Nitric oxide and peroxynitrite signalling triggers homocysteine-mediated apoptosis in trigeminal sensory neurons in vitro.
The neurotoxic actions of homocysteine on central nervous system neurons have been well established, yet its effects on the neurons of the peripheral nervous system remain largely unknown. We analysed the consequences of homocysteine exposure for the in vitro survival of embryonic and postnatal murine trigeminal sensory neurons from E14 to P1, and also quantified the effects of homocysteine exposure on neurite outgrowth. We discovered that homocysteine was toxic to these neurons when they were grown with NGF, or, in the case of P1 trigeminal neurons, with CNTF. Cell death induced by homocysteine was blocked using caspase inhibitors indicating that this cell loss was apoptotic. In addition, we demonstrated that homocysteine toxicity was mediated through the actions of the NMDA receptor, nitric oxide and peroxynitrite. We found that homocysteine had no effect on neurite outgrowth. Taken together our data show that homocysteine induces apoptosis in trigeminal sensory neurons via a nitric oxide-dependent mechanism. These data represent the first demonstration that homocysteine is toxic to a population of cranial sensory neurons and elucidate key components of the signalling pathway engaged to bring this about. These findings are of importance to our understanding of homocysteine's influence on neurodevelopment and on peripheral neuropathies.
Williams
Hannah M
HM
School of Biology, Bute Medical Buildings, St. Andrew's University, St. Mary's Quad, St. Andrews, Fife KY16 9TS, UK.
Lippok
Hannah
H
Doherty
G H
GH
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006710:Homocysteine / Q000494:pharmacology*; D007211:Indoles; D051379:Mice; D008810:Mice, Inbred C57BL; D020932:Nerve Growth Factor / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D012668:Trigeminal Ganglion / Q000166:cytology*
D000590:Amino Acid Chloromethyl Ketones; D020934:Ciliary Neurotrophic Factor; D004791:Enzyme Inhibitors; D007211:Indoles; D018696:Neuroprotective Agents; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D006710:Homocysteine; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C007293:DAPI; D020932:Nerve Growth Factor