Disease -modifying strategies for nigrostriatal neurodegeneration.

Abstract

Parkinson's disease (PD) is associated with progressive degeneration of nigrostriatal dopamine (DA) neurons. There is an intensive search for neuroprotective treatments that promote survival of DA neurons. Neuroprotective agents, however, may also exert symptomatic effects, confounding assessments of their potential disease-modifying properties. Objective biomarkers of DA neurons and terminals are needed. Prior studies in our laboratory suggest that the vesicular monoamine transporter type-2 (VMAT2) is a quantitative biomarker of nigrostriatal projection integrity. In the present work, interventions were assessed for their disease-modifying potentials in rodent models of PD, using striatal VMAT2 as an outcome biomarker. We examined the possibility that DA turnover might affect survival of DA neurons after unilateral, partial 6-hydroxydopamine (6-OHDA) nigrostriatal lesions. Levodopa treatment promotes endogenous DA turnover, whereas DA D2 receptor agonists suppress it. No differential effects on striatal VMAT2 were found in lesioned rats receiving levodopa vs. D2 agonist treatments. Neither were there treatment effects on VMAT2 levels in the contralateral (unlesioned) striatum, further supporting our hypothesis that VMAT2 expression is not affected by altered DA turnover. Subsequent experiments assessed potential protection against toxin-induced nigrostriatal lesions. Promising neuroprotective strategies include atrophic factors such as glial cell line-derived neurotrophic factor (GDNF) or erythropoietin (EPO), that enhance survival of DA neurons <italic>in vitro</italic>. In our initial studies, striatal VMAT2 binding revealed no benefit of EPO either when administered systemically or when injected directly into the mouse midbrain followed by administration of the toxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. We then evaluated effects of GDNF on VMAT2 expression and found that GDNF caused an unexpected transient reduction in striatal VMAT2 in the intact striatum. We extended earlier reports that GDNF provides neuroprotection against 6-OHDA toxicity, including preservation of striatal VMAT2 levels 6 months after lesion. Our findings support an ongoing role of GDNF in maintenance of the adult nigrostriatal projection. Pharmacological dosages of exogenous GDNF have the potential to transiently interfere with effects of endogenous GDNF in addition to affording protection against neurotoxin exposure. Our studies indicate that VMAT2 is a valid nigrostriatal biomarker in assessments of potential disease-modifying treatments.