Homeostatic Imbalance of Purine Catabolism in First-Episode Neuroleptic-Naïve Patients with Schizophrenia

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.

Metabolic Profiling and Phenotyping of Central Nervous System Diseases: Metabolites Bring Insights into Brain Dysfunctions

“…This hypo-uremia was also detected in the plasma of an independent cohort of SCZ patients (Yao et al 2010a;Yao et al 2010b). Uric acid being the main plasmatic antioxidant, decreased levels in biofluids of SCZ patients is indicative of increased susceptibility to oxidative stress, corroborating several studies in animal models and patients (Emiliani et al 2014).…”

“…This study highlights at the metabolic level the importance of early therapeutic intervention for schizophrenic patients. In two independent studies using different metabolomics platforms plasmatic metabolic signature of schizophrenia was normalized upon treatment with the antipsychotic risperidone (Cai et al 2012;Yao et al 2010a). One study studied in details the plasmatic lipidic profiles of SCZ patients before and after 3 weeks treatment with the antipsychotics olanzapine, risperidone or aripiprazole ).…”

Phospholipid, arachidonate and eicosanoid signaling in schizophrenia

“…However, this expected correlation is abolished in SZ (Messamore et al, 2010). Similar precursor-product dysregulations have also shown in tryptophan (Yao et al, 2010b) and purine (Yao et al, 2010a) pathways. Although many of these correlated relationships persist across disease or medication status, others are lost among patients with SZ.…”

Oxidative Stress in Schizophrenia: Pathogenetic and Therapeutic Implications

“…Thus, it has been hypothesized that the broad mitochondrial processes are affected in schizophrenia such as calcium homeostasis, neurotransmitter transport, synaptic plasticity, and exacerbate ROS production (2). Most probably, higher ROS concentrations are not properly processed in early schizophrenia patients because key processes of stress response such as the purine catabolism are disturbed (30), leading to DNA damage, impaired energy production, altered gene and protein expression and, finally, in apoptosis and cell death, together leading to faulty neuronal plasticity, and perturbed neurotransmission. Such processes may start during neurodevelopment in schizophrenia and coincide with manifestation of symptoms during early adulthood (3,33).…”