Aldosterone synergizes with peripheral inflammation to induce brain IL-1ß expression and depressive-like effects.

Recent findings have shown that the physiological functions of the hormone aldosterone go far beyond its well-known role in blood-pressure regulation and salt/water homeostasis. Aldosterone is for example involved in the regulation of inflammation, and also binds directly to mineralocorticoid receptors in specific brain regions. Interestingly, depressive symptoms appear to correlate with alterations of the aldosterone system but the underlying mechanisms have not been elucidated. In this study aldosterone (2 µg/100g body weight/day) was continuously administered via osmotic minipumps for 5 days. Lipopolysaccharide (LPS) was administered once a day for 5 days in a dose of 1mg/kg ip. The rats were tested for depressive-like behavior 24h after the last LPS injection. Protein levels of cytokines were measured in serum and cerebrospinal fluid (CSF). mRNA expression of interleukin (IL)-1ß and IL-6 in the prefrontal cortex (PFC) was analyzed using reverse transcriptase qPCR. We found that aldosterone treatment increased LPS-induced IL-1ß mRNA expression in the PFC and CSF. Moreover, there was a positive correlation between IL-1ß in CSF and depressive-like behaviors. These findings suggest that IL-1ß is affected by the renin-aldosterone-angiotensin system (RAAS) activity and connected to symptoms of depression.

Decreased aldosterone in the plasma of suicide attempters with major depressive disorder.

Hormones and neurobiological factors may be regulated differently in suicidal versus non-suicidal depressive patients. There is currently limited knowledge about the relation of substances in the Renin-Angiotensin-Aldosterone system to depression and suicidality. We therefore investigated whether plasma levels of renin and aldosterone differ between suicide attempters, non-suicidal depressive patients and healthy controls. Furthermore, we analyzed the relation of renin and aldosterone to psychiatric symptoms in the patients. Suicidal patients with MDD, adjustment disorder and dysthymia, as well as two control groups consisting of non-suicidal MDD patients and healthy subjects, were rated using the Comprehensive Psychopathological Rating Scale (CPRS), including the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Plasma samples were frozen immediately after collection and stored at -80°C for 5-18years. Aldosterone and renin levels were analyzed using radioactive- and chemiluminescent immunoassays. We found that suicide attempters with MDD had significantly lower plasma levels of aldosterone than the other patient groups, as well as than the healthy controls. Moreover, increasing severity of psychiatric symptoms was associated with lower aldosterone levels in the suicide attempters with MDD. Non-suicidal patients with MDD did not differ significantly compared to healthy controls with respect to aldosterone and renin levels. These findings may indicate that low aldosterone levels could be a marker of suicidality in patients with MDD.

Changes in behaviour and cytokine expression upon a peripheral immune challenge.

Depression is frequently associated with inflammation. Animal studies have shown that peripheral inflammation induces depressive-like behaviour, but the underlying mechanisms remain unclear. A distinction between sickness- and depressive-like behaviour has been proposed. We hypothesize that the behavioural distinction is due to changes in the central production of immune mediators. As a model of peripheral inflammation, we administered lipopolysaccharide (LPS) intraperitoneally daily for 4 days in rats. The effect of LPS on sickness- and depressive-like behaviour was assessed. We examined protein levels and mRNA expression of cytokines and cyclooxygenase (COX) enzymes in serum, cerebrospinal fluid (CSF) and specific brain regions. Two hours post-LPS, the rats displayed sickness behaviour and cytokine levels were elevated in both serum and CSF. This was paralleled by specific alterations of mRNA transcription of IL-1ß, IL-6 and TNF-α in frontal cortex, hippocampus and striatum. Twenty-four hours post-LPS the rats showed depressive-like behaviour and peripheral cytokine levels were back close to baseline. In contrast, the central transcription of IL-1ß mRNA had increased even further, as well as IL-1ß CSF levels. IL-6 and TNF-α transcription was unaltered compared to controls. COX enzymes were downregulated in the hippocampus during sickness behaviour and unaltered during depressive-like behaviour. Our results show for the first time that a peripheral immune challenge induces a region specific transcription of cytokines and COX-enzymes in the brain, at time-points corresponding to behavioural sickness and depression. When the peripheral inflammation and sickness behaviour had ceased, a production of proinflammatory cytokines remained within the brain parenchyma.

Exercise-induced release of cytokines in patients with major depressive disorder.

BACKGROUND: Patients with major depressive disorder (MDD) may display elevated plasma levels of pro-inflammatory substances. Although the underlying mechanisms are unknown, inflammation has been proposed to play a direct role in the generation of depressive symptoms. Skeletal muscle is a potent producer of cytokines, and physical exercise has been suggested to alleviate symptoms of depression. In this study we therefore addressed the question of whether MDD patients display altered levels of pro-, anti-inflammatory and regulatory factors in the blood in response to acute exercise. METHODS: Eighteen MDD patients and 18 healthy controls performed a maximal-workload exercise challenge. Blood samples were taken before the test, at sub-maximal and maximal workload, as well as 30 and 60 min after testing. The plasma levels of SAA, TNF-alpha, S-VCAM, S-ICAM, CRP, IFN-gamma, IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12 and IL-13 were assayed using multiplex sandwich ELISA. RESULTS: Exercise-induced significant changes in the plasma levels of inflammatory substances in both MDD patients and controls. IL-8, IL-6 and TNF-alpha increased, and IL-4 decreased during the challenge in both groups. In addition, IFN-gamma decreased in the controls. There was a significant difference in IL-6 reactivity between the groups at the sub-max timepoint. LIMITATIONS: Group sizes are comparably limited. CONCLUSION: Exercise induces changes in the blood levels of cytokines in unmedicated MDD patients. Whether these changes affect symptoms of depression should be evaluated in long-term studies of the anti-depressive effects of exercise.