Biol. Pharm. Bull. 30(8) 1390—1394 (2007)

earth’s crust and has been implicated as an etiologic factor in neurological disorders including Alzheimer’s disease, Parkinson’s dementia syndrome, and dialysis encephalopathy syndrome. In fact, some evidence supports the selective accumulation of Al within neurons containing neurofibrillay tangles in patients with Alzheimer’s disease and within the aging human brain. Meiri et al., have also reported that brain Al concentrations reach submilimolar levels in some encephalopathies. Several lines of research that use cultured cells and the aluminum–maltolate complex (Al(maltol)3), which is a membrane permeable, lipophilic complex of Al, also showed that the exposure of cells such as the Neuro-2a murine neuroblastoma cells, human NT2 neuroblastoma cells, and PC12 cells to the Al complex results in a decrease in cell viability via the apoptotic cell death pathway. Recently, we have reported that the treatment of PC12 cells with Al(maltol)3 causes a decrease in the levels of the intracellular reduced glutathione depending on the amount of Al(maltol)3 accumulated in the cells. 11) These findings strongly suggested that Al accumulation in tissues is closely related to the development of neurodegenerative disorders although a causal relationship between Al and neurodegenerative disorders remains unclear. NO is considered to be a modulator and a simple and diffusible free radical. It is believed to play an important role in physiological and pathophysiological events in many cellular systems. Furthermore, it has also been reported that NO concentration increased in the brain during the course of ischemia, Alzheimer’s disease, and other degenerative conditions. Numerous studies in several cell systems have demonstrated that NO is closely related to cell death mechanisms and plays the role of a mediator. A recent study has reported that NO is produced in the mitochondria via Ca -dependent mitochondrial NO synthases (mtNOS). The NO produced in the mitochondria by mtNOS plays the role of a modulator of mitochondrial oxygen consumption and transmembrane potential via a reversible reaction with cytochrome c oxidase. It is well-known that NO rapidly reacts with superoxide anion radicals to form peroxynitrite, which is an oxidant substance producing cytotoxic effects in many cells. Previously, we have reported that accumulation of Al(maltol)3 in PC12 cells results in apoptotic cell death depending on the intracellular generation of reactive oxygen species (ROS). Therefore, it would be interesting to determine if intracellular NO generation is involved in the onset mechanism of Al-mediated-cytotoxicity. Therefore, in the present study, we examined the effects of a NO generator and NO synthase inhibitors on Al(maltol)3-induced cell death. Our results suggest that intracellular NO generation may play an important role in the development of cell toxicity associated with Al(maltol)3 treatment.