Glial-mediated neuroprotection: evidence for the protective role of the NO-cGMP pathway via neuron-glial communication in the peripheral nervous system.
The NO-cGMP pathway has emerged as a neuroprotective signaling system involved in communication between neurons and glia. We have previously shown that axotomy or nerve growth factor (NGF)-deprivation of dorsal root ganglion (DRG) neurons leads to increased production of NO and at the same time an increase in cGMP production in their satellite glia cells. Blockade of NO or its receptor, the cGMP synthesizing enzyme soluble guanylate cyclase (sGC), results in apoptosis of neurons and glia. We now show that co-culture of neonatal DRG neurons with either Schwann cells pre-treated with an NO donor or a membrane-permeant cGMP analogue; or neurons maintained in the medium from Schwann cell cultures treated in the same way, prevents neuronal apoptosis. Both NO donor and cGMP treatment of Schwann cells results in synthesis of NGF and NT3. Furthermore, if the Schwann cells are previously infected with adenoviral vectors expressing a dominant negative sGC mutant transgene, treatment of these Schwann cells with an NO donor now fails to prevent neuronal apoptosis. Schwann cells treated in this way also fail to express neither cGMP nor neurotrophins. These findings suggest NO-sGC-cGMP-mediated NGF and NT3 synthesis by Schwann cells protect neurons.
Thippeswamy
Thimmasettappa
T
Department of Veterinary Preclinical Science, University of Liverpool, Liverpool, United Kingdom. tswamy@liv.ac.uk
McKay
Jennifer S
JS
Morris
Richard
R
Quinn
John
J
Wong
Liang-Fong
LF
Murphy
David
D
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D019610:Cytoprotection; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006162:Guanylate Cyclase; D009410:Nerve Degeneration / Q000378:metabolism / Q000517:prevention & control; D009457:Neuroglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D017933:Peripheral Nervous System / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020800:Receptor, Nerve Growth Factor / Q000187:drug effects / Q000378:metabolism; D020812:Receptor, trkC / Q000187:drug effects / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D000071756:Soluble Guanylyl Cyclase; D014162:Transfection
D017077:Culture Media, Conditioned; D018696:Neuroprotective Agents; D020030:Nitric Oxide Donors; D020800:Receptor, Nerve Growth Factor; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D020812:Receptor, trkC; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP