Inhibitory effect of 5,6,7,8-tetrahydroneopterin on adriamycin-induced cardiotoxicity.
The protective effect of the reduced form of neopterin, 5,6,7,8-tetrahydroneopterin (NPH4), against the cardiotoxicity of adriamycin (ADR) was evaluated in mice by assay of serum creatine phosphokinase (CPK) and heart lipid peroxide (i.e., thiobarbituric acid reactive substances, TBARS). The activity of CPK was drastically elevated at around 3 days after a single s.c. injection of ADR and had returned to normal at 6 days. There were no marked changes in the TBARS content of the heart by 6 days, but a significant increase was apparent at about 8 days after ADR treatment. The effect of NPH4 was evaluated in terms of the serum CPK activity at the 4th day and in terms of TBARS content at the 8th day after ADR treatment. The elevation of CPK activity induced by ADR was significantly suppressed by two treatments with NPH4 every day for 4 days, i.e., from day 0 to day 3 after injection of ADR, at doses of 3 mg/kg and 0.3 mg/kg. The increase of TBARS content in the heart at 8 days after ADR treatment was also suppressed at both doses of NPH4. The effect of the timing of NPH4 treatment on the suppression of elevated CPK was examined. The suppressive potency of NPH4 could not be elicited by any treatment schedule that terminated at or before 2 days after injection of ADR. Consecutive treatments from day 0 to day 3 after injection of ADR were effective, as was a simple schedule of only two treatments with NPH4 on day 3.(ABSTRACT TRUNCATED AT 250 WORDS)
Kojima
S
S
Research Institute for Biosciences, Science University of Tokyo, Japan.
Icho
T
T
Hayashi
M
M
Kajiwara
Y
Y
Kitabatake
K
K
Kubota
K
K
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001708:Biopterins / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003402:Creatine Kinase / Q000097:blood; D004317:Doxorubicin / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D006331:Heart Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008854:Microscopy, Electron; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013997:Time Factors
D000975:Antioxidants; D017392:Thiobarbituric Acid Reactive Substances; D001708:Biopterins; C023455:tetrahydroneopterin; D004317:Doxorubicin; D003402:Creatine Kinase; D005978:Glutathione