Homeostatic imbalance of purine catabolism in first-episode neuroleptic-naïve patients with schizophrenia.

Jeffrey K Yao,Debra M Montrose,Rima Kaddurah-Daouk,Wayne R Matson,George G Dougherty,Ravinder D Reddy,Matcheri S Keshavan,Joseph Mcevoy,Kenji Hashimoto

doi:10.1371/journal.pone.0009508

Abstract

BackgroundPurine catabolism may be an unappreciated, but important component of the homeostatic response of mitochondria to oxidant stress. Accumulating evidence suggests a pivotal role of oxidative stress in schizophrenia pathology.Methodology/Principal FindingsUsing high-pressure liquid chromatography coupled with a coulometric multi-electrode array system, we compared 6 purine metabolites simultaneously in plasma between first-episode neuroleptic-naïve patients with schizophrenia (FENNS, n = 25) and healthy controls (HC, n = 30), as well as between FENNS at baseline (BL) and 4 weeks (4w) after antipsychotic treatment. Significantly higher levels of xanthosine (Xant) and lower levels of guanine (G) were seen in both patient groups compared to HC subjects. Moreover, the ratios of G/guanosine (Gr), uric acid (UA)/Gr, and UA/Xant were significantly lower, whereas the ratio of Xant/G was significantly higher in FENNS-BL than in HC. Such changes remained in FENNS-4w with exception that the ratio of UA/Gr was normalized. All 3 groups had significant correlations between G and UA, and Xan and hypoxanthine (Hx). By contrast, correlations of UA with each of Xan and Hx, and the correlation of Xan with Gr were all quite significant for the HC but not for the FENNS. Finally, correlations of Gr with each of UA and G were significant for both HC and FENNS-BL but not for the FENNS-4w.Conclusions/SignificanceDuring purine catabolism, both conversions of Gr to G and of Xant to Xan are reversible. Decreased ratios of product to precursor suggested a shift favorable to Xant production from Xan, resulting in decreased UA levels in the FENNS. Specifically, the reduced UA/Gr ratio was nearly normalized after 4 weeks of antipsychotic treatment. In addition, there are tightly correlated precursor and product relationships within purine pathways; although some of these correlations persist across disease or medication status, others appear to be lost among FENNS. Taken together, these results suggest that the potential for steady formation of antioxidant UA from purine catabolism is altered early in the course of illness.

Highlights

Schizophrenia (SZ) is a highly disabling disease characterized by widespread structural and functional brain alterations, the pathogenesis of which remains poorly understood
Trend-level differences are noted for uric acid (UA) and guanine (G) between FENNS-BL patients and Healthy controls (HC)
Homeostatic Imbalance of Purine Catabolism In mammalian cells, purines are synthesized de novo from amino acids, formate and carbon dioxide as nitrogen and carbon donors

Summary

Introduction

Schizophrenia (SZ) is a highly disabling disease characterized by widespread structural and functional brain alterations, the pathogenesis of which remains poorly understood. Under physiological conditions the potential for free radical-mediated damage is kept in check by the antioxidant defense system (AODS), comprising a series of enzymatic and non-enzymatic components. These enzymes act cooperatively at different sites in the free radical pathways. Our previous data showing altered membrane dynamics and AODS enzyme activities, and findings from other investigators [8,9,10,12,13] are consistent with the notion of free radical-mediated neurotoxicity in schizophrenia [2]. Accumulating evidence suggests a pivotal role of oxidative stress in schizophrenia pathology

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