J Psychiatry Neurosci 2014;39(4):276-85
Helena Kyunghee Kim, BSc; Ana Cristina Andreazza, Pharm, PhD; Pok Yik Yeung, BSc; Cameron Isaacs-Trepanier; L. Trevor Young, MD, PhD
Kim, Andreazza, Yeung, Young — Departments of Psychiatry and Pharmacology, University of Toronto, Toronto, Ont.; Andreazza, Isaacs-Trepanier, Young — Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ont., Canada
Background: Increased oxidative stress is strongly implicated in bipolar disorder (BD), where protein oxidation, lipid peroxidation and oxidative damage to DNA have been consistently reported. High levels of dopamine (DA) in mania are also well-recognized in patients with BD, and DA produces reactive oxygen species and electron-deficient quinones that can oxidize proteins when it is metabolized.
Methods: Using immunohistochemistry and acceptor photobleaching Förster resonance energy transfer (FRET), we examined oxidation and nitration of areas immunoreactive for the DA transporter (DAT) and tyrosine hydroxylase (TH) in the postmortem prefrontal cortex from patients with BD, schizophrenia and major depression as well as nonpsychiatric controls.
Results: We found increased oxidation of DAT-immunoreactive regions in patients with BD (F3,48 = 6.76, p = 0.001; Dunnett post hoc test p = 0.001) and decreased nitration of THimmunoreactive regions in both patients with BD (F3,45 = 3.10, p = 0.036; Dunnett post hoc test p = 0.011) and schizophrenia (p = 0.027). On the other hand, we found increased global levels of oxidation in patients with BD (F3,44 = 6.74, p = 0.001; Dunnett post hoc test p = 0.001) and schizophrenia (p = 0.020), although nitration levels did not differ between the groups (F3,46 = 1.75; p = 0.17).
Limitations: Limitations of this study include the use of postmortem brain sections, which may have been affected by factors such as postmortem inter val and antemortem agonal states, although demographic factors and postmortem interval were accounted for in our statistical analysis.
Conclusion: These findings suggest alterations in levels of protein oxidation and nitration in DA-rich regions of the prefrontal cortex in patients with BD and schizophrenia, but more markedly in those with BD.
Submitted July 29, 2013; Revised Oct. 29, Nov. 29, 2013; Accepted Dec. 2, 2013.
Acknowledgements: We thank Ginnie Ng for her contributions in cell counting of the Nissl stained sections and Dr. Dennis Grant for donating the mice for the postmortem interval experiment. We also declare CIHR, Brain and Behaviour Research Foundation (NARSAD), and OGS as sources of funding, and Stanley Foundation Neuropathology Consortium as source of human postmortem brain sections.
Competing interests: None declared.
Contributors: H.K. Kim, A.C. Andreazza and L.T. Young designed the study. H.K. Kim, D.P.Y. Yeung and C. Isaacs-Trépanier acquired the data, which H.K. Kim, A.C. Andreazza, D.P.Y. Yeung and L.T. Young analyzed. H.K. Kim, A.C. Andreazza and L.T. Young wrote the article, which all authors reviewed and approved for publication.
Correspondence to: L.T. Young, Centre for Addiction and Mental Health, Clarke Site, 250 College St., Rm 835, Toronto ON M5T 1R8;