Effect of cdk5 antagonist on L-dopa-induced dyskinesias in a rat model of Parkinson's disease.
Increased cyclin-dependent kinase 5 (Cdk5) has associated with the development of L-dopa-induced dyskinesias (LID). To explore the mechanisms underlying the action of Cdk5 in the development of LID, we examined the impact of treatment with Cdk5 inhibitor, roscovitine, on the severity of LID in a rat model of Parkinson's disease (PD) induced by 6-OHDA. The expressions of Cdk5 and phosphorylation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) in the striatum of LID rats were determined by Western blotting. The result showed that the induction of LID upregulated the expression of Cdk5 and phosphorylation of DARPP-32 at Thr34. Roscovitine inhibited apomorphine-stimulated rotations in PD rats and enhanced L-dopa-induced abnormal involuntary movement (AIM), but downregulated the expression of Cdk5 in LID rats. These findings suggest that up-regulated expression of Cdk5 may compensate the high levels of phosphorylation of DARPP-32 at Thr34 in LID rats. Therefore, modulation of Cdk5 for therapy of human PD should be carefully reconsidered.
Guan
Qiang
Q
Department of Neurology, Tongji Hospital, Tongji University, Shanghai 200065, China. guanqianglu@126.com
Liu
Xueyuan
X
He
Yusheng
Y
Jin
Lingjing
L
Zhao
Lijuan
L
D000818:Animals; D000977:Antiparasitic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D007980:Levodopa / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011687:Purines / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077546:Roscovitine; D012720:Severity of Illness Index; D016896:Treatment Outcome
D000977:Antiparasitic Agents; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C497930:Ppp1r1b protein, rat; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D007980:Levodopa; D016627:Oxidopamine; D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat