Antioxidants are exogenous (natural or synthetic) or endogenous compounds acting to reduce or diminish the oxidative stress. The natural antioxidant system includes enzymes (i.e. superoxide dismutase (SOD), catalase, peroxidase, and some supporting enzymes), and low-molecular-weight antioxidants (LMWA), which contain ascorbic acid, lipoic acid, polyphenols, carotenoids, and vitamin E (14). The pathogenic role of oxygen and nitrogen free radicals in MS led to the recognition that antioxidants might prevent free-radical-mediated tissue damage and inhibit some of the early proinflammatory events that lead to inflammation and tissue destruction in EAE and MS. However, the main obstacle and challenge in MS treatment are to introduce substances into the brain through the BBB (14).
Lehmann et al. (68) showed that administration of the oxidant-scavenger N-acetyl-L-cysteine (NAC) inhibited the induction of acute EAE in mice. The protection was associated with enhancement of the specific lymphocyte proliferative response to the immunizing antigens (spinal cord homogenate) at early stages, post encephalitogenic injection (68). Recently, we reported that N-acetylcysteine amide (AD4), a novel antioxidant, crosses the BBB, chelates Cu(2+), and prevents ROS-induced activation of JNK, p38 and MMP-9 in vitro. In addition, AD4 was found to be extremely efficacious in MOG-induced EAE mice, and it was shown that AD4-treated mice demonstrated a marked delay in EAE onset and a significant reduction in the severity of the clinical EAE signs. Moreover, AD4 was found to be highly effective at suppressing the EAE score even if it was administered after the appearance of clinical signs. Furthermore, histological analysis of the AD4-treated mice revealed that AD4 inhibits inflammation, MMP-9 activity, axonal damage, and demyelination in the myelin oligodendrocyte glycoprotein (MOG)-induced EAE (29). In another study, we examined the molecular mechanism by which AD4 exerts protection in MOG-induced EAE mice using a cDNA microarray. We demonstrated that MOG treatment up-regulated genes encoding growth factors, cytokines, death receptors, proteases, and myelin structure proteins, whereas MOG- and AD4-treated mice demonstrated gene expression profiles similar to that seen in healthy, naive mice (69). The conclusion of these two studies and others performed by us (70,71) was that the nontoxic features of AD4, its oral bioavailability, its BBB penetration capability, and its antioxidant properties make it an excellent candidate for evaluation in treatment of MS and other neurodegenerative diseases.
Another antioxidant that has shown promise in EAE is alpha lipoic acid (-lipoate thioctic acid, 1,2-dithiolane-3-pentanoic acid; 1,2-dithiolane-3 valeric acid, and 6,8-dithiooctanoic acid). It was shown that alpha lipoic acid (alpha-LA) had dose-dependent reduction in the 10-day cumulative disease score and suppressed inflammation, demyelination, and axonal damage in the spinal cord of EAE-induced mice. Moreover, there was a marked reduction in CD3+ T cells and CD11b+ monocyte/macrophage cells within the spinal cord, and inhibition of matrix metalloproteinase-9 (MMP-9) activity in a dose-dependent fashion (72). Another study showed that daily oral administration of alpha-LA, starting at the time of immunization, significantly prevented EAE progression, as compared to control mice.
This was associated with a reduction of CNS-infiltrating T cells and macrophages, as well as decreased demyelination. In addition, alpha-LA inhibited the proteolytic activity of MMP2 and MMP9 only at very high doses (73).
These studies suggest that alpha-LA can effectively interfere with the autoimmune reaction associated with EAE through mechanisms other than its antioxidant activity and supports further studies on the use of alpha-LA as a potential therapy for MS.
Uric acid (UA) is the naturally occurring product of purine metabolism, and it is known as a strong peroxynitrite scavenger (a product of nitric oxide and superoxide radicals). Hooper et al. (74,75) demonstrated that the inhibition of iNOS or scavenging of NO* or peroxynitrite by UA inhibited neurological deficits in mice with EAE, while withdrawal of iNOS inhibitor resulted in the appearance of neurological signs within 24 h (74,75).
One study showed that intraperitoneal administration of catalase before the onset of neurological deficit delayed the onset of EAE and reduced its severity and duration (41). A synthetic salen-manganese complex, Euk-8, which may be regarded as a prototype molecule of a new class of synthetic catalytic scavengers with combined SOD and catalase activity, was also shown to ameliorate EAE in mice. The authors showed that repeated injection of Euk-8 starting at the time of EAE induction delayed the onset and markedly reduced the severity of the disease. In addition, all Euk-8-treated mice completely recovered after 40 days. Moreover, the authors showed that posttreatment with Euk-8, 4 days after EAE induction, also resulted in a significant amelioration of EAE disease (76).
Several other antioxidants/radical scavengers were found to be effective in preventing or alleviating EAE in mice and rats. These antioxidants included tirilazad mesylate, a member of the lazaroids family (77), butylated hydroxyanisole (78), iNOS inhibitors/NO scavengers (79-83), thymoquinone (84), methalothionine (85), and bilirubin (86).
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