Effects of cinnarizine, a calcium antagonist that produces human parkinsonism, in parkin knock out mice.
Cinnarizine, a calcium antagonist that produces parkinsonism in humans, induces behavioural changes such as alopecia, buco-lingual dyskinesia and reduction of motor activity in female parkin knock out (PK-KO) mice but not in wild-type (WT) controls. PK-KO mice have high striatal dopamine levels and increased dopamine metabolism in spite of low reduced tyrosine hydroxylase protein. Cinnarizine, which blocks dopamine receptors and increases dopamine release, further increased dopamine metabolism. PK-KO mice increased GSH levels as a compensatory mechanism against enhanced free radical production related to acceleration of dopamine turnover. Neuronal markers, such as beta-tubulin slightly increased in PK-KO and furthermore with cinnarizine. Astroglial markers were decreased in PK-KO mice, and this effect was potentiated by cinnarizine, suggesting abnormal glia in these animals. Microglia was hyperactivated in PK-KO midbrain, suggesting inflammation in these animals. Proapoptotic proteins were increased by cinnarizine and, to a lesser extent, in PK-KO mice. Our data indicate that mutation of parkin is a risk factor for drug-induced parkinsonism.
Department of Neurology, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avda. de Reyes Católicos, 2. 28040 Madrid, Spain.
A
A
Serrano
J
J
Menéndez
M J
MJ
Casarejos
R M
RM
Solano
E
E
Gallego
M
M
Sánchez
M A
MA
Mena
J
J
García de Yebenes
D000704:Analysis of Variance; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D015306:Biogenic Monoamines / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D001835:Body Weight / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000009:adverse effects*; D002845:Chromatography / Q000379:methods; D002936:Cinnarizine / Q000009:adverse effects*; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D020734:Parkinsonian Disorders / Q000139:chemically induced* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000235:genetics; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D000943:Antigens, Differentiation; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D015306:Biogenic Monoamines; D002121:Calcium Channel Blockers; D005904:Glial Fibrillary Acidic Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D002936:Cinnarizine; D014446:Tyrosine 3-Monooxygenase; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D005978:Glutathione