Ghrelin signaling attenuates the inflammatory activation of neuroimmune system in senescence

概要

(Introduction)
In the senescent brain, the chronical activation of the neuroimmune system takes place and causes the degeneration of adult neurogenesis associated with cognitive impairment or locomotion. However, to date the treatment of aberrant neuroinflammation in senescence and its related neurological and mental disorders has not been established. In the present study the involvement of ghrelin and its downstream sirtuin1 (SIRT1) in the amelioration of inflammatory activation of microglia, a major neuroimmune cell in the central nervous system, was investigated in klotho-deficient mouse, a model of senescence.

(Results)
1. The morphological analyses of neuroinflammatory activation in rikkunshito-administered klotho-deficient mice.
In rikkunshito-administered mice adult neurogenesis in the hippocampus was considerably restored after 1 week of administration.

2. The effects of ghrelin on microglial production of neuroprotective and inflammatory factors
The data demonstrated that ghrelin induced microglial production of several neuroprotective factors, BDNF, IGF-1, while ghrelin reduced its production of various inflammatory factors, IL-1E, IL-6, TNFD.

3. The in vitro examination of anti-inflammatory activity of ghrelin on neural stem cells The results showed that ghrelin induced microglial characteristic transition to neuroprotective, in which ghrelin reduced microglial neurotoxicity on neural stem cells and restored their proliferation .

4. The involvement of signaling pathway through SIRT1 downstream ghrelin receptor in modulation of neuroinflammation
Our data demonstrated that the stimulation of ghrelin-SIRT1 signaling cascade with the administration of rikkunshito, Japanese Kampo medicine, reduced microglial inflammatory activation and restored the degenerated hippocampal adult neurogenesis.

(Discussion)
These results imply that the therapeutic intervention targeting at microglial activation through ghrelin-SIRT1 signaling cascade might be beneficial to treat neuroinflammation in the senescent brain and its associated diseases such as dementia and locomotive syndrome.