On the track of cell survival pharmaceuticals in the oligodendrocyte type-2 astrocyte lineage.

The identification of compounds that can protect cells against death induced by exposure to noxious stimuli and against programmed cell death (apoptosis) associated with exposure to inadequate amounts of trophic factors is of great interest in contemporary biology. We have found that N-acetyl-L-cysteine (NAC) is able to promote cell survival in these two distinct experimental paradigms of, respectively, "death by murder" and "death by neglect." In the former case, NAC prevented the death of oligodendrocytes induced by glutamate or tumor necrosis factor-alpha (TNF-alpha), and also prevented TNF-alpha-induced death of L929 cells. NAC also acted in synergy with ciliary neurotrophic factor (CNTF) to prevent killing of oligodendrocytes by TNF-alpha. In analysis of "death by neglect," NAC markedly enhanced the extent of spinal ganglion neuron survival obtained with suboptimal concentrations of nerve growth factor and of oligodendrocyte survival obtained with suboptimal concentrations of CNTF or insulin-like growth factor-1. Surprisingly, significant rescue of oligodendrocytes from apoptosis was also observed with combinations of NAC with progesterone, vitamin C, or Trolox, a water-soluble vitamin E analogue, although not with any of these compounds applied individually. These results demonstrate that cocktails of small molecules such as those we have studied may have beneficial effects not predictable from the action of any individual member of the cocktail. In light of the long clinical history of therapeutic use of NAC and the other compounds identified in our studies, we suggest that it may be of interest to examine use of NAC alone, or combinations of NAC with the other small molecules we have studied, in conditions in which certain toxin-mediated forms of cell death or apoptosis contribute significantly to disease.