175.1 Homeostatic Imbalance of Adenosine Signaling and Uric Acid Production in Schizophrenia

Abstract

Abstract Background: A multiplicity of theories has been proposed over the years that aim to conceptualize the pathological processes inherent to schizophrenia (SZ), which led to a number of potential targets for therapeutic interventions. However, treatment likely modifies these metabolic processes, but which of the many metabolic pathways are modified and of what relevance they are to clinical outcome remains unclear. Previous studies in SZ indicated that purine catabolism may contribute to mitochondrial antioxidant defense by producing uric acid. Failure to maintain elevated xanthine and uric acid occurred contemporaneous to progressive mitochondrial dysfunction. Thus, purine catabolism appears to be a homeostatic response of mitochondria to oxidant stress and may act against progressive mitochondrial dysfunction in SZ. Methods: We applied a targeted electrochemistry based metabolomics platform to determine multiple key metabolites from purine, tryptophan, and tyrosine pathways, a capillary gas chromatography to measure amino acids and membrane phospholipid fatty acids, and enzyme immunoassay to profile human growth factors, pro-inflammatory cytokines and adenosine levels. Results: 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 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 pathway metabolites. Moreover, hypofunction of adenosine signaling is closely related to the activation of the angiogenic cascade, decreased excitatory amino acids, and reduced dietary intake of n-3 polyunsaturated fatty acids. On the other hand, there is an association between optimal levels of uric acid and dynamics in clinical symptoms and adjustment. Conclusion: Rather than replacing neurotransmission-based theories, we propose that homeostatic imbalance of purine signaling model can extend the current theories by integrating the abnormalities not only within the purine pathways but also across the multiple metabolic pathways to further understanding the biochemical cause(s) of the core deficits associated with SZ. Both adenosine (precursor) and uric acid (end-product) in the purine pathway may be considered as nexus in the stress cascade leading to highly heterogeneous symptomatology and course of SZ. Given increasing evidence linking purine signaling to other metabolic pathways involving SZ pathology, efforts to identify the specific role of purine signaling in SZ and novel targets for pharmacological enhancement are of paramount clinical importance.