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Self‐protection of PC12 cells by 6R‐tetrahydrobiopterin from nitric oxide toxicity
Author(s) -
Koshimura Kunio,
Murakami Yoshio,
Tanaka Junko,
Kato Yuzuru
Publication year - 1998
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/(sici)1097-4547(19981201)54:5<664::aid-jnr11>3.0.co;2-u
Subject(s) - tetrahydrobiopterin , biopterin , hypoxanthine , toxicity , superoxide , nitric oxide , chemistry , nitric oxide synthase , biochemistry , nitrite , xanthine oxidase , pharmacology , biology , nitrate , enzyme , organic chemistry
Nitric oxide (NO) has cytotoxic effects but NO producing neurons are resistant to NO toxicity. These results suggest the presence of self‐protecting factors for NO toxicity. Recently, 6R‐tetrahydrobiopterin (6R‐BH 4 ), a cofactor for NO synthase (NOS), has been reported to degrade NO raising the possibility that 6R‐BH 4 acts as a self‐protecting factor for NO toxicity. In PC12 cells which have NOS, three‐day culture with sodium nitroprusside (SNP) or NOC‐12, NO generators, at 10–100 μM increased nitrite and nitrate concentrations in the culture medium and induced death of PC12 cells. Coadministration of 6R‐BH 4 (10 or 30 μM) with SNP or NOC‐12 prevented cell death with reduction of nitrite and nitrate in the medium. Inhibition of 6R‐BH 4 synthesis by 2,4‐diamino‐6‐hydroxypyrimidine (DAHP), an inhibitor for GTP cyclohydrolase I, decreased cellular 6R‐BH 4 content and viable cell number. The inhibiting effects of DAHP were restored by exogenous 6R‐BH 4 . NOS activity, as estimated by nitrite concentrations in the medium, was unchanged by DAHP. Hypoxanthine and xanthine oxidase, which produce superoxide, mimicked the cell‐protecting effect of 6R‐BH 4 which is reported to generate superoxide during its autoxidation. These results suggest that 6R‐BH 4 acts as a self‐protecting factor for NO toxicity with generation of superoxide in NO‐producing neurons. J. Neurosci. Res. 54:664–672, 1998. © 1998 Wiley‐Liss, Inc.