sirolimus and Depressive-Disorder

The role of the mechanistic target of rapamycin (mTOR) signaling in the antidepressant effects of ketamine is controversial. In addition to mTOR, extracellular signal-regulated kinase (ERK) is a key signaling molecule in prominent pathways that regulate protein synthesis. (R)-Ketamine has a greater potency and longer-lasting antidepressant effects than (S)-ketamine. Here we investigated whether mTOR signaling and ERK signaling play a role in the antidepressant effects of two enantiomers.. The effects of mTOR inhibitors (rapamycin and AZD8055) and an ERK inhibitor (SL327) on the antidepressant effects of ketamine enantiomers in the chronic social defeat stress (CSDS) model (n = 7 or 8) and on those of ketamine enantiomers in these signaling pathways in mouse brain regions were examined.. The intracerebroventricular infusion of rapamycin or AZD8055 blocked the antidepressant effects of (S)-ketamine, but not (R)-ketamine, in the CSDS model. Furthermore, (S)-ketamine, but not (R)-ketamine, significantly attenuated the decreased phosphorylation of mTOR and its downstream effector, ribosomal protein S6 kinase, in the prefrontal cortex of susceptible mice after CSDS. Pretreatment with SL327 blocked the antidepressant effects of (R)-ketamine but not (S)-ketamine. Moreover, (R)-ketamine, but not (S)-ketamine, significantly attenuated the decreased phosphorylation of ERK and its upstream effector, mitogen-activated protein kinase/ERK kinase, in the prefrontal cortex and hippocampal dentate gyrus of susceptible mice after CSDS.. This study suggests that mTOR plays a role in the antidepressant effects of (S)-ketamine, but not (R)-ketamine, and that ERK plays a role in (R)-ketamine's antidepressant effects. Thus, it is unlikely that the activation of mTOR signaling is necessary for antidepressant actions of (R)-ketamine.

Topics: Aminoacetonitrile; Animals; Antidepressive Agents; Brain; Chronic Disease; Depressive Disorder; Disease Models, Animal; Dominance-Subordination; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Ketamine; Male; Mice, Inbred C57BL; Morpholines; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Stress, Psychological; TOR Serine-Threonine Kinases

Accumulated data support a relationship between mood disorders and cellular plasticity and resilience, some suggesting relevance to autophagy. Our previous data show that pharmacological enhancement of autophagy results in antidepressant-like effects in mice. The current study was designed to further examine the effects of autophagy enhancement on mood by testing the effects of subchronic treatment with the mammalian target of rapamycin (mTOR) inhibitors and autophagy enhancers rapamycin and temsirolimus in a model for mania and in a model for antidepressant action, respectively. The results show that rapamycin reduced mania-like aggression and reward-seeking behaviors, with no effects on locomotion. Temsirolimus reduced depression-related immobility in the forced-swim test without effects on locomotion in the open field or on anxiety-related measures in the elevated plus maze. Taken together with our previous findings, these data support the notion that enhancing autophagy may have mood-stabilizing effects.

Topics: Affect; Aggression; Animals; Antidepressive Agents; Antimanic Agents; Anxiety; Anxiety Disorders; Autophagy; Behavior, Animal; Depression; Depressive Disorder; Male; Mice; Mice, Inbred ICR; Sirolimus

Resolvins are bioactive lipid mediators that are generated from docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). We recently demonstrated that the DHA-derived resolvins D1 and D2 exert antidepressant effects. However, whether the EPA-derived resolvins E1 (RvE1) and E2 (RvE2) produce antidepressant effects is not clear.. We examined the antidepressant effects of RvE1/RvE2 in a murine lipopolysaccharide (LPS)-induced depression model using the tail suspension and forced swim tests. RvE1/RvE2 reportedly possesses both chemerin receptor ChemR23 agonistic activity and leukotriene B. Intracerebroventricular infusions of RvE1 (1 ng)/RvE2 (10 ng) produced significant antidepressant effects. An intracerebroventricular infusion of chemerin (500 ng), but not U75302 (a BLT1 antagonist; 10 or 50 ng), produced antidepressant effects. Intraperitoneal rapamycin (an mTORC1 inhibitor; 10 mg/kg) blocked the antidepressant effect of intracerebroventricular RvE1. Bilateral intra-mPFC and intra-DG infusions of RvE1 (50 pg/side) exerted antidepressant effects.. The results of this study demonstrate that (1) RvE1/RvE2 produce antidepressant effects likely via ChemR23, (2) mTORC1 signaling mediates the antidepressant effect of RvE1, and (3) mPFC and DG are the key brain regions involved in these actions. RvE1/RvE2 and their receptors may be promising targets for the development of novel antidepressants.

Topics: Analysis of Variance; Animals; Antidepressive Agents; Brain; Depressive Disorder; Disease Models, Animal; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Alcohols; Glycols; Hindlimb Suspension; Lipopolysaccharides; Locomotion; Male; Mice; Prefrontal Cortex; Signal Transduction; Sirolimus; Swimming; TOR Serine-Threonine Kinases