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3‐Hydroxykynurenine, an Endogenous Oxidative Stress Generator, Causes Neuronal Cell Death with Apoptotic Features and Region Selectivity
Author(s) -
Okuda Shoki,
Nishiyama Nobuyoshi,
Saito Hiroshi,
Katsuki Hiroshi
Publication year - 1998
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1998.70010299.x
Subject(s) - programmed cell death , oxidative stress , apoptosis , neurotoxin , neurotoxicity , biology , microbiology and biotechnology , toxicity , neurodegeneration , biochemistry , endogeny , intracellular , reactive oxygen species , chemistry , pharmacology , medicine , disease , organic chemistry
3‐Hydroxykynurenine (3‐HK) is a potential endogenous neurotoxin whose increased levels have been described in several neurodegenerative disorders. Here, we characterized in vitro neurotoxicity of 3‐HK. Of the tested kynurenine pathway metabolites, only 3‐HK, and to a lesser extent 3‐hydroxyanthranilic acid, were toxic to primary cultured striatal neurons. 3‐HK toxicity was inhibited by various antioxidants, indicating that the generation of reactive oxygen species is essential to the toxicity. 3‐HK‐induced neuronal cell death showed several features of apoptosis, as determined by the blockade by macromolecule synthesis inhibitors, and by the observation of cell body shrinkage with nuclear chromatin condensation and fragmentation. In addition, 3‐HK toxicity was dependent on its cellular uptake via transporters for large neutral amino acids, because uptake inhibition blocked the toxicity. Cortical and striatal neurons were much more vulnerable to 3‐HK toxicity than cerebellar neurons, which may be attributable to the differences in transporter activities of these neurons. These results indicate that 3‐HK, depending on transporter‐mediated cellular uptake and on intracellular generation of oxidative stress, induces neuronal cell death with brain region selectivity and with apoptotic features, which may be relevant to pathology of neurodegenerative disorders.