dofetilide Previous studies reported that NE and MHPG are de
Previous studies reported that NE and MHPG are deeply involved in depression and that NE reuptake inhibitors are approved for use in patients with depression (for review, see ). We found increased hippocampal content of NE and MHPG in the CORT-treated CRTH2−/− mice (Fig. 3). In the hippocampus, activation of β-adrenoreceptors by NE modulates synaptic transmission through cyclic adenosine monophosphate-mediated signaling . Given that depression as well as stress has profound effects on synaptic function in several dofetilide regions, including prefrontal cortex and hippocampus , CRTH2 may modulate depression through NE-mediated regulation of synaptic function in the hippocampus. It would be important to examine whether synaptic function is altered in CRTH2−/− mice. We also found that L-PGDS mRNA expression was increased in the hippocampus after chronic CORT treatment (Table 2). The blockade of hippocampal glucocorticoid receptor, one of the CORT receptors, attenuates immobility in the FST . These results suggest that CRTH2-mediated pathway in the hippocampus mediates depression-related behaviors induced by chronic CORT treatment; however, other brain regions such as hypothalamus are also involved critically in depression , , . For comprehensive understanding, the role of CRTH2-mediated signaling in depression, it would be needed to examine the various brain systems on depression including hypothalamic–pituitary–adrenal axis function.
The precise mechanisms by which the CRTH2-mediated pathway regulates the noradrenergic system are currently unknown. The norepinephrine transporter, which rapidly clears synaptic NE, is a primary determinant of NE levels . The norepinephrine transporter is phosphorylated and activated by p38-MAP kinase, leading to the rapid clearing of synaptic NE . We recently found that a selective CRTH2 agonist stimulates p38-MAP kinase and enhances NGF-induced neurite outgrowth in PC12 cells , suggesting that the CRTH2-mediated pathway may directly regulate NE content through the phosphorylation of the norepinephrine transporter in the hippocampus. In addition, corticotropin-releasing hormone mediates PGD2-mediated regulation of NE content . Further studies are needed to unravel the precise molecular mechanisms of CRTH2-mediated regulation of NE system.
In summary, using various depression-related animal models, the current study was the first to demonstrate that the central CRTH2-mediated pathway is involved in depression. Importantly, CRTH2−/− mice also showed selective impairment in depression-related behavior in the FST in their basal state, suggesting that the CRTH2-mediated pathway is an important endogenous determinant of emotional state. We propose that the CRTH2-mediated pathway could be a new target for the treatment of depression and that CRTH2−/− mice undergoing pharmacological manipulations could be represent an effective mouse model for developing novel therapeutic interventions for depression.
Acknowledgments This work was supported in part by the Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research, KAKENHI; the Funding Program for Next Generation World-Leading Researchers, Grant No. LS081 (H.H.); Research Fellowships for Young Scientists (Y.O. and R. Hab); the Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers, Grant No. S2603; and grants for research from the Uehara Memorial Foundation, Japan.
Mast cells, which play important roles in allergic diseases, are activated by immunoglobulin E (IgE). Activated mast cells produce a variety of inflammation mediators, of which prostaglandin D2 (PGD) is representative. It has been reported that antigen-challenge-induced PGD production is promoted in the airway of asthmatic patients and that overexpression of PGD synthase enhances airway eosinophil infiltration and Th2 cytokine production in an asthma model. These reports indicate that PGD is closely related to the pathogenesis of allergic diseases, such as asthma, allergic rhinitis, and atopic dermatitis.