p38 MAP kinase mediates nitric oxide-induced apoptosis of neural progenitor cells

Neural progenitor cells (NPC) can proliferate, differentiate into neurons o r glial cells, or undergo a form of programmed cell death called apoptosis. Although death of NPC occurs during development of the nervous system and in the adult, the underlying mechanisms are unknown. Here we show that nitr ic oxide (NO) can induce death of C17.2 NPC by a mechanism requiring activa tion of p38 MAP kinase, poly(ADP-ribose) polymerase, and caspase-3. Nitric oxide causes release of cytochrome c from mitochondria, and Bcl-2 protects the neural progenitor cells against nitric oxide-induced death, consistent with a pivotal role for mitochondrial changes in controlling the cell death process. Inhibition of p38 MAP kinase by SB203580 abolished NO-induced cel l death, cytochrome c release, and activation of caspase-3, indicating that p38 activation serves as an upstream mediator in the cell death process. T he antiapoptotic protein Bcl-2 protected NPC against nitric oxide-induced a poptosis and suppressed activation of p38 MAP kinase. The ability of nitric oxide to trigger death of NPC by a mechanism involving p38 MAP kinase sugg ests that this diffusible gas may regulate NPC fate in physiological and pa thological settings in which NO is produced.