NGF acts via p75 low-affinity neurotrophin receptor and calpain inhibition to reduce UV neurotoxicity.
The relative roles of the high-affinity nerve growth factor (NGF) receptor, TrkA, and low-affinity p75 neurotrophin receptor (p75NTR) in neuronal survival are an active research area. We reported previously that UV treatment induces a calpain-dependent, delayed neuronal death. We show here that NGF inhibits this UV-induced cortical neuron death. Interestingly, NGF neuroprotection requires p75NTR. Because it has been reported that NGF binding to p75NTR leads to ceramide generation, we evaluated whether ceramide was also neuroprotective. We found that ceramide also inhibits UV toxicity, and that the actions of ceramide and NGF were not additive. Moreover, cycloheximide inhibited ceramide and NGF neuroprotection, suggesting that their actions require new protein synthesis. Consistent with this possibility, we found that NGF activates the expression of genes such as calbindin. Lastly, we explored the role of calpain in NGF actions. NGF and ceramide both reduced the level of calpain activation after UV treatment. This NGF effect was p75NTR dependent. Overall, we interpret these results as consistent with an NGF neuroprotective pathway wherein p75NTR activation leads sequentially to ceramide generation, new protein synthesis, and inhibition of calpain activation. Overall, these results provide insight into a p75NTR dependent pathway of NGF neuroprotection.
McCollum
Adrian T
AT
Department of Physiology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA.
Estus
Steven
S
D000818:Animals; D064026:Calbindins; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D002478:Cells, Cultured; D002518:Ceramides / Q000037:antagonists & inhibitors / Q000378:metabolism; D004347:Drug Interactions / Q000502:physiology; D005333:Fetus; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D020932:Nerve Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000187:drug effects / Q000378:metabolism*; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects
D064026:Calbindins; D002518:Ceramides; D018696:Neuroprotective Agents; D011500:Protein Synthesis Inhibitors; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D064030:S100 Calcium Binding Protein G; D020932:Nerve Growth Factor; D002154:Calpain