Involvement of No in Neuronal Apoptosis In- Duced by Cerebral Ischemia

Neuronal death seems to play crucial roles in the cognitive deficits of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and cerebral ischemic-induced dementia. Cerebral ischemia causes the expression of an inducible type of nitric oxide (NO) synthase (iNOS) in glial cells as well as the activation of a type of neuronal NOS (nNOS) in neurons, resulting in neuronal apoptosis due to excessive amounts of NO (Fig. 1). Reactive peroxynitrite generated by the reaction of NO with superoxide could be involved in NO-induced neuronal death. Cellular and molecular pharmacological studies using cultured neuroblatoma SHSY5Y cells have suggested that NO causes apoptosis through the following process: 1) the decrease in mitochondrial membrane potential, 2) release of cytochrome c from the mitochondria, 3) caspase activation, 4) degradation of caspase-acticated DNase (CAD) inhibitors and 5) CAD activation (Fig. 1). As mentioned above, one of the primary targets of NO action seems to be the mitochondria, since NO leads to the release of cytochrome c from the mitochondria, and the subsequent formation of a complex of cytochrome c, apoptotic protease activity factor-1 (Apaf-1) and caspase-9, which initiates the cleavage and activation of caspase-3. It is of interest that cyclosporin A (CsA, an inhibitor of cyclophilin D) and bongkrekic acid {BA, an adenine neulotides translocator (ANT) in mitochondrial permeability transition pore complex (PTPC)}, can recover from the loss of mitochondrial membrane potential in response to NO (Fig. 2). Furthermore the findings that 1) CsA is able to decrease NOinduced cytochrome c release from the mitochondria and 2) apoptotic cell death is reduced by BA treatment, suggesting July 2004 Biol. Pharm. Bull. 27(7) 961—963 (2004) 961