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 role of the free radical nitric oxide (NO) in the development of fetal rat mesencephalic neurons grafted in a 6-hydroxydopamine (6-OHDA) lesioned rat model of Parkinson's disease. First, using nitric oxide synthase (NOS)-immunocytochemistry and reduced nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry, we investigated the presence of the neuronal isoform of NOS (nNOS) in intrastriatal mesencephalic grafts. During the course of the experiment (16 weeks) an increase in the staining intensity and the number of nNOS/NADPH-d positive cells within the grafts was observed, as well as a gradual maturation of dopaminergic neurons. In addition, within both the host striatal and grafted mesencephalic tissue, a NO-dependent accumulation of cyclic guanosine monophosphate (cGMP) was detected, indicating the presence of guanylate cyclase, i.e., the target-enzyme for NO. Secondly, to determine the impact of NO on the survival of grafted dopaminergic neurons, 6-OHDA lesioned rats received mesencephalic grafts and were subsequently treated with the competitive NOS-inhibitor Nomega-nitro-l-arginine methylester (l-NAME). After chronic treatment for 4 weeks, tyrosine hydroxylase immunocytochemistry revealed no apparent differences between the survival of grafted dopaminergic neurons in control- or l-NAME treated animals, respectively. As the maturation of grafted dopaminergic neurons coincides with a gradual increase in the expression of nNOS within the graft and since dopaminergic cell numbers are not changed upon administration of l-NAME, it is concluded that endogenously produced and potentially toxic NO does not affect the survival of grafted fetal dopaminergic neurons.
Van Muiswinkel
F L
FL
Graduate School Neurosciences Amsterdam, Research Institute Neurosciences, Vrije Universiteit, Faculty of Medicine, Department of Pharmacology, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. flv.muiswinkel.pharm@med.vu.nl
Drukarch
B
B
Steinbusch
H W
HW
De Vente
J
J
D000818:Animals; D016380:Brain Tissue Transplantation / Q000502:physiology*; D006152:Cyclic GMP / Q000378:metabolism; D004298:Dopamine / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006085:Graft Survival / Q000187:drug effects*; D006162:Guanylate Cyclase / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008636:Mesencephalon / Q000637:transplantation*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D017072:Neostriatum / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D016627:Oxidopamine; D051381:Rats; D017208:Rats, Wistar; D013238:Stereotaxic Techniques; D013563:Sympathectomy, Chemical; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D004791:Enzyme Inhibitors; D016627:Oxidopamine; D019001:Nitric Oxide Synthase; D014446:Tyrosine 3-Monooxygenase; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester; D004298:Dopamine