Neuroimmunophilin ligand enhances neurite outgrowth and effect of fetal dopamine transplants.
Neuroimmunophilin ligands have been shown to enhance neurite outgrowth in several neuronal systems in culture, including primary dopaminergic neurons from fetal ventral mesencephalon. We investigated the ability of neuroimmunophilin ligands to enhance outgrowth of transplanted fetal dopamine neurons in vivo. Rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal dopamine system were transplanted with rat embryonic day 14 ventral mesencephalon into the striatum, then treated orally with a neuroimmunophilin ligand (15mg/kg) or vehicle once per day for 14 days. All transplanted animals regained dopamine function over a 10 week behavioral test period, as indicated by decrease and reversal of amphetamine-induced rotation. In addition, neuroimmunophilin ligand-treated animals showed a more pronounced motor response during the first 10min after amphetamine injection, possibly reflecting increased striatal reinnervation or increased functional capacity. At post-mortem analyses, neuroimmunophilin ligand-treated rats showed a significantly higher density of tyrosine hydroxylase-positive fibers reinnervating the lesioned striatum, both immediately surrounding the transplant (92% of unlesioned density in neuroimmunophilin-treated rats vs 67% of unlesioned levels in vehicle-treated rats) and at some distance from the transplant/host interface. The number of tyrosine hydroxylase-positive cells within the transplants was not different between groups. This study demonstrates that short-term oral administration of a neuroimmunophilin ligand can enhance neurite outgrowth from fetal dopamine neuronal transplants.
Costantini
L C
LC
Neuroregeneration Laboratory, Harvard Medical School/McLean Hospital, Belmont, MA 02178, USA.
Isacson
O
O
D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D016332:Fetal Tissue Transplantation; D008024:Ligands; D008636:Mesencephalon / Q000196:embryology* / Q000378:metabolism* / Q000502:physiology; D009416:Nerve Regeneration / Q000502:physiology; D016501:Neurites / Q000502:physiology*; D011725:Pyridines / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D008024:Ligands; D011725:Pyridines; C108850:V 10367; D004298:Dopamine