Acute and chronic stress differentially regulate cyclin-dependent kinase 5 in mouse brain: implications to glucocorticoid actions and major depression.

Stress activates the hypothalamic-pituitary-adrenal axis, which in turn increases circulating glucocorticoid concentrations and stimulates the glucocorticoid receptor (GR). Chronically elevated glucocorticoids by repetitive exposure to stress are implicated in major depression and anxiety disorders. Cyclin-dependent kinase 5 (CDK5), a molecule essential for nervous system development, function and pathogenesis of neurodegenerative disorders, can modulate GR activity through phosphorylation. We examined potential contribution of CDK5 to stress response and pathophysiology of major depression. In mice, acute immobilized stress (AS) caused a biphasic effect on CDK5 activity, initially reducing but increasing afterwards in prefrontal cortex (PFC) and hippocampus (HIPPO), whereas chronic unpredictable stress (CS) strongly increased it in these brain areas, indicating that AS and CS differentially regulate this kinase activity in a brain region-specific fashion. GR phosphorylation contemporaneously followed the observed changes of CDK5 activity after AS, thus CDK5 may in part alter GR phosphorylation upon this stress. In the postmortem brains of subjects with major depression, CDK5 activity was elevated in Brodmann's area 25, but not in entire PFC and HIPPO. Messenger RNA expression of glucocorticoid-regulated/stress-related genes showed distinct expression profiles in several brain areas of these stressed mice or depressive subjects in which CDK5-mediated changes in GR phosphorylation may have some regulatory roles. Taken together, these results indicate that CDK5 is an integral component of stress response and major depression with regulatory means specific to different stressors, brain areas and diseases in part through changing phosphorylation of GR.

Mortality in Cushing's syndrome: systematic analysis of a large series with prolonged follow-up.

OBJECTIVE: In this study, we aim to assess the long-term survival and causes of death in a retrospective cohort study on patients with all aetiologies of endogenous Cushing's syndrome (CS) (except adrenal cancer), presenting to two large tertiary endocrine referral centres, and to identify variables predicting mortality. SUBJECTS AND METHODS: The records of all patients presenting with endogenous CS in the Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, UK and the Department of Endocrinology, 'Evangelismos' General Hospital, Athens, Greece between 1967-2009 (Oxford series) and 1962-2009 (Athens series) were reviewed. The standardised mortality ratio (SMR) was calculated for the Oxford series. RESULTS: In total, 418 subjects were identified (311 with Cushing's disease (CD), 74 with adrenal Cushing's (AC) and 33 with ectopic Cushing's (EC)). In CD, the probability of 10-year survival was 95.3% with 71.4% of the deaths attributed to cardiovascular causes or infection/sepsis. SMRs were significantly high overall (SMR 9.3; 95% CI, 6.2-13.4, P<0.001), as well as in all subgroups of patients irrespective of their remission status. In AC, the probability of 10-year survival was 95.5% and the SMR was 5.3 (95% CI, 0.3-26.0) with P=0.2. Patients with EC had the worst outcome with 77.6% probability of 5-year survival. CONCLUSIONS: In this large series of patients with CS and long-term follow-up, we report that in CD the mortality is significantly affected, even after apparently successful treatment. The SMR of patients with AC was high, but this was not statistically significant. The implicated pathophysiological mechanisms for these findings need to be further elucidated aiming to improve the long-term outcome.