Apoptosis-related proteins and proliferation markers in the orbitofrontal cortex in major depressive disorder

• Published in: Journal of affective disorders Vol. 158; pp. 62 - 70
• Main Authors: Miguel-Hidalgo, Jose J., Whittom, Angela, Villarreal, Ashley, Soni, Madhav, Meshram, Ashish, Pickett, Jason C., Rajkowska, Grazyna, Stockmeier, Craig A.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier B.V 01.04.2014; Elsevier
• Subjects: Adult and adolescent clinical studies; Antidepressant drugs; Antidepressive Agents - therapeutic use; Apoptosis; Biological and medical sciences; Biomarkers - metabolism; Case-Control Studies; Caspase 8 - metabolism; Cell Proliferation; Comorbidity; Cortex; Density; Depression; Depressive Disorder, Major - drug therapy; Depressive Disorder, Major - metabolism; Depressive personality disorders; Female; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Ki-67 Antigen - metabolism; Male; Medical sciences; Miscellaneous; Mitochondrial Proteins - metabolism; Mood disorders; Postmortem; Prefrontal cortex; Prefrontal Cortex - metabolism; Proliferating Cell Nuclear Antigen - metabolism; Proteins; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Vulnerability; X-Linked Inhibitor of Apoptosis Protein - metabolism; Depression; Vulnerability; Prefrontal cortex; Comorbidity; Postmortem; Mood disorder; Cell proliferation; Orbitofrontal cortex; Central nervous system; Protein; Encephalon; Concomitant disease; Apoptosis
• ISSN: 0165-0327; 1573-2517; 1573-2517
• DOI: 10.1016/j.jad.2014.02.010

In major depressive disorder (MDD), lowered neural activity and significant reductions of markers of cell resiliency to degeneration occur in the prefrontal cortex (PFC). It is still unclear whether changes in other relevant markers of cell vulnerability to degeneration and markers of cell proliferation are associated with MDD. Levels of caspase 8 (C8), X-linked inhibitor of apoptosis protein (XIAP), direct IAP binding protein with low pI (DIABLO), proliferating cell nuclear antigen (PCNA) and density of cells immunoreactive (-IR) for proliferation marker Ki-67 were measured in postmortem samples of the left orbitofrontal cortex (OFC) of subjects with MDD, and psychiatrically-normal comparison subjects. There was significant increase in C8, a higher ratio of DIABLO to XIAP, lower packing density of Ki-67-IR cells, and an unexpected age-dependent increase in PCNA in subjects with MDD vs. controls. PCNA levels were significantly higher in MDD subjects unresponsive to antidepressants or untreated with antidepressants. The DIABLO/XIAP ratio was higher in MDD subjects without antidepressants than in comparison subjects. Qualitative nature of responsiveness assessments; definition of resistance to antidepressant treatment is still controversial; and unclear role of PCNA. Markers of cell vulnerability to degeneration are increased and density of Ki67-positive cells is low MDD, but accompanied by normal XIAP levels. The results suggest increased vulnerability to cell pathology in depression that is insufficient to cause morphologically conspicuous cell death. Persistent but low-grade vulnerability to cell degeneration coexisting with reduced proliferation readiness may explain age-dependent reductions in neuronal densities in the OFC of depressed subjects.