Tamoxifen effect on L-DOPA induced response complications in parkinsonian rats and primates.
The contribution of striatal protein kinase C (PKC) isoform changes in levodopa (L-DOPA) induced motor response complications in parkinsonian rats was investigated and the ability of tamoxifen, an antiestrogen with a partial PKC antagonist property, to prevent these response alterations in 6-hydroxydopamine (6-OHDA) lesioned rats as well as in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated cynomologous monkeys was studied. Following treatment of adult male rats with L-DOPA twice daily for 3 weeks, protein levels of left (lesioned) and right (intact) striatal PKC isoforms were measured. Western blot analysis showed increased protein expression of both the novel PKC epsilon isoform and the atypical PKC lambda isoform ipsilateral to the lesion (174+/-17% for epsilon, 140+/-9% for lambda, of intact striatum in 6-OHDA lesioned plus chronic L-DOPA treated animals) in acute L-DOPA treated rats. No enhancement was observed in PKC immunoreactivity for other isoforms. Tamoxifen (5.0 mg/kg p.o.) significantly attenuated the L-DOPA induced augmentation of protein expression of PKC epsilon and PKC lambda, but had no effect on immunoreactivity for other PKC isoforms. In chronic L-DOPA treated parkinsonian rats, tamoxifen prevented (5.0 mg/kg p.o.) as well as ameliorated (5.0 mg/kg p.o.) the characteristic shortening in duration of motor response to L-DOPA challenge. In MPTP lesioned primates, similar to the ameliorative effect seen in rats, tamoxifen (1 and 3 mg/kg p.o) reduced the appearance of L-DOPA induced dyskinesia by 61% and 55% respectively (p<0.05). These results suggest that changes in specific striatal PKC isoforms contribute to the pathogenesis of L-DOPA induced motor complications and further that drugs able to selectively inhibit these signaling kinases might provide adjunctive benefit in the treatment of Parkinson's disease.
Smith
C P S
CP
Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Oh
J D
JD
Bibbiani
F
F
Collins
M A
MA
Avila
I
I
Chase
T N
TN
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology; D000882:Haplorhini; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use*; D013629:Tamoxifen / Q000627:therapeutic use*; D013997:Time Factors
D000978:Antiparkinson Agents; D009419:Nerve Tissue Proteins; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D007980:Levodopa; D016627:Oxidopamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D011493:Protein Kinase C