Abstract
Interleukins and neurotrophins levels are altered in the periphery of patients with major depression and suicidal behavior, however it is not clear if similar abnormalities occur in the central nervous system. Our objective was to examine the association of IL-6, IL-1β, BDNF, and GDNF levels between postmortem plasma, cerebrospinal fluid (CSF), and brain tissue in a heterogeneous diagnostic subject groups including normal controls, mood disorders only, mood disorders with AUD/SUD (alcohol abuse disorder, substance abuse disorder), and AUD/SUD without mood disorders. To address these questions we collected postmortem plasma (n = 29), CSF (n = 28), and brain (BA10) (n = 57) samples from individuals with mood disorder, mood disorder with AUD/SUD, AUD/SUD and normal controls. These samples were analyzed using a multiplex based luminex assay with a customized 4-plex cytokine/interleukins- IL-6, IL-1β, BDNF, and GDNF human acute phase based on xMAP technology platform. Protein levels were determined using a Luminex 200 instrument equipped with Xponent-analyzing software. We observed IL-6 (p = 2.1e-07), and GDNF (p = 0.046) were significantly correlated between brain and CSF. In addition, IL-6 (p = 0.031), were significantly correlated between brain and plasma. Overall diagnostic group analysis showed a significant difference with brain GDNF, p = 0.0106. Pairwise comparisons showed that GDNF level is—39.9 ± 12 pg/ml, p = 0.0106, was significantly higher than in the brains derived from mood disorders compared to normal controls, —23.8 ± 5.5 pg/ml, p = 0.034. Brain BDNF was higher in suicide (p = 0.0023), males compared to females (p = 0.017), and psychiatric medication treated vs. non-treated (p = 0.005) individuals. Overall, we demonstrate that blood IL-6, GDNF and BDNF could be informative peripheral biomarkers of brain biology associated with mood disorders, substance disorders, and suicide.
Highlights
Understanding the pathophysiology of mood and substance use disorders will involve integrating multiple biological pathways
The present study is the first to look at the levels of interleukins Il-6, IL-1β; neurotrophins Brain derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) in human postmortem cerebrospinal fluid (CSF), plasma, and brain from the same individuals
We report in the study the differential levels of interleukins and neurotrophins based on gender, suicidal vs. non-suicidal and psychiatric medications across periphery and central nervous system (CNS)
Summary
Understanding the pathophysiology of mood and substance use disorders will involve integrating multiple biological pathways. Two areas of growing interest are the inflammation/interleukin and cell growth/neurotrophic. Brain derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) are crucial brain signaling proteins whose deficiency in key neural pathways has been associated with the development of psychiatric disorders[1,3]. Interleukins are responsible for promoting cell growth, differentiation, functional activation, and play a crucial role in mediating the interaction of inflammatory and immune cells[5]. The role of interleukins, neurotrophic factors and immune dysregulation has been studied in many psychiatric disorders and suicide[6,7]. Aberrant levels of proinflammatory interleukins have been reported in major depressive disorder (MDD), schizophrenia, bipolar disorder (BD), alcohol use disorder (AUD), suicidality and substance abuse disorder (SUD)[8,9,10,11]
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