3-HYDROXYKYNURENINE, AN ENDOGENOUS OXIDATIVE STRESS GENERATOR, CAUSESNEURONAL CELL-DEATH WITH APOPTOTIC FEATURES AND REGION SELECTIVITY

3-Hydroxykynurenine (3-HK) is a potential endogenous neurotoxin whose increased levels have been described in several neurodegenerative diso rders. Here, we characterized in vitro neurotoxicity of 3-HK. Of the t ested kynurenine pathway metabolites, only 3-HK, and to a lesser exten t 3-hydroxyanthranilic acid, were toxic to primary cultured striatal n eurons. 3-HK toxicity was inhibited by various antioxidants, indicatin g that the generation of reactive oxygen species is essential to the t oxicity. 3-HK-induced neuronal cell death showed several features of a poptosis, as determined by the blockade by macromolecule synthesis inh ibitors, and by the observation of cell body shrinkage with nuclear ch romatin condensation and fragmentation, In addition, 3-HK toxicity was dependent on its cellular uptake via transporters for large neutral a mino acids, because uptake inhibition blocked the toxicity. Cortical a nd striatal neurons were much more vulnerable to 3-HK toxicity than ce rebellar neurons, which may be attributable to the differences in tran sporter activities of these neurons. These results indicate that 3-HK, depending on transporter-mediated cellular uptake and on intracellula r generation of oxidative stress, induces neuronal cell death with bra in region selectivity and with apoptotic features, which may be releva nt to pathology of neurodegenerative disorders.