Role of Janus-Kinases in Major Depressive Disorder

Abstract

Background/Aims: Major depressive disorder is a severe, common and often chronic disease with a significant mortality due to suicide. The pathogenesis of major depression is still unknown. It is assumed that a reduction of neurogenesis in the hippocampus plays an important role in the development of major depressive disorder. However, the mechanisms that control proliferation of neuronal stem cells in the hippocampus require definition. Here, we investigated the role of Janus-Kinase 3 (Jak-3) for stress-induced inhibition of neurogenesis and the induction of major depression symptoms in mice. Methods: Stress was induced by the application of glucocorticosterone. Brain sections were stained with phospho-specific antibodies and analysed by confocal microscopy to measure phosphorylation of Jak-3 specifically in the hippocampus. Jak-3 inhibitors and the antidepressant amitriptyline were applied to counteract stress. The effects of the inhibitors were determined by a set of behavioural tests and analysis of Jak-3 phosphorylation in brain sections. Acid sphingomyelinase-deficient mice were employed to test whether Jak3 is downstream of ceramide. Results: The data show that stress reduces neurogenesis, which is restored by simultaneous application of Jak-3 inhibitors. Inhibition of neurogenesis correlated with an anxious-depressive behaviour that was also normalized upon application of a Jak-3-inhibitor. Confocal microscopy data revealed that stress triggers a phosphorylation and thereby activation of Jak-3 in the hippocampus. Amitriptyline, a commonly used antidepressant that blocks the acid sphingomyelinase, or acid sphingomyelinase-deficiency reduced stress-induced phosphorylation of Jak-3. Conclusion: Our data show that Jak-3 is activated by stress at least partially via the acid sphingomyelinase and is involved in the mediation of stress-induced major depression.

Ceramides affect alcohol consumption and depressive‐like and anxiety‐like behavior in a brain region‐ and ceramide species‐specific way in male mice

“…39 The stress-induced depressive-like and anxiogenic-like phenotypes in wild-type mice were reversed by administration of a Jak-3 inhibitor, suggesting that Jak-3 is involved in the mediation of stress-induced depression and anxiety, which is at least partly dependent on ASM and its product ceramide. 39 The reason for the lack of behavioral effects of C8 and C20 ceramides is unclear to date. Other brain regions might mediate their effects on alcohol consumption and depressive-like and/or anxietylike behavior, or C8 and C20 ceramides might influence completely different behaviors not tested in this study.…”

“…As such, chronic CORT treatment (i.e., exogenous CORT) for 28 days did not affect ASM activity and ceramide concentrations in the hippocampus in C57BL/6J mice, although it induced depressive‐like and anxiogenic‐like phenotypes in these mice 11 . Another mechanism might be via the activation of Janus kinase 3 (Jak‐3), as chronic stress induced a higher phosphorylation of Jak‐3 in wild‐type mice compared with ASM‐deficient mice 39 . Additionally, administration of amitriptyline, which was previously shown to reduce ceramide concentrations and ASM activity in the hippocampus and to normalize the depressive‐like and anxiogenic‐like phenotypes in tgASM mice, 11 also reduced stress‐induced Jak‐3 phosphorylation in wild‐type mice, but not in ASM‐deficient mice 39 .…”

“…Another mechanism might be via the activation of Janus kinase 3 (Jak‐3), as chronic stress induced a higher phosphorylation of Jak‐3 in wild‐type mice compared with ASM‐deficient mice 39 . Additionally, administration of amitriptyline, which was previously shown to reduce ceramide concentrations and ASM activity in the hippocampus and to normalize the depressive‐like and anxiogenic‐like phenotypes in tgASM mice, 11 also reduced stress‐induced Jak‐3 phosphorylation in wild‐type mice, but not in ASM‐deficient mice 39 . The stress‐induced depressive‐like and anxiogenic‐like phenotypes in wild‐type mice were reversed by administration of a Jak‐3 inhibitor, suggesting that Jak‐3 is involved in the mediation of stress‐induced depression and anxiety, which is at least partly dependent on ASM and its product ceramide 39 …”

“…Effects of DH infusions of C8 and C20 ceramides on alcohol drinking, depressive-like behavior, and anxiety-like behavior. Mice were infused with C8 ceramide, C20 ceramide, or vehicle bilaterally into the dorsal hippocampus (DH) on days21,23,25,28,30,32,35,37,39, 42, and 44. Alcohol consumption was assessed between days 28 and 32 in the drinking in the dark paradigm (A), defined as days 1-5 in the figure.…”

The Neuroprotective Effect of Amitriptyline on Radiation-Induced Impairment of Hippocampal Neurogenesis

“…42,43 Glucocorticosterone stress activates Jak-3, at least in part, via the ASMase and inhibition of this enzyme using amitriptyline reduces Jak-3 phosphorylation and improves behavior as well as hippocampal neurogenesis. 44 Glucocorticosterone stress may also induce p38K phosphorylation/activation in the hippocampus and thereby reduces neurogenesis and induces depression-like symptoms which are prevented by antidepressants via inhibition of the ASMase/CE system. It suggests that inhibition of ASMase by amitriptyline may prevent glucocorticoid-mediated stress and induce phosphorylation/ activation of p38K.…”