Rapamycin, but not FK506 and GPI-1046, increases neurite outgrowth in PC12 cells by inhibiting cell cycle progression

• Published in: Neuropharmacology Vol. 39; no. 10; pp. 1913 - 1919
• Main Authors: Parker, Eric M, Monopoli, Angela, Ongini, Ennio, Lozza, Gianluca, Babij, Carol M
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.09.2000; Elsevier
• Subjects: Animals; Biological and medical sciences; Brain Ischemia - pathology; Brain Ischemia - prevention & control; Cell Cycle - drug effects; Cell Cycle - physiology; Ciclopirox; Dose-Response Relationship, Drug; FK506; Flavonoids - pharmacology; GPI-1046; Growth factor; Growth Inhibitors - pharmacology; Immunophilin; Male; Medical sciences; Nerve Growth Factor - pharmacology; Neurites - drug effects; Neurites - physiology; Neuropharmacology; Neuroprotective agent; Neurotrophic; PC12 Cells; Pharmacology. Drug treatments; Piperidines - pharmacology; Pyridones - pharmacology; Pyrrolidines - pharmacology; Rapamycin; Rats; Rats, Sprague-Dawley; Sirolimus - pharmacology; Tacrolimus - pharmacology; Rapamycin; FK506; Neurotrophic; GPI-1046; Immunophilin; Growth factor; Neurite; Intravenous administration; Rat; Sirolimus; Growth; Central nervous system; Cardiovascular disease; Nerve growth factor; Neurotrophism; Vascular disease; Ischemia; Cell cycle; Established cell line; Mechanism of action; Cerebrovascular disease; Nervous system diseases; Rodentia; Neuroprotective agent; In vitro; Macrolide; Biological activity; Cerebral disorder; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Polypeptide; Animal; Central nervous system disease; Inhibitor; Immunosuppressive agent; Brain (vertebrata)
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/S0028-3908(00)00028-9

Immunophilin ligands such as rapamycin, FK506 and GPI-1046 have been reported to increase neurite outgrowth in vitro and to have neuroprotective activity in vitro and in vivo. In this study, however, FK506 and GPI-1046 (0.1–1000 nM) had little effect on neurite outgrowth in PC12 cells in either the presence or absence of nerve growth factor. In contrast, rapamycin markedly increased neurite outgrowth in PC12 cells in the presence of a low concentration of nerve growth factor (EC 50=10 nM). Unlike FK506 and GPI-1046, rapamycin is an inhibitor of cell cycle progression. Other cell cycle inhibitors such as ciclopirox and flavopiridol also increased neurite outgrowth in PC12 cells in the presence of a low concentration of nerve growth factor (EC 50=250 nM and 100 nM, respectively). The neuroprotective effects of FK506, rapamycin and GPI-1046 were also tested in a rodent model of permanent focal cerebral ischemia. FK506 and rapamycin decreased infarct volume by 40% and 37%, respectively, whereas GPI-1046 was ineffective. These data do not support the previous suggestion that FK506 and GPI-1046 increase neurite outgrowth of PC12 cells in vitro. Rapamycin increases neurite outgrowth of PC12 cells, an effect that can be ascribed to its ability to inhibit cell cycle progression. The neuroprotective effect of FK506 and rapamycin against cerebral ischemia is probably not due to differentiation of neuronal precursors or stimulation of neuronal regeneration.