alvocidib and Parkinson-Disease

Recent evidence indicates that cyclin-dependent kinases (CDKs, cdks) may be inappropriately activated in several neurodegenerative conditions. Here, we report that cdk5 expression and activity are elevated after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that damages the nigrostriatal dopaminergic pathway. Supporting the pathogenic significance of the cdk5 alterations are the findings that the general cdk inhibitor, flavopiridol, or expression of dominant-negative cdk5, and to a lesser extent dominant-negative cdk2, attenuates the loss of dopaminergic neurons caused by MPTP. In addition, CDK inhibition strategies attenuate MPTP-induced hypolocomotion and markers of striatal function independent of striatal dopamine. We propose that cdk5 is a key regulator in the degeneration of dopaminergic neurons in Parkinson's disease.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Adenoviridae; Animals; Blotting, Western; Chromatography, High Pressure Liquid; Cyclin-Dependent Kinase 5; Cyclin-Dependent Kinases; Disease Models, Animal; Dopamine; Dopamine Agents; Flavonoids; Genes, Dominant; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Neurons; Parkinson Disease; Piperidines; Time Factors