title: A novel target of action of minocycline in NGF-induced neurite outgrowth in PC12 cells: translation initiation [corrected] factor eIF4AI.
abstract: BACKGROUND
  Minocycline, a second-generation tetracycline antibiotic, has potential activity for the treatment of several neurodegenerative and psychiatric disorders. However, its mechanisms of action remain to be determined.
  
  
  RESULTS
  We found that minocycline, but not tetracycline, significantly potentiated nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells, in a concentration dependent manner. Furthermore, we found that the endoplasmic reticulum protein inositol 1,4,5-triphosphate (IP3) receptors and several common signaling molecules (PLC-γ, PI3K, Akt, p38 MAPK, c-Jun N-terminal kinase (JNK), mammalian target of rapamycin (mTOR), and Ras/Raf/ERK/MAPK pathways) might be involved in the active mechanism of minocycline. Moreover, we found that a marked increase of the eukaryotic translation initiation factor eIF4AI protein by minocycline, but not tetracycline, might be involved in the active mechanism for NGF-induced neurite outgrowth.
  
  
  CONCLUSIONS
  These findings suggest that eIF4AI might play a role in the novel mechanism of minocycline. Therefore, agents that can increase eIF4AI protein would be novel therapeutic drugs for certain neurodegenerative and psychiatric diseases.
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. hashimoto@faculty.chiba-u.jp
authors.forename: Kenji
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Tamaki
authors.initials: T
authors.lastname: Ishima
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology; D004357:Drug Synergism; D039601:Eukaryotic Initiation Factor-4A / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D047028:Macrocyclic Compounds / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008911:Minocycline / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects* / Q000502:physiology; D010080:Oxazoles / Q000494:pharmacology; D016716:PC12 Cells; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013754:Tetracyclines / Q000494:pharmacology; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D053496:Inositol 1,4,5-Trisphosphate Receptors; D047028:Macrocyclic Compounds; D008869:Microtubule-Associated Proteins; D010080:Oxazoles; D013754:Tetracyclines; C511704:xestospongin C; D020932:Nerve Growth Factor; D048490:raf Kinases; D020928:Mitogen-Activated Protein Kinases; D039601:Eukaryotic Initiation Factor-4A; D018631:ras Proteins; D008911:Minocycline; D004318:Doxycycline