Schizophrenia (SZ) is a severe psychiatric disorder that results in significant disability. All currently approved antipsychotic medications work by primarily blocking D2-type dopamine receptors. Many patients are partially or completely unresponsive to them, and suffer significant side effects. Developing new SZ treatments is a critical need. However, we lack a clear understanding of disease progression mechanisms and have no specific targets for effective treatment and early intervention. Recently several lines of evidence suggest that brain oxidative stress and disturbances in neuroinflammatory system play key roles in SZ. And several antioxidants and anti-inflammatory medications have been tested in some small clinical trials as a supplemental to antipsychotics. However, to date, clinical trials have produced mixed results. The effect of these interventions may greatly depend on the integrity of the antioxidant glutathione (GSH) system and the intrinsic redox status. It is well known that intensive energy demand of brain cells leads to accumulation of toxic reactive oxygen species such as H2O2 and free radicals O2* (i.e. oxidative stress). These are eliminated by GSH, a critical molecule in resisting oxidative stress. These chemical processes also are strongly mediated by the redox state of NAD+/NADH. Dysregulations of the redox state may affect anti-oxidative defense, anti- inflammation and energy homestasis as well as exert downstream effects on synaptic function and plasticity in the brain. Therefore, methods to monitor GSH level and redox state are critically needed. Despite the essential role of redox balance in the human brain, few methods are available to access it in vivo. Most data reported to date have been collected from cell-cultures or postmortem studies. There is a large gap in our knowledge to show how the phenomena observed ex vivo relate to brain function in vivo. The current study aims to develop an in vivo biomarker reflecting oxidative stress in SZ patients. In this proposal, we will utilize in vivo 1H- and 31P-MRS to 1) directly quantify both antioxidant level-GSH and redox state (NAD+/NADH) in 1st episode SZ patients, and healthy controls and 2) validate whether reduced antioxidant GSH level is associated with the reduced redox state in SZ. We will also explore the relationships between clinic measures (negative/positive symptoms and cognitive performance) and experimental measures (redox balance and antioxidant levels indicated by NADH/NAD+ and GSH, respectively). Redox dysregulation would be the upstream molecular mechanism of GSH depletion, oxidative stress and neuroinflammation in SZ. The results would provide new insights into the central ?immuno-oxidative? pathway of SZ, a promising therapeutic target. To the best of our knowledge, the current proposal is the first to measure redox state and antioxidant GSH in vivo and link them to the pathophysiology of SZ. The insights obtained from redox state and associated antioxidant GSH levels may help to develop strategies to promote neuronal survival and protection in brain pathologies.
Schizophrenia is a devastating psychiatric disorder that results in significant disability. Our current project aims to look for a new biomarker reflecting oxidative stress in schizophrenia though measuring redox status and associated antioxidant glutathione level in the human brain. It may help to develop strategies to promote neuronal survival and protection in brain pathologies.
| Dogan, Asli Ercan; Yuksel, Cagri; Du, Fei et al. (2018) Brain lactate and pH in schizophrenia and bipolar disorder: a systematic review of findings from magnetic resonance studies. Neuropsychopharmacology 43:1681-1690 |
