SUSTAINED PHARMACOLOGICAL INHIBITION OF NITRIC-OXIDE SYNTHASE DOES NOT AFFECT THE SURVIVAL OF INTRASTRIATAL RAT FETAL MESENCEPHALIC TRANSPLANTS

The objective of the present study was to investigate the potential ro le of the free radical nitric oxide (NO) in the development of fetal r at mesencephalic neurons grafted in a 6-hydroxydopamine (6-OHDA) lesio ned rat model of Parkinson's disease. First, using nitric oxide syntha se (NOS)-immunocytochemistry and reduced nicotinamide adenine dinucleo tide phosphate-diaphorase (NADPH-d) histochemistry, we investigated th e presence of the neuronal isoform of NOS (nNOS) in intrastriatal mese ncephalic grafts. During the course of the experiment (16 weeks) an in crease in the staining intensity and the number of nNOS/NADPH-d positi ve cells within the grafts was observed, as well as a gradual maturati on of dopaminergic neurons. In addition, within both the host striatal and grafted mesencephalic tissue, a NO-dependent accumulation of cycl ic guanosine monophosphate (cGMP) was detected, indicating the presenc e of guanylate cyclase, i.e., the target-enzyme for NO. Secondly, to d etermine the impact of NO on the survival of grafted dopaminergic neur ons, 6-OHDA lesioned rats received mesencephalic grafts and were subse quently treated with the competitive NOS-inhibitor N-omega-nitro-L-arg inine methylester (L-NAME). After chronic treatment for 4 weeks, tyros ine hydroxylase immunocytochemistry revealed no apparent differences b etween the survival of grafted dopaminergic neurons in control-or L-NA ME treated animals, respectively. As the maturation of grafted dopamin ergic neurons coincides with a gradual increase in the expression of n NOS within the graft and since dopaminergic cell numbers are not chang ed upon administration of L-NAME, it is concluded that endogenously pr oduced and potentially toxic NO does not affect the survival of grafte d fetal dopaminergic neurons. (C) 1998 Elsevier Science B.V.