Abstract
Schizophrenia (SZ) is a biochemically complex disorder characterized by widespread defects in multiple metabolic pathways whose dynamic interactions, until recently, have been difficult to examine. Rather, evidence for these alterations has been collected piecemeal, limiting the potential to inform our understanding of the interactions amongst relevant biochemical pathways. We herein review perturbations in purine and neurotransmitter metabolism observed in early SZ using a metabolomic approach. Purine catabolism is an underappreciated, but important component of the homeostatic response of mitochondria to oxidant stress. We have observed a homeostatic imbalance of purine catabolism in first-episode neuroleptic-naïve patients with SZ (FENNS). Precursor and product relationships within purine pathways are tightly correlated. Although some of these correlations persist across disease or medication status, others appear to be lost among FENNS suggesting that steady formation of the antioxidant uric acid (UA) via purine catabolism is altered early in the course of illness. As is the case for within-pathway correlations, there are also significant cross-pathway correlations between respective purine and tryptophan (TRP) pathway metabolites. By contrast, purine metabolites show significant cross-pathway correlation only with tyrosine, and not with its metabolites. Furthermore, several purine metabolites (UA, guanosine, or xanthine) are each significantly correlated with 5-hydroxyindoleacetic acid (5-HIAA) in healthy controls, but not in FENNS at baseline or 4-week after antipsychotic treatment. Taken together, the above findings suggest that purine catabolism strongly associates with the TRP pathways leading to serotonin (5-hydroxytryptamine, 5-HT) and kynurenine metabolites. The lack of a significant correlation between purine metabolites and 5-HIAA, suggests alterations in key 5-HT pathways that may both be modified by and contribute to oxidative stress via purine catabolism in FENNS.
Highlights
Schizophrenia (SZ) is a common and highly disabling mental disorder without a clearly identified pathophysiology
Precursor and product relationships within purine pathways are tightly correlated. Some of these correlations persist across disease or medication status, others appear to be lost among firstepisode neuroleptic-naïve patients with SZ (FENNS) suggesting that steady formation of the antioxidant uric acid (UA) via purine catabolism is altered early in the course of illness
The data collected from HPLC–CMEAS system reflect fingerprinting of the disorder or state/trait-related markers, which will greatly improve the predictive diagnostics for phenotypes that directly involve in the oxidative stress
Summary
Schizophrenia (SZ) is a common and highly disabling mental disorder without a clearly identified pathophysiology. A number of putative mechanisms have been proposed to explain the etiopathogenesis and illness presentation of SZ including abnormal neuronal development, impaired neurotransmission, viral infections in utero, autoimmune dysfunction, and many others. Free radical-mediated, can significantly alter a broad range of membrane functions. There is abundant evidence that alterations in key neurotransmitters can both be modified by and contribute to oxidative stress and membrane dysfunction (Figure 1), suggesting a link among oxidative stress, membrane dysfunction, and multi-neurotransmitter pathologies in SZ (Yao and Keshavan, 2011). METABOLOMIC INVESTIGATION Schizophrenia is a heterogeneous disease with various abnormal metabolites involving multiple biochemical pathways. To identify candidate pathological process(es) that account for the constellation of clinical and biological features in SZ, it is necessary to simultaneously evaluate multiple metabolites in a network of interacting biochemical pathways. The development of Frontiers in Cellular Neuroscience www.frontiersin.org
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