Dysregulation of IRAS/nischarin and other potential I 1 -imidazoline receptors in major depression postmortem brain: Downregulation of basal contents by antidepressant drug treatments

• Published in: Journal of affective disorders Vol. 208; pp. 646 - 652
• Main Authors: Keller, Benjamin, García-Sevilla, Jesús A.
• Format: Journal Article
• Language: English
• Published: Netherlands 15.01.2017
• Subjects: Adult; Antidepressive Agents - therapeutic use; Autopsy; Brain - drug effects; Brain - metabolism; Case-Control Studies; Depressive Disorder, Major - drug therapy; Down-Regulation - drug effects; Female; Humans; Imidazoline Receptors - drug effects; Imidazoline Receptors - metabolism; Male; Middle Aged; Prefrontal Cortex - drug effects; Suicide; Up-Regulation - drug effects; Imidazoline receptors; IRAS/nischarin; Postmortem human brain; Major depressive disorder; Antidepressant drugs
• ISSN: 0165-0327; 1573-2517
• DOI: 10.1016/j.jad.2016.10.007

Major depressive disorder (MDD) has been associated with altered brain densities of imidazoline receptors (I -IR and I -IR types). The contents of potential I -IR IRAS/nischarin (167kDa) and, for comparison, those of I - (85kDa) and I - (45kDa and 30kDa) IR proteins were quantified by western blotting in postmortem prefrontal cortex (PFC/BA9) of antidepressant-free ([MDD(-)], n=9) and antidepressant-treated ([MDD(+)], n=12) subjects and matched controls (n=19). In MDD, regardless of antidepressant treatment (n=21), IRAS/nischarin was not altered in PFC/BA9. However, the content of IRAS/nischarin was found modestly and not significantly increased (+19%, p=0.075) in MDD(-) and significantly decreased (-24%, p=0.001) in MDD(+), revealing that basal I -IR content was downregulated by antidepressants. Putative 85kDa I -IR was upregulated (+35%, p=0.035) in MDD(-) but it was not reduced (-14%, p=0.37) in MDD(+). There was a positive correlation (r=0.33, p=0.037, n=40) between the contents of IRAS/nischarin and 85kDa IR proteins in PFC/BA9 (control and MDD subjects). In MDD and regardless of antidepressants, the content of cortical 45kDa I -IR was increased (+31%, p=0.006) and that of 30kDa I -IR decreased (-14%, p=0.002), indicating basal dysregulations of these potential IRs. MDD(+) subjects had been treated with a variety of antidepressant drugs. The results must be understood in the context of suicide victims with MDD. The dysregulation of IRAS/nischarin in depressed brains is a major novel finding that supports a role of this potential I -IR in the neurobiology of MDD and in the molecular mechanisms of antidepressant drugs.