Role of nitric oxide as mediator of nerve injury in inflammatory neuropathies.
Different lines of evidence suggest that nitric oxide (NO) plays a key role in the pathogenesis of inflammatory neuropathies; however, it is still unclear which structures in the peripheral nerve are the primary targets of NO-mediated nerve injury. To address this issue, we determined the expression of NO metabolites in sural nerve biopsies and in cerebrospinal fluid from patients with inflammatory neuropathies and studied the pathologic effects of NO in an in vitro model of myelinated Schwann cell-neuron cocultures. In cerebrospinal fluid samples, nitrite levels remained unaltered; however, nitrotyrosine, a marker for peroxynitrite formation, could be identified in nerve biopsies from patients with inflammatory neuropathies. In an in vitro model of Schwann cell neuron cocultures, high concentrations of NO induced robust demyelination, which was the result of NO-mediated axonal injury, whereas Schwann cell viability remained unaffected. These findings suggest that in contrast to Schwann cells, sensory neurons are the primary target of NO-mediated cytotoxicity and the loss of myelin is the result of selective damage to axons rather than a direct harmful effect to Schwann cells. Our findings imply that NO contributes to the pathologic changes seen in the inflamed peripheral nervous system, which is characterized by the features of axonal injury and subsequent myelin degradation, previously described as Wallerian-like degeneration.
Lehmann
Helmar C
HC
Department of Neurology, Heinrich-Heine-University, Düsseldorf, Germany. helmar.lehmann@uni-duesseldorf.de
Köhne
Angelika
A
Meyer zu Hörste
Gerd
G
Dehmel
Thomas
T
Kiehl
Olivia
O
Hartung
Hans-Peter
HP
Kastenbauer
Stefan
S
Kieseier
Bernd C
BC
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D016166:Free Radical Scavengers / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000737:chemistry; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000633:toxicity; D009603:Nitroso Compounds / Q000633:toxicity; D011129:Polyradiculoneuropathy / Q000201:enzymology* / Q000473:pathology*; D051381:Rats; D012583:Schwann Cells / Q000737:chemistry; D013497:Sural Nerve / Q000378:metabolism* / Q000473:pathology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000134:cerebrospinal fluid
D017077:Culture Media, Conditioned; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D007093:Imidazoles; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine