Peripheral adenosine levels in euthymic patients with bipolar disorder
Introduction
Bipolar disorder is a severe and chronic psychiatric disorder associated with increased morbidity, mortality and suicide rates (Kupfer, 2005, Roshanaei-Moghaddam and Katon, 2009). This lifelong episodic illness has a variable course and can often result in functional and cognitive impairment that could lead to an important reduction in patients' quality of life (Grande et al., 2016, Martinez-Aran et al., 2007). People with bipolar disorder have functional impairment even during euthymic phases (Rosa et al., 2010). Recently, an idea of neuroprogression for bipolar disorder has been established, with a theory of progressive modifications that includes a decrease in functioning as a fundamental factor (Grande et al., 2016, Kapczinski et al., 2014, Kapczinski and Streb, 2014).
There is increasing evidence suggesting an important role of inflammatory processes in the periphery and the brain (neuroinflammation) (Berk et al., 2011, Pfaffenseller et al., 2013, Stertz et al., 2013), with the presence of increased plasma and post-mortem frontal cortex levels of pro-inflammatory cytokines in people with bipolar disorder (Kim et al., 2007, Ortiz-Domínguez et al., 2007, Rao et al., 2010). Recent evidences also indicate the involvement of purinergic signaling in the pathophysiology of bipolar disorder, such as an increasing in uric acid levels in bipolar disorder subjects and the involvement of the purinergic receptor P2×7 in a preclinical model of mania (Albert et al., 2015, Gubert et al., 2014, Ortiz et al., 2015). This system includes extracellular nucleotides and nucleosides (e.g. adenosine), representing signaling molecules involved in several pathways, such as immune response and neuromodulation (Burnstock, 2008).
Adenosine, particularly, has gained special attention in psychiatric disorders (Krügel, 2016, Lara et al., 2006). It modifies cell function by operating four different cell membrane G-protein-coupled receptors (A1, A2A, A2B and A3), all widely distributed in the central nervous system (CNS) (Burnstock et al., 2011). Adenosine is involved in the regulation of important CNS mechanisms, such as cognition and memory, aggression, anxiety (Ribeiro et al., 2003) and appears to modulate glutamatergic and dopaminergic neurotransmission (Boison, 2008), important molecules in bipolar disorder. Thereby, adenosine is an endogenous neuroprotective compound and has been shown to have anti-inflammatory properties in several in vitro and in vivo systems (Cekic and Linden, 2016), with the ability to decrease levels of pro-inflammatory cytokines via the activation of adenosine receptors (Cekic and Linden, 2016, Haskó et al., 1996, Montes et al., 2016, Sajjadi et al., 1996).
Since adenosine has been implicated as an anti-inflammatory molecule in bipolar disorder, its measurement in patients with bipolar disorder would be relevant, and to our knowledge no work so far has done. Therefore, the aim of this study was to assess the serum levels of adenosine and its degradation products, e.g., inosine, xanthine, hypoxanthine and uric acid, and to evaluate the relationship between psychosocial functioning in euthymic patients with bipolar disorder type I and healthy controls.
Section snippets
Subjects
The present study was approved by the Ethical and Research Committee of Hospital de Clínicas de Porto Alegre, Brazil, protocol number 12-0102. All procedures were performed in accordance with the ethical standards set forth in the Declaration of Helsinki. Moreover, all subjects provided written informed consent after receiving a complete description of the study before their inclusion.
Twenty four chronic treated euthymic patients with bipolar disorder type I were recruited at the Bipolar
Results
Characteristics of patients with bipolar disorder and healthy controls are shown in Table 1.
Results of the purine levels are shown in Fig. 1. We found a significant decrease in blood serum adenosine levels in patients with bipolar disorder compared to matched controls (t= −4.8, df= 43.96, p<0.001) (Fig. 1a). There were no differences between patients and controls in inosine (t= −0.002, df= 46, p= 0.998) (Fig. 1b), xanthine (t= −1.96, df= 46, p= 0.84) (Fig. 1c), hypoxanthine (t= 1.26, df= 47,
Discussion
Our data shows a decrease in serum adenosine levels in euthymic bipolar disorder patients compared with healthy controls, as well as a significant negative correlation between adenosine levels and depression scale scores among patients. Interestingly, we found that higher functioning impairment was linked to lower levels of adenosine in patients, which could indicate an association between adenosine levels and functioning in bipolar disorder.
Decreased serum adenosine levels in bipolar disorder
Author disclosure
Dr Battastini has received grant/research from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), number 303264-2013-6. Dr Kapczinski has received grant/research support from CNPq, number 573671-2008-7.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Contributors
CG, GRF, AMOB and PVSM designed the study; MPV, BTMQS, JS and AF screened the study participants; CG and CEJM performed the experimental analyses; CG and PVSM undertook the statistical analysis; CG, GRF, AMOB, MK, FK and PVSM interpreted the results; CG, AMOB and PVSM supervised the data analysis and writing of the paper, which was revised and approved by all authors.
Conflict of interest
All other authors declare no possible conflicts of interest, financial or otherwise, or grants or other forms of financial support.
Acknowledgement
This work was supported by Fundo de Incentivo à Pesquisa–Hospital de Clínicas de Porto Alegre (FIPE-HCPA) and CNPq: National Science and Technology Institute for Translational Medicine and Research Fellowship. The funding agencies did not have any role in study design, data collection and analysis, the decision to publish, or manuscript preparation. C. Gubert was supported by a doctoral scholarship from CAPES and CNPq.
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