The immunosuppressant drug FK506 is a potent trophic agent for human fetal neurons.
FK506 is a potent immunosuppressive drug used to prevent rejection post-organ transplantation. It is activated upon binding to members of the immunophilin chaperone proteins (e.g. FK506-binding protein, FKBP 12). Studies of the distribution of FKBP12 reveal that it is enriched in neurons throughout the central and peripheral nervous system. In vitro, FK506 augments neurite outgrowth; in animal models, it enhances axonal re-growth and functional recovery following lesioning. The effects on human neurons and glial cells have not yet been studied. Using immunofluorescent laser scanning confocal microscopy we demonstrate that in human fetal brain cultures FK506 significantly increases cell numbers, including neurons, and the expression of the neuronal marker MAP-2. This suggests that the drug has a potent effect in stimulating neuronal survival, proliferation and dendrite extension. Interestingly, in combination with brain-derived neurotrophic factor, FK506 induces a prominent decrease in glial fibrillary acidic protein expression, which indicates an inhibitory effect on astrogliosis in vitro. Our data support a potential role for FK506 and its analogues in the treatment of neurodegenerative disorders.
Avramut
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Department of Pathology, Division of Neuropathology, University of Pittsburgh School of Medicine, S 406 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261, USA.
Zeevi
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Achim
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D001253:Astrocytes / Q000166:cytology / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D005333:Fetus / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D016559:Tacrolimus / Q000494:pharmacology*
D019208:Brain-Derived Neurotrophic Factor; D007166:Immunosuppressive Agents; D016559:Tacrolimus