Michael A. Schwarzschild

Adenosine inhibits IL-12 and TNF-α production via adenosine A2a receptor-dependent and independent mechanisms

Interleukin 12 (IL‐12) is a crucial cytokine in the regulation of T helper 1 vs. T helper 2 immune responses. In the present study, we investigated the effect of the endogenous purine nucleoside adenosine on the production of IL‐12. In mouse macrophages, adenosine suppressed IL‐12 production. Although the order of potency of adenosine receptor agonists suggested the involvement of A2a receptors, data obtained with A2a receptor‐deficient mice showed that the adenosine suppression of IL‐12 and even TNF‐α production is only partly mediated by A2a receptor ligation. Studies with adenosine receptor antagonists or the adenosine uptake blocker dipyridamole showed that adenosine released endogenously also decreases IL‐12. Although adenosine increases IL‐10 production, the inhibition of IL‐12 production is independent of the increased IL‐10. The mechanism of action of adenosine was not associated with alterations of the activation of the p38 and p42/p44 mitogen‐activated protein kinases or the phosphorylation of the c‐Jun terminal kinase. Adenosine failed to affect steady‐state levels of either IL‐12 p35 or p40 mRNA, but augmented IL‐10 mRNA levels. In summary, adenosine inhibits IL‐12 production via various adenosine receptors. These results support the notion that adenosinebased therapies might be useful in certain autoimmune and/or inflammatory diseases.—Haskó, G., Kuhel, D. G., Chen, J.‐F., Schwarzschild, M. A., Deitch, E. A., Mabley, J. G., Marton, A., Szabó, C. Adenosine inhibits IL‐12 and TNF‐a production via adenosine A2a receptor‐dependent and independent mechanisms. FASEB J. 14, 2065–2074 (2000)

Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine.

Caffeine, a component of tea, coffee and cola, induces wakefulness. It binds to adenosine A1 and A2A receptors as an antagonist, but the receptor subtype mediating caffeine-induced wakefulness remains unclear. Here we report that caffeine at 5, 10 and 15 mg kg−1 increased wakefulness in both wild-type mice and A1 receptor knockout mice, but not in A2A receptor knockout mice. Thus, caffeine-induced wakefulness depends on adenosine A2A receptors.

Molecular markers of early Parkinson's disease based on gene expression in blood

Parkinsons disease (PD) progresses relentlessly and affects five million people worldwide. Laboratory tests for PD are critically needed for developing treatments designed to slow or prevent progression of the disease. We performed a transcriptome-wide scan in 105 individuals to interrogate the molecular processes perturbed in cellular blood of patients with early-stage PD. The molecular multigene marker here identified is associated with risk of PD in 66 samples of the training set comprising healthy and disease controls [third tertile cross-validated odds ratio of 5.7 (P for trend 0.005)]. It is further validated in 39 independent test samples [third tertile odds ratio of 5.1 (P for trend 0.04)]. Insights into disease-linked processes detectable in peripheral blood are offered by 22 unique genes differentially expressed in patients with PD versus healthy individuals. These include the cochaperone ST13, which stabilizes heat-shock protein 70, a modifier of α-synuclein misfolding and toxicity. ST13 messenger RNA copies are lower in patients with PD (mean ± SE 0.59 ± 0.05) than in controls (0.96 ± 0.09) (P = 0.002) in two independent populations. Thus, gene expression signals measured in blood can facilitate the development of biomarkers for PD.

Nonsteroidal antiinflammatory drug use and the risk for Parkinson's disease.

We investigated whether nonsteroidal antiinflammatory drug use was associated with a lower risk for Parkinsons disease (PD) in a large cohort of US men and women. PD risk was lower among ibuprofen users than nonusers. Compared with nonusers, the relative risks were 0.73 for users of fewer than 2 tablets/week, 0.72 for 2 to 6.9 tablets/week, and 0.62 for 1 or more tablets/day (p trend = 0.03). No association was found between the use of aspirin, other nonsteroidal antiinflammatory drugs, or acetaminophen and PD risk. The results suggest that ibuprofen use may delay or prevent the onset of PD. Ann Neurol 2005

Pesticide exposure and risk for Parkinson's disease

Chronic, low‐dose exposure to pesticides is suspected to increase the risk for Parkinsons disease (PD), but data are inconclusive.

Novel pharmacological targets for the treatment of Parkinson's disease

Dopamine deficiency, caused by the degeneration of nigrostriatal dopaminergic neurons, is the cause of the major clinical motor symptoms of Parkinsons disease. These symptoms can be treated successfully with a range of drugs that include levodopa, inhibitors of the enzymatic breakdown of levodopa and dopamine agonists delivered by oral, subcutaneous, transcutaneous, intravenous or intra-duodenal routes. However, Parkinsons disease involves degeneration of non-dopaminergic neurons and the treatment of the resulting predominantly non-motor features remains a challenge. This review describes the important recent advances that underlie the development of novel dopaminergic and non-dopaminergic drugs for Parkinsons disease, and also for the motor complications that arise from the use of existing therapies.

Physical activity and the risk of Parkinson disease

Objective: To investigate whether greater physical activity is associated with a lower risk of Parkinson disease (PD). Methods: The authors prospectively followed 48,574 men and 77,254 women who provided information on physical activity in 1986 or in early adulthood. During the follow-up, a total of 252 (male) and 135 (female) incident PD cases were identified. Results: In men, greater baseline physical activity was associated with a lower PD risk; compared with the lowest quintile, the multivariate relative risk (RR) of PD for the highest quintile was 0.7 (95% CI 0.5 to 1.1; p value, test for trend = 0.007), and the inverse association was still present after excluding the first 10 years of follow-up (RR = 0.5; p value, test for trend = 0.02). Further, strenuous exercise in early adult life was also inversely related to PD risk in men: compared with men who regularly exercised ≤2 months/year, those with ≥10 months of strenuous exercise had a 60% lower PD risk (RR = 0.4; p value, test for trend = 0.005). In women, physical activity assessed at baseline was not related to PD risk, whereas strenuous exercise in early adulthood tended to be inversely related to PD risk later in life (highest vs lowest categories, RR = 0.5, 95% CI 0.2 to 1.4; p value, test for trend = 0.06). Conclusion: This study suggests either that higher levels of physical activity may lower the risk of Parkinson disease (PD) in men or that men predisposed to PD tend to avoid strenuous physical activity in their early adult years.

Urate as a Predictor of the Rate of Clinical Decline in Parkinson Disease

BACKGROUND The risk of Parkinson disease (PD) and its rate of progression may decline with increasing concentration of blood urate, a major antioxidant. OBJECTIVE To determine whether serum and cerebrospinal fluid concentrations of urate predict clinical progression in patients with PD. DESIGN, SETTING, AND PARTICIPANTS Eight hundred subjects with early PD enrolled in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial. The pretreatment urate concentration was measured in serum for 774 subjects and in cerebrospinal fluid for 713 subjects. MAIN OUTCOME MEASURES Treatment-, age-, and sex-adjusted hazard ratios (HRs) for clinical disability requiring levodopa therapy, the prespecified primary end point of the original DATATOP trial. RESULTS The HR of progressing to the primary end point decreased with increasing serum urate concentrations (HR for highest vs lowest quintile = 0.64; 95% confidence interval [CI], 0.44-0.94; HR for a 1-SD increase = 0.82; 95% CI, 0.73-0.93). In analyses stratified by alpha-tocopherol treatment (2000 IU/d), a decrease in the HR for the primary end point was seen only among subjects not treated with alpha-tocopherol (HR for a 1-SD increase = 0.75; 95% CI, 0.62-0.89; vs HR for those treated = 0.90; 95% CI, 0.75-1.08). Results were similar for the rate of change in the Unified Parkinsons Disease Rating Scale score. Cerebrospinal fluid urate concentration was also inversely related to both the primary end point (HR for highest vs lowest quintile = 0.65; 95% CI, 0.44-0.96; HR for a 1-SD increase = 0.89; 95% CI, 0.79-1.02) and the rate of change in the Unified Parkinsons Disease Rating Scale score. As with serum urate concentration, these associations were present only among subjects not treated with alpha-tocopherol. CONCLUSIONS Higher serum and cerebrospinal fluid urate concentrations at baseline were associated with slower rates of clinical decline. The findings strengthen the link between urate concentration and PD and the rationale for considering central nervous system urate concentration elevation as a potential strategy to slow PD progression.

Renal protection from ischemia mediated by A2A adenosine receptors on bone marrow–derived cells

Activation of A2A adenosine receptors (A2ARs) protects kidneys from ischemia-reperfusion injury (IRI). A2ARs are expressed on bone marrow-derived (BM-derived) cells and renal smooth muscle, epithelial, and endothelial cells. To measure the contribution of A2ARs on BM-derived cells in suppressing renal IRI, we examined the effects of a selective agonist of A2ARs, ATL146e, in chimeric mice in which BM was ablated by lethal radiation and reconstituted with donor BM cells derived from GFP, A2AR-KO, or WT mice to produce GFP-->WT, A2A-KO-->WT, or WT-->WT mouse chimera. We found little or no repopulation of renal vascular endothelial cells by donor BM with or without renal IRI. ATL146e had no effect on IRI in A2A-KO mice or A2A-KO-->WT chimera, but reduced the rise in plasma creatinine from IRI by 75% in WT mice and by 60% in WT-->WT chimera. ATL146e reduced the induction of IL-6, IL-1beta, IL-1ra, and TGF-alpha mRNA in WT-->WT mice but not in A2A-KO-->WT mice. Plasma creatinine was significantly greater in A2A-KO than in WT mice after IRI, suggesting some renal protection by endogenous adenosine. We conclude that protection from renal IRI by A2AR agonists or endogenous adenosine requires activation of receptors expressed on BM-derived cells.

Serum Urate as a Predictor of Clinical and Radiographic Progression in Parkinson Disease

OBJECTIVE To determine whether concentration of serum urate, a purine metabolite and potent antioxidant that has been linked to a reduced risk of Parkinson disease (PD), predicts prognosis in PD. DESIGN Prospective study. SETTING The Parkinson Research Examination of CEP-1347 Trial (PRECEPT) study, which investigated the effects of a potential neuroprotectant on rates of PD progression, was conducted between April 2002 and August 2005 (average follow-up time 21.4 months). PARTICIPANTS Eight hundred four subjects with early PD enrolled in the PRECEPT study. MAIN OUTCOME MEASURES The primary study end point was progression to clinical disability sufficient to warrant dopaminergic therapy. Cox proportional hazards models were used to estimate the hazard ratio (HR) of reaching end point according to quintiles of baseline serum urate concentration, adjusting for sex, age, and other potential covariates. Change in striatal uptake of iodine I 123-labeled 2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane ([(123)I]beta-CIT), a marker for the presynaptic dopamine transporter, was assessed with linear regression for a subset of 399 subjects. RESULTS The adjusted HR of reaching end point declined with increasing baseline concentrations of urate; subjects in the top quintile reached the end point at only half the rate of subjects in the bottom quintile (HR, 0.51; 95% confidence interval [CI], 0.37-0.72; P for trend < .001). This association was markedly stronger in men (HR, 0.39; 95% CI, 0.26-0.60; P for trend < .001) than in women (HR, 0.77; 95% CI, 0.39-1.50; P for trend = .33). The percentage of loss in striatal [(123)I]beta-CIT uptake also improved with increasing serum urate concentrations (overall P for trend = .002; men, P = .001; women, P = .43). CONCLUSIONS These findings identify serum urate as the first molecular factor directly linked to the progression of typical PD and suggest that targeting urate or its determinants could be an effective disease-modifying therapy in PD. Trial Registration clinicaltrials.gov Identifier: NCT00040404.