Niacinamide blocks 3-acetylpyridine toxicity of cerebellar granule cells in vitro.
3-Acetylpyridine (3AP) is a potent neurotoxin when administered to laboratory animals. However, its neurotoxic effects have not been investigated extensively in vitro. Cultured cerebellar granule cells are killed by concentrations of 3AP of 0.1-1 mM (ED50 = 220 microM) but not by its 2-acetyl and 4-acetyl analogues. The toxicity of 3AP is enhanced by preexposure to subtoxic concentrations of N-methyl-D-aspartate (NMDA) and is unaffected by the NMDA receptor antagonists MK-801 or APV, as well as by deprenyl, mazindol, or tetrahydrofolic acid. However, 3AP toxicity is completely blocked by preincubating cerebellar granule cells with low concentrations of niacinamide. These data lead us to suggest that 3AP toxicity is due to the substitution of 3AP for niacinamide in the formation of niacinamide adenine dinucleotides (NAD(P)).
Section on Molecular Pharmacology, National Institute of Mental Health, Bethesda, MD 20892.
M
M
Weller
A M
AM
Marini
S M
SM
Paul
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates / Q000633:toxicity; D018698:Glutamic Acid; D008454:Mazindol / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D009536:Niacinamide / Q000494:pharmacology*; D011725:Pyridines / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012642:Selegiline / Q000494:pharmacology; D013763:Tetrahydrofolates / Q000494:pharmacology
D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D011725:Pyridines; D013763:Tetrahydrofolates; C010835:3-acetylpyridine; D009536:Niacinamide; D012642:Selegiline; D018698:Glutamic Acid; C030371:5,6,7,8-tetrahydrofolic acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D008454:Mazindol