Possible implications are that all / much of the research done to date has been a waste of time. £millions have been spent on treatments which have no real effect in the long run (maybe a bit of delay at best).
But at the moment we are sure of one thing....nobody's been able to prove the cause of MS and there certainly isn't anything close to a cure.
These include the cytokines tumor necrosis factor- (TNF) and interleukin-1 (IL-1), free radicals such as nitric oxide (NO) and superoxide, fatty acid metabolites such as eicosanoids, and quinolinic acid. Studies using cell culture and animal models have demonstrated that excessive quantities of individual factors produced by activated microglia can be deleterious to neurons (Boje and Arora, 1992; Chao et al., 1992; McGuire et al., 2001). Furthermore, individual factors often work in concert to induce neurodegeneration. For example, Chao et al. (1995) reported that the combination of IL-1 and TNF, but not either cytokine alone, induced the degeneration of
cortical neurons. Jeohn and colleagues (1998) have shown that the combination of IL-1, TNF, and interferon-y work in synergy to induce degeneration of cortical neurons. Recently, Xie et al. (2002) showed that peroxynitrite, possibly a product of superoxide and NO, is a major mediator of neurotoxicity induced by lipopolysaccharide (LPS) or -amyloid peptide (1-42).
Experimental autoimmune encephalomyelitis (EAE) is mediated by inflammatory cells recruited from the circulation to the CNS. We used intravital microscopy to investigate the mechanisms of this recruitment. No leukocyte rolling and very little adhesion was observed in healthy control mice. In contrast, both rolling and adhesion was observed in brain postcapillary venules before onset of physical symptoms of EAE. Rolling and adhesion remained elevated for 2 wk and returned to near normal levels by 5 wk postsymptom onset. Consistent with a role for P-selectin in recruitment to the CNS, P-selectin protein was detected in the brains and spinal cords of EAE mice. Expression was highest before symptom onset and decreased over the next 2 wk. The importance of alpha(4)
integrin increased with time as anti-alpha(4) integrin blocked approximately 20, 50, and 60% of leukocyte rolling 2 days before disease onset, 5 days and 2 wk postonset of symptoms, respectively, and 85% of rolling 5 wk postsymptoms. Addition of anti-P-selectin to alpha(4) integrin Ab-treated mice blocked all remaining rolling at each time point. Interestingly, however, alpha(4) integrin-mediated rolling appeared to be entirely dependent on P-selectin as anti-P-selectin alone was able to completely block all leukocyte rolling. In the absence of rolling (with P-selectin Ab), a 70% reduction in adhesion was noted. A very similar reduction was seen when mice were treated with alpha(4) integrin-blocking Ab. In conclusion, we describe increased leukocyte trafficking in
the brains of EAE mice with important overlapping roles for both P-selectin and alpha(4) integrin in mediating leukocyte-endothelial cell interactions.
For those of you who don't like the "mice" (what's that saying Harry quoted about MS in mice? Darn...what was that, Harry?
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