Inhibition of neuronal nitric oxide synthase results in neurodegenerative changes in the axotomised dorsal root ganglion neurons: evidence for a neuroprotective role of nitric oxide in vivo.
In axotomised adult rat dorsal root ganglion (DRG), many neurons show a marked increase in expression of neuronal nitric oxide synthase (nNOS). It has been established that NO functions as a neuron-glial signalling molecule by generating cGMP in glia cells that surround the neuron in DRG. Furthermore, in cultures of dissociated DRG deprived of nerve growth factor, many neurons expressed nNOS and cGMP and subsequently died if either enzyme's activity was inhibited suggesting that NO-cGMP pathway could be neuroprotective in stressed DRG neurons. This has now been tested in vivo. It was found, 10 days after sciatic axotomy that nNOS was expressed in 36% of DRG neurons in the L5 and L6 ganglia giving rise to the damaged nerve, compared with 6% in contralateral ganglia. Almost all nNOS neurons and 24% of non-nNOS neurons expressed c-Jun in their nuclei. Ten days following axotomy, treatment with the relatively selective nNOS-blocker, 1-(2-trifluoromethylphenyl) imidazole (TRIM), caused morphology changes in approximately 50% of neurons that consisted of vacuolations, blebbing and highly irregular cell boundaries. Sham operated, TRIM treated, nerve-sectioned, vehicle treated, and controls did not show these changes. These observations further support the view that NO could be neuroprotective in some injured/stressed primary sensory neurons.
Thippeswamy
T
T
Department of Veterinary Preclinical Sciences, University of Liverpool, Veterinary Science Building, Crown Street, Liverpool, L69 7ZJ, UK. tswamy@loverpool.ac.uk
Jain
R K
RK
Mumtaz
N
N
Morris
R
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D019771:Axotomy / Q000009:adverse effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D006152:Cyclic GMP / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D009410:Nerve Degeneration / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000172:deficiency*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013312:Stress, Physiological / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology
D004791:Enzyme Inhibitors; D007093:Imidazoles; D018696:Neuroprotective Agents; D016755:Proto-Oncogene Proteins c-jun; C098186:1-(2-trifluoromethylphenyl)imidazole; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP