Regeneration of dopaminergic function in 6-hydroxydopamine-lesioned rats by neuroimmunophilin ligand treatment.

C. Zhang, J. P. Steiner, G. S. Hamilton, T. P. Hicks, M. O. Poulter

Research output: Contribution to journalArticle

Abstract

Nonimmunosuppressant immunophilin ligands have been found previously to stimulate neurite growth in culture and to promote regeneration of peripheral and central nerve fibers in vivo. To further characterize the effectiveness of these ligands, we have investigated the effect of the immunophilin ligand GPI-1046 in 6-hydroxydopamine (6-OHDA)-lesioned rats. In unlesioned rats, tetanic stimulation of the white matter induced long-term potentiation (LTP) of corticostriatal synaptic transmission as indicated by a 40-100% increase in the field potential amplitudes recorded in striatal brain slices. Unilateral microinjection of 6-OHDA into the substantia nigra resulted in a loss of corticostriatal LTP and in significant abnormality of motor behavior as assessed by amphetamine-induced ipsilateral rotations. Daily treatment of 6-OHDA-lesioned rats with GPI-1046 (10 mg/kg, s.c.) for 1 week reduced amphetamine-induced rotations by 75% and greatly restored the striatal tyrosine hydroxylase immunostaining. In addition, GPI-1046 almost completely restored corticostriatal LTP in 6-OHDA-lesioned animals. LTP in normal animals and that restored by GPI-1046 in lesioned animals were both blocked by the NMDA receptor antagonist APV, suggesting mediation by NMDA receptors. Both LTPs were sensitive to dopamine (DA) receptor antagonists. The nonselective DA receptor antagonist chlorpromazine and the selective D1-D5 receptor antagonist SCH23390 reduced the LTP by 90%. These results demonstrate that the immunophilin ligand GPI-1046 can reverse the abnormalities in the substantia nigra-striatal dopaminergic system that are caused by 6-OHDA, thus providing a potential therapeutic agent for Parkinson's disease.

Original languageEnglish (US)
JournalJournal of Neuroscience
Volume21
Issue number15
StatePublished - 2001
Externally publishedYes

Fingerprint

Oxidopamine
Long-Term Potentiation
Regeneration
Immunophilins
Ligands
Corpus Striatum
Dopamine Antagonists
Substantia Nigra
Amphetamine
N-Methyl-D-Aspartate Receptors
Therapeutics
Chlorpromazine
Tyrosine 3-Monooxygenase
Microinjections
Neurites
Peripheral Nerves
Nerve Fibers
Synaptic Transmission
Parkinson Disease
GPI 1046

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Zhang, C., Steiner, J. P., Hamilton, G. S., Hicks, T. P., & Poulter, M. O. (2001). Regeneration of dopaminergic function in 6-hydroxydopamine-lesioned rats by neuroimmunophilin ligand treatment. Journal of Neuroscience, 21(15).

Regeneration of dopaminergic function in 6-hydroxydopamine-lesioned rats by neuroimmunophilin ligand treatment. / Zhang, C.; Steiner, J. P.; Hamilton, G. S.; Hicks, T. P.; Poulter, M. O.

In: Journal of Neuroscience, Vol. 21, No. 15, 2001.

Research output: Contribution to journalArticle

Zhang, C. ; Steiner, J. P. ; Hamilton, G. S. ; Hicks, T. P. ; Poulter, M. O. / Regeneration of dopaminergic function in 6-hydroxydopamine-lesioned rats by neuroimmunophilin ligand treatment. In: Journal of Neuroscience. 2001 ; Vol. 21, No. 15.
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