6-Aminonicotinamide (6-AN) is a nicotinic acid (vitamin B3) antagonist which, when administered to immature animals, has a profound influence on brain development. To explore the biochemical mechanisms which underlie these actions, we evaluated effects of 6-aminonicotinamide on ornithine decarboxylase, an enzyme involved in cellular replication and differentiation. The cerebellum of the neonatal rat was chosen for study because it represents a brain region which undergoes major maturational events postnatally. When given to neonatal rats, 6-aminonicotinamide (10 mg/kg, i.p., on days 1, 3, 5 and 7) caused a prompt and persistent inhibition of the enzyme well in advance of adverse effects on tissue weight or on general growth. In addition, the ability of the cerebellum to respond to trophic stimulation by a β-adrenergic agonist, isoproterenol, was attenuated markedly. Assessment of cerebellar morphology indicated an early adverse effect of 6-AN on granule cell division, resulting in eventual disruption of the characteristic laminar structure of this brain region. These data support the view that reduced ornithine decarboxylase activity and impairment of its reactivity to growth stimuli participate in the toxic effects of 6-aminonicotinamide on brain development.
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