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Clinical Significance of Adenosine Signaling Deficits in Schizophrenia Pathology: From Theoretical Foundations to Symptomatology

Zhou, Xiang (2018) Clinical Significance of Adenosine Signaling Deficits in Schizophrenia Pathology: From Theoretical Foundations to Symptomatology. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Schizophrenia (SZ) is a devastating mental illness characterized by complicated pathophysiology. Adenosine theory was proposed recently and showed the potential to combine classic theories into one common pathway. It is hypothesized that the reduction of adenosinergic activity in CNS could serve as a possible common explanation for the alterations of dopaminergic and glutamatergic neurotransmission in SZ. Based on previous reports and preliminary data, adenosine signaling might be an interesting and meaningful target to study. This dissertation thus was dedicated to test adenosine theory and to explore its clinical significance in SZ.
This dissertation consists of four parts. First, we tested if levels of analytes in adenosine signaling was altered in SZ patients. We observed significant level changes of adenosine, adenosine deaminase (ADA) and inosine in SZ patients. We also observed disrupted connections between adenosine and ADA in SZ patients when comparing with that in controls. Second, we tested if such deficits could be affected by antipsychotic treatments. In this part results implied that antipsychotics could have an impact on adenosine signaling. However, treatments cannot fully restore the altered levels of those analytes. Third, we tested associations between the adenosine signaling within purine pathway and with other important biochemical pathways in SZ pathology. A homeostasis imbalance of purine pathway were observed and the pathway was shifted towards the direction in favor of uric acid production. We also observed that reduced uric acid levels were linked to elevated levels of oxidative stress. For inter-pathway correlations, we found significant correlations between adenosine levels and red blood cell membrane defects. We also observed inverse correlation between adenosine and homovanillic acid. Fourth, significant correlations were observed between analytes’ levels and positive symptoms as well as between analytes’ levels and global functioning scale. Findings here suggested that levels of adenosine and ADA in plasma and CSF may have important clinical implications.
In summary, adenosine signaling deficits were suggested to be present in SZ patients and can be linked to classical SZ theories. Also, findings revealed the clinical significance of adenosine signaling and may shed light on the endeavors for new antipsychotics R&D.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Zhou, Xiangxiz102@pitt.eduxiz1020000-0002-4066-857X
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairGibbs, Robertgibbsr@pitt.edugibbsr
Thesis AdvisorHaas, Gretchengretchen.haas@va.gov
Committee MemberMa, XiaochaoMXIAOCHA@pitt.eduMXIAOCHA
Committee MemberDougherty, Georgeggd@pitt.eduggd
Committee MemberKirisci, Leventlevent@pitt.edulevent
Committee MemberPoloyac, Samuelpoloyac@pitt.edupoloyac
Date: 3 December 2018
Date Type: Publication
Defense Date: 27 September 2018
Approval Date: 3 December 2018
Submission Date: 26 November 2018
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 154
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: schizophrenia; adenosine signaling; symptoms; clinical significance; purine pathway
Date Deposited: 03 Dec 2018 15:07
Last Modified: 03 Dec 2018 15:07
URI: http://d-scholarship.pitt.edu/id/eprint/35607

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