Caffeine, Adenosine Receptors and Estrogen in Toxin Models of Parkinson's Disease
Abstract
Continued progress has been made toward each of the 3 Specific Aims (SAs) of our research project, Caffeine, adenosine receptors and estrogen in toxin models of Parkinson's disease (PD) . The overarching hypothesis of the project is that multiple environmental protectants and toxins interact to influence of the health of the dopaminergic neurons lost in PD. To that end we are characterizing the interplay between several environmental agents (pesticides, caffeine and estrogen) that are leading candidate modulators of PD risk. Main accomplishments during the Year 3 of the project: 1)Demonstration that neuronal forebrain A2A receptors can play a critical role in dopaminergic neuron injury in the MPTP model of neurodegeneration in Parkinson s disease. 2) Using a powerful newly Cre/LoxP conditional knockout system, we have obtained evidence that it is the neuronal forebrain A2A receptors in the striatum that are responsible for this toxicity. Thus it is through these receptors that caffeine and more specific antagonists of the adenosine A2A receptor may offer neuroprotection against the development or progression of PD. 3) Demonstration for the first time that caffeine s neuroprotective effect extends to the dual pesticide parequat plus maneb model of PD, a chronic, potentially more environmentally relevant model of the disease. 4) Demonstration for the first time that urate -- a caffeine analog and antioxidant linked to slower PD progression and risk -- can be neuroprotective in an in vivo model of PD. This finding may have a particularly rapid translational impact as urate-elevating therapy is now being pursued as potential neuroprotectant for PD patients. 5) Methodological advances were achieved with a viral vector-based Cre/LoxP conditional knockout system. It will allow us to dissect caffeine and A2A receptor involvement in neurotoxin models of PD with an unprecedented combination of anatomical and molecular precision in different brain structures.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2007
- Accession Number
- ADA478278
Entities
People
- Michael A Schwarzschild
Organizations
- Massachusetts General Hospital