Caffeine, Adenosine Receptors and Estrogen in Toxin Models of Parkinson's Disease.

摘要

Substantial progress has been made toward our original Specific Aims (SAs) in pursuit of the core hypothesis that multiple environmental protectants and toxins interact to influence of the health of the dopaminergic neurons lost in PD. SA#1: Using a series of global and conditional knockout mice lacking the adenosine A2A receptor, we characterized the molecular and cellular basis of caffeine s protective actions in acute toxin models of PD. Recently we showed that caffeine also confers protection in a chronic pesticide model of PD. SA#2: We have validated a powerful (AAV) virus-based (cre) gene delivery system to conditionally knock out adenosine receptors from specific brain regions, enabling us to determine in which brain region(s) A2A receptors contribute to neurotoxicity. Despite technical challenges of viral and/or cre gene toxicity, we have obtained initial evidence of striatal A2A receptor-dependence of MPTP toxicity with this system. SA#3: We systematically demonstrated that endogenous estrogen (in females) and exogenous estrogen (e.g., in ovariectomized females) can prevent the protective effect of caffeine on MPTP toxicity, without altering caffeine pharmacokinetics. The findings provide insight into epidemiological studies consistently identifying coffee and caffeine consumption as an inverse risk factor for PD in men, and only in women who have not taken estrogen replacement therapy. These data have helped substantiate that critical interactions between environmental toxicants and protectants influencing the neurodegeneration of PD. Finally, our demonstrations of adenosine A2A receptor-dependent protection by caffeine, and of the prognostic biomarker potential of another purine urate, have directly contributed to the rationale for novel clinical trials with disease-modification designs currently in progress.