , 1985Dusart et al 1992;Felts et al 2005). Schwann cell remyelination occurs preferentially where astrocytes are absent, for example, where they have been killed along with oligodendrocytes by the demyelinating agent (Blakemore 1975;Itoyama et al 1985).…”

Calcineurin in Reactive Astrocytes Plays a Key Role in the Interplay between Proinflammatory and Anti-Inflammatory Signals

“…Injection of bacterial endotoxins (LPS) into the brain is a well established model of inflammatory processes associated with human neurotropic infections (Fassbender et al, 2004;Felts et al, 2005). After brain LPS injection to AIC mice, pathological alterations peaked within 1-3 d and were resolved 10 d later.…”