Differential effects of immunophilin-ligands (FK506 and V-10,367) on survival and regeneration of rat retinal ganglion cells in vitro and after optic nerve crush in vivo.
Immunophilins belong to the large family of peptidyl-prolyl-cis-trans-isomerases known to be involved in many cellular processes (e.g., protein trafficking and transcriptional regulation). Beside the widespread therapeutic use of ligands of immunophilins as immunosuppressants, it has been shown that some of these compounds such as FK506 and V-10,367 may mediate neuroprotection and improve axonal regeneration following damage to peripheral nerve fibers. Here, we have analyzed the effects of these two compounds on neurite outgrowth of retinal explants in vitro and on axonal regeneration of retinal ganglion cells, a population of central intrinsic neurons, ten days following optic nerve crush in vivo. FK506 enhanced neurite outgrowth/regrowth in vitro in a dose dependent manner up to 135% (control = 100%), while V-10,367 was more effective (up to 168%). In vivo, intravitreal V-10,367 and FK506 significantly reduced the number of dying retinal ganglion cells as demonstrated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Local application of FK506 into the vitreous body, but not V-10,367, immediately provided after the optic nerve crush induced the elongation of regenerating fibers across the lesion site for around 1.2 mm. Our data provide evidence that the ligands of the FK506-binding proteins FK506 and V-10,367 protect (otherwise dying) retinal ganglion cells from optic nerve crush-induced cell death, promote neurite outgrowth in vitro and that locally applied FK506 enhances the sprouting of axotomized central intrinsic neurons such as retinal ganglion cells in vivo after optic nerve crush.
Rosenstiel
Philip
P
Institute of Anatomy, University of Kiel, Kiel, Germany.
Schramm
Peter
P
Isenmann
Stefan
S
Brecht
Stefan
S
Eickmeier
Christian
C
Bürger
Erich
E
Herdegen
Thomas
T
Sievers
Jobst
J
Lucius
Ralph
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D003511:Cyclohexanols / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019922:GAP-43 Protein / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000187:drug effects; D016501:Neurites / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020221:Optic Nerve Injuries / Q000473:pathology / Q000503:physiopathology; D011714:Pyrans / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D016559:Tacrolimus / Q000008:administration & dosage / Q000494:pharmacology*
D003511:Cyclohexanols; D019922:GAP-43 Protein; D018696:Neuroprotective Agents; D011714:Pyrans; D011725:Pyridines; C108850:V 10367; C066205:immunophilin ligand 506BD; D016559:Tacrolimus