Mechanism of systemically injected interferon-alpha impeding monoamine biosynthesis in rats: role of nitric oxide as a signal crossing the blood-brain barrier

The serious and characteristic side effects of interferon-alpha (IFN-alpha) therapy on the central nervous system, resulting in such problems as affective disorders or parkinsonism, have led us to investigate the biochemical mechanism of the effects of IFN-alpha on the monoaminergic neurotransmitter system using an animal model (rats). We first examined the concentrations of tetrahydrobiopterin (BH4) and monoamines in several regions of the brain after the intramuscular injection of IFN-alpha into rats; the levels of BH4 and dopamine significantly decreased in the amygdala and raphe areas as compared with those of the controls. Based on these results, we further examined the concentrations of BH4 and nitrite (NO2-) plus nitrate (NO3-), metabolites of nitric oxide (NO), in the amygdala and raphe areas after the intramuscular injection of IFN-alpha; the concentrations of both BH4 and NO2-+NO3- significantly decreased as compared with the control. Furthermore, the addition of N-G-monomethyl L-arginine, an inhibitor of NO synthase, after the injection of IFN-alpha restored the decreased levels of both NO2-+NO3- and BH4 to control levels. As a result, nitric oxide induced by the intramuscular injection of IFN-a was found to cross the blood-brain barrier and suppress both tetrahydrobiopterin biosynthesis and dopamine production in the amygdala and raphe areas. (C) 2003 Elsevier Science B.V. All rights reserved.