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

Abstract

Background: Purine 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 findings: Using 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/significance: During 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.

Figure 1. Cross-validation (5-fold) for the logistic regression classifier of HC vs FENNS-BL groups.

A series of models was chosen by forward selection using as criterion the minimizing of the estimated prediction error (−2 x log likelihood), displayed for each model ± its own standard error. Note that predictors are plasma purine concentrations, only guanine (x = 1) is significant contributor (since its prediction error is within the standard error bar of the 4-variable model, which is the lowest in prediction error). Abbreviations: HC, healthy controls; FENNS-BL, first-episode neuroleptic-naïve schizophrenic patients at baseline.

Figure 2. Altered purine catabolism in first-episode neuroleptic-naïve patients with schizophrenia (FENNS).

Metabolites identified by purple color were measured in the present study. Red arrows indicate shifts toward an increase of xanthosine and a decrease of uric acid productions in FENNS patients at baseline. Reactions shown with dotted lines represent the “salvage pathways”, which purine bases can be reutilized resulting in considerably energy saving for the cell. Abbreviations: NP, nucleoside phosphorylase; DA, deaminase; HL, hydrolase; XO, xanthine oxidase; HGPRT, hypoxanthine-guanine phosphoribosyl transferase; PRPP, 5-phosphoribosyl pyrophosphate; AMP, adenosine monophosphate; ATP, adenosine triphosphate; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; GMP, guanosine monophosphate; GTP, guanosine triphosphate; IMP, inosine monophosphate; XMP, xanthosine monophosphate.

Figure 3. Significant correlations of uric acid to guanine, and xanthine to hypoxanthine in healthy control subjects (A), first-episode neuroleptic-naïve schizophrenic (FENNS) patients at baseline (B), and FENNS patients after 4-week treatment with antipsychotic drugs (C).

The p values correspond to the computed values of Kendall's tau rank correlations.

Figure 4. Significant correlations of uric acid to xanthine, uric acid to hypoxanthine, and xanthine to guanosine in healthy control (A) subjects, but not in first-episode neuroleptic-naïve schizophrenic (FENNS) patients at baseline (B) and FENNS patients after 4-week treatment with antipsychotic drugs (C).

The p values correspond to the computed values of Kendall's tau rank correlations.

Figure 5. Significant correlations of uric acid to guanosine, and guanine to guanosine in healthy control (A) subjects, and first-episode neuroleptic-naïve schizophrenic (FENNS) patients at baseline (B), but not in FENNS patients after 4-week treatment with antipsychotic drugs (C).

The p values correspond to the computed values of Kendall's tau rank correlations.

Figure 6. Possible mechanisms involving promotion and removal of free radicals by uric acid.

Abbreviations: Xan, xanthine; XO, xanthine oxidase; SOD, superoxide dismutase; CAT, catalase; GSH, glutathione; O₂ ^{^•}, superoxide anion radical; H₂O₂, hydrogen peroxide; NO^•, nitric oxide; ONOO ^{^}, peroxynitrite; NO₂ ^•, nitrogen dioxide radical; OH^•, hydroxyl radical; LOO^•, lipid peroxyl radical; LVCa, L-type voltage-gated calcium channel; ERK_1/2; extracellular signal-regulated kinases_1/2.

Figure 7. Flow chart of data analyses.