Partial dopamine loss enhances activated caspase-3 activity: differential outcomes in striatal projection systems

Abstract

Parkinson's disease (PD) is a basal ganglia disorder. Motor symptoms develop insidiously following substantial neurodegeneration of the dopamine (DA) neurons in the nigrostriatal system and produce slowed, infrequent movements, postural instability, and gait changes. A thorough understanding of neurochemical compensations occurring in the striatum during early stages of PD is crucial in identifying components that are altered initially as the DA is depleted. Producing an incomplete lesion of the nigrostriatal DA system in rats would mimic the principal early neurochemical features of human PD. We infused 6-hydroxydopamine unilaterally into the substantia nigra to reach a target of approximately 50% depletion in striatal DA at 4 weeks. This was evaluated by HPLC analysis of tissue DA content and monitored behaviorally by forepaw use reflecting asymmetries in striatal DA levels. DA loss was assessed by using tyrosine hydroxylase immunohistochemical staining, and the data were conjoined with the behavioral assessments. We found that activated caspase-3, its actin cleavage product fractin, and components of the apoptosome were increased significantly in DA-depleted striatum. Thus mobilization of the intrinsic programmed cell death pathway occurred, without cell loss. Elevations in apoptogenic proteins were pronounced in enkephalinergic striatopallidal neurons compared with the substance P-containing striatonigral neurons. Our findings suggest that cellular homeostatic imbalances that accompany even mild striatal DA depletion take time to develop, differentially affect the striatal output pathways, and may be an important feature of early-stage PD. These observations could be capitalized upon to develop therapeutic interventions in the preclinical phases of the disorder.