The Role Of Apoptotic Genes In Ms And

Apoptosis is associated with activation or deacti-vation of proteolytic enzymes, such as caspases, that execute the death process by cutting the DNA into distinct fragments and deaggregating the DNA and proteins.15 Studying the oligodendro-cytes in the lesioned brain and spinal cord, Kuhlmann et al16 demonstrated a strong association between the presence of bcl-2 -positive oligodendrocytes and the presence of remyelina-tion. Moreover, they found that the highest proportion of bcl-2-positive oligodendrocytes was observed in a subgroup of patients with a relaps-ing-remitting disease course, indicating that Bcl-2 increases the viability of the oligodendrocytes in MS. In EAE, it was also shown that expression of another anti-apoptotic protein, oligodendrocyte baculovirus p35 caspase inhibitor, protected mice from EAE.17 Double staining of the EAE brains by the TUNEL method and immunocytochemistry revealed that astrocytes were more likely to be eliminated by apoptotic cell death than microglia.3 Extracts of EAE spinal cord showed that significantly increased expression of the two pro-apoptotic regulators, p53 and Bax, correlated with disease severity. This elevated expression could be seen in inflammatory cells but not in neurons or glia.18 White et al19 measured the expression of the apoptotic inducer proteins, Fas and Fas-ligand, and the Bcl-2 family of proteins in rat EAE induced by MBP. They found that cells over-expressing Fas and Fas-ligand were represented in the apoptotic population, in contrast to the cells expressing Bcl-2, which were protected from apoptotic cell death. Alcazar et al20 found that cerebrospinal fluid (CSF) from patients with aggressive MS contains soluble mediators that induce axonal damage and apoptosis of neurons in culture. Furthermore, intraperitoneal or intracis-ternal administration of the apoptotic inhibitors Ac-YVAD-cmk and zVAD-fmk impaired the recovery or the earlier relapse.21 The histological examination revealed that zVAD-fmk suppressed apoptotic cell death of inflammatory cells in the CNS of mice with EAE. This indicates that apoptosis of the infiltrated cells might be one of the recovery mechanisms in EAE.

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