Background: As yet no therapy has been found to slow the underlying neurodegeneration and the resultant inexorable clinical progression of Parkinson's disease (PD). Epidemiologic as well as genetic clues to the risk of PD have begun to suggest novel molecular targets in the search for disease-modifying strategies. Working at the interface of neuroepidemiology and laboratory models of PD, the PI and his colleagues have obtained convergent evidence that two ubiquitous purines might reduce the risk of developing PD: caffeine (an adenosine receptor antagonist) and urate (the end product of adenosine metabolism and a major antioxidant in humans). Moreover, they recently identified urate in the blood and cerebrospinal fluid (CSF) of early PD patients as the first known molecular predictor of clinical progression in idiopathic PD. Although the association does not address causality, it provides a valuable new clue to the pathophysiology of PD. This finding has already led to the development of a clinical trial of a novel urate-elevating treatment for PD under the direction of the PI, who is an experienced clinical investigator in the Parkinson Study Group (PSG) as well as a leading international investigator and educator on adenosine receptors in basal ganglia pathophysiology. Goal: Building on the PI's basic science and clinical epidemiology advances, the project seeks to establish a translational research and mentoring program that pursues purinergic pathways to successful neuroprotective therapy for PD.
Specific Aims /Design: To achieve this goal the PI and his team aim to: 1) further correlate baseline exposures to purines (urate, its precursors, and caffeine) with rates of clinical progression in PD patients, and investigate a protective effect of urate or its precursor inosine in a mouse model of PD. 2) maximize the yield of our Phase II clinical trial of the urate precursor inosine (designed to assess its safety and ability to elevate CSF urate) by mining the trial's biological and clinical databases, and by developing a Phase III efficacy trial based on its results. 3) establish a mentorship program that integrates the project's clinical research opportunities with the career development of junior investigators locally, while teaching translational neuroscience approaches to neurology residents and fellows at the national level. Relevance: The support and protected time afforded by an NINDS K24 award will allow the PI to transition his primarily laboratory-based research program to a fully integrated translational endeavor dedicated to developing clinical trials of putative neuroprotective agents. Urate is a particularly promising candidate because of its unprecedented ability to predict both the risk of PD and its rate of progression, its biological plausibility, and its suitability to pharmacological manipulation. The award will also help ensure the training of a new generation of clinical neuroscientists capable of transforming molecular insights into therapeutic advances for patients with PD and other neurodegenerative diseases.
|Crotty, Grace F; Ascherio, Alberto; Schwarzschild, Michael A (2017) Targeting urate to reduce oxidative stress in Parkinson disease. Exp Neurol 298:210-224|
|Chen, Xiqun; Chen, Hongxiang; Cai, Waijiao et al. (2017) The melanoma-linked ""redhead"" MC1R influences dopaminergic neuron survival. Ann Neurol 81:395-406|
|Xu, K; Di Luca, D G; Orrú, M et al. (2016) Neuroprotection by caffeine in the MPTP model of parkinson's disease and its dependence on adenosine A2A receptors. Neuroscience 322:129-37|
|Bakshi, Rachit; Zhang, Hong; Logan, Robert et al. (2015) Neuroprotective effects of urate are mediated by augmenting astrocytic glutathione synthesis and release. Neurobiol Dis 82:574-579|
|McFarland, Nikolaus R; Dimant, Hemi; Kibuuka, Laura et al. (2014) Chronic treatment with novel small molecule Hsp90 inhibitors rescues striatal dopamine levels but not ?-synuclein-induced neuronal cell loss. PLoS One 9:e86048|
|Kachroo, Anil; Schwarzschild, Michael A (2014) Allopurinol reduces levels of urate and dopamine but not dopaminergic neurons in a dual pesticide model of Parkinson's disease. Brain Res 1563:103-9|
|Simon, Kelly Claire; Eberly, Shirley; Gao, Xiang et al. (2014) Mendelian randomization of serum urate and parkinson disease progression. Ann Neurol 76:862-8|
|Parkinson Study Group SURE-PD Investigators; Schwarzschild, Michael A; Ascherio, Alberto et al. (2014) Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial. JAMA Neurol 71:141-50|
|Hung, Albert Y; Schwarzschild, Michael A (2014) Treatment of Parkinson's disease: what's in the non-dopaminergic pipeline? Neurotherapeutics 11:34-46|
|Cipriani, S; Bakshi, R; Schwarzschild, M A (2014) Protection by inosine in a cellular model of Parkinson's disease. Neuroscience 274:242-9|
Showing the most recent 10 out of 39 publications