Effects of 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol) and nerve growth factor on DNA, RNA and protein syntheses in neonatal rat superior cervical ganglia.
To investigate molecular mechanisms involved in the neurotoxicity of clioquinol (5-chloro-7-iodo-8-hydroxyquinoline), the inhibitory effects of this drug on DNA, RNA and protein syntheses were examined, in relation to the action of nerve growth factor (2.5S NGF). We used an organ culture of neonatal rat superior cervical ganglion (SCG). Ten microM clioquinol inhibited completely DNA and protein syntheses and abolished the stimulatory effect of NGF on RNA synthesis. With regard to the chemical structure of clioquinol, hydroxylation at the 8th carbon of quinoline is essential for the inhibition of DNA, RNA and protein syntheses, and the hydrophobicity of the 8-HQ derivatives is a required property for potent inhibition. Compared with effects of EDTA, alizarine, sodium alizarine sulfate, o-phenanthroline and alpha,alpha'-dipyridyl, the loss of the NGF-induced stimulation of RNA synthesis by clioquinol does not seem to be primarily caused by its metal-chelating property. Clioquinol did not significantly alter the uptake rate of thymidine, uridine and leucine, thereby suggesting that the primary action of clioquinol on inhibition of DNA, RNA and protein syntheses does not relate to uptake of the precursor into SCG. Clioquinol did not significantly alter the degradation of 3H-uridine-labeled RNA. NGF suppressed the degradation of RNA and this suppression was overcome by clioquinol. The release of free uridine from SCG into the culture medium was enhanced by clioquinol and was partially suppressed by NGF. The inhibitory effects of clioquinol were completely prevented by bovine serum albumin (BSA), but not by NGF even at a 5-fold concentration of clioquinol.(ABSTRACT TRUNCATED AT 250 WORDS)
Hori
S
S
Department of Neurochemistry, Tokyo Metropolitan Institute for Neurosciences, Japan.
Kayanuma
K
K
Ohtani
S
S
Sugiura
H
H
Kotaki
H
H
Tsubaki
T
T
D000818:Animals; D000831:Animals, Newborn; D002614:Chelating Agents / Q000494:pharmacology; D007464:Clioquinol / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis*; D005728:Ganglia, Sympathetic / Q000187:drug effects* / Q000378:metabolism; D006912:Hydroxyquinolines / Q000494:pharmacology*; D007930:Leucine / Q000378:metabolism; D008297:Male; D051379:Mice; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009924:Organ Culture Techniques; D014176:Protein Biosynthesis; D012313:RNA / Q000096:biosynthesis*; D051381:Rats; D011919:Rats, Inbred Strains; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D014529:Uridine / Q000378:metabolism
D002614:Chelating Agents; D006912:Hydroxyquinolines; D009414:Nerve Growth Factors; D012710:Serum Albumin, Bovine; D012313:RNA; D007464:Clioquinol; D004247:DNA; D007930:Leucine; D013936:Thymidine; D014529:Uridine