Effects of repeated cyclosporin A administration on iminodipropionitrile-induced dyskinesia and TRE-/CRE-binding activities in rat brain.
To clarify the involvement of immunophilin ligands in the pathogenesis and pathophysiology of dyskinesia, we examined the effects of repeated administration of cyclosporin A (CsA) on rat dyskinesia induced by repeated injection of iminodipropionitrile (IDPN 100 mg/kg, i.p., for 7 days). The addition of CsA treatment (5 mg/kg, s.c., 1 h before each IDPN injection) exacerbated IDPN-induced dyskinesia. In the group treated with both CsA and IDPN, the concentration of dopamine was significantly increased in the striatum and nucleus accumbens compared with the group treated with IDPN alone. Furthermore, in the electrophoretic mobility shift assay, the injection of CsA + IDPN increased binding activities of transcription factors to the TPA (12-O-tetradecanoylphorbol-13-acetate)-responsive element (TRE) and to the cAMP response element (CRE) in the striatum and nucleus accumbens, compared with those in rats treated with IDPN alone. The levels of D1-receptor mRNA in the striatum were significantly decreased in the IDPN-treated rats but were at the control level in the rats given CsA + IDPN. These findings suggest that the behavioral aggravation of the IDPN-induced dyskinesia caused by CsA administration may be due to the acceleration of the pre- and post-synaptic dopaminegic systems via activation of transcription factors which bind upstream to tyrosine hydroxylase and D1-receptor genes, and that the immunophilin binding agents such as CsA are involved in this aggravated dyskinesia.
Iida
K
K
Department of Neuroscience, Institute of Molecular and Cellular Medicine, Okayama University Medical School, Japan.
Iwata
E
E
Asanuma
M
M
Asanuma
S N
SN
Gómez-Vargas
M
M
Miyazaki
I
I
Nakanishi
T
T
Ogawa
N
N
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D004334:Drug Administration Schedule; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism* / Q000503:physiopathology*; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D009928:Organ Specificity; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000096:biosynthesis; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D009570:Nitriles; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D015102:3,4-Dihydroxyphenylacetic Acid; C008110:3,3'-iminodipropionitrile; D016572:Cyclosporine; D000242:Cyclic AMP; D013755:Tetradecanoylphorbol Acetate; D004298:Dopamine; D006719:Homovanillic Acid