title: p75-mediated neuroprotection by NGF against glutamate cytotoxicity in cortical cultures.
abstract: Accumulating evidence suggests that the neurotrophin receptors, Trks and p75, play distinct roles in regulating cells survival and death, with Trks important for cell survival, and p75 acting to induce cell death. Here, we provide evidence that, in neuronal cultures from rat cerebral cortex, nerve growth factor (NGF) exerts neuroprotective actions via p75. Incubating cultures with NGF for 1-24 h protected cortical neurons from delayed cytotoxicity induced by brief exposure to glutamate. Delayed neurotoxicity induced by a calcium ionophore, ionomycin, or nitric oxide (NO) donors such as S-nitrosocysteine (SNOC) and 3-morpholinosydnonimine (SIN-1), was also attenuated by pretreatment with NGF. RT-PCR analysis revealed the presence of p75 and trkB transcripts in cortical cultures, but did not detect transcripts of trkA, a high-affinity receptor for NGF. Brain-derived neurotrophic factor (BDNF), but not NGF, induced tyrosine phosphorylation of Trks, indicating that NGF does not activate Trks in cortical neurons. Concurrent application of anti-p75 neutralizing antibody markedly reduced the neuroprotective effect of NGF, but resulted in only a modest reduction of that of BDNF. BDNF-induced neuroprotection, but not NGF-induced neuroprotection, was inhibited by a protein synthesis inhibitor cycloheximide. Distinct signaling pathways mobilized by NGF and BDNF were also revealed in that NGF but not BDNF stimulated significant production of ceramides, whereas BDNF but not NGF caused persistent activation of mitogen-activated protein kinases. These results indicate that, although NGF and BDNF both protect cortical neurons from excitotoxicity, the mechanisms involved in their effects are totally different. The present results are, to our knowledge, the first to demonstrate the principal involvement of p75 in cytoprotective actions of neurotrophins.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kume
authors.forename: H
authors.initials: H
authors.lastname: Nishikawa
authors.forename: H
authors.initials: H
authors.lastname: Tomioka
authors.forename: H
authors.initials: H
authors.lastname: Katsuki
authors.forename: A
authors.initials: A
authors.lastname: Akaike
authors.forename: S
authors.initials: S
authors.lastname: Kaneko
authors.forename: T
authors.initials: T
authors.lastname: Maeda
authors.forename: T
authors.initials: T
authors.lastname: Kihara
authors.forename: S
authors.initials: S
authors.lastname: Shimohama
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D002518:Ceramides / Q000096:biosynthesis / Q000494:pharmacology; D002540:Cerebral Cortex / Q000166:cytology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005333:Fetus / Q000166:cytology; D018698:Glutamic Acid / Q000633:toxicity*; D007476:Ionophores / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016202:N-Methylaspartate / Q000494:pharmacology; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009474:Neurons / Q000737:chemistry* / Q000166:cytology / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D016716:PC12 Cells; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000502:physiology*; D020917:Receptor, trkA / Q000502:physiology; D020813:Receptor, trkB / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D015220:Calcium Channels; D002518:Ceramides; D018690:Excitatory Amino Acid Agonists; D007476:Ionophores; D018696:Neuroprotective Agents; D020030:Nitric Oxide Donors; D020800:Receptor, Nerve Growth Factor; D018698:Glutamic Acid; D016202:N-Methylaspartate; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D020813:Receptor, trkB; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium