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Ghrelin/GHSR System in Depressive Disorder: Pathologic Roles and Therapeutic Implications - PubMed

  • ️Mon Jan 01 2024

Review

Ghrelin/GHSR System in Depressive Disorder: Pathologic Roles and Therapeutic Implications

Xingli Pan et al. Curr Issues Mol Biol. 2024.

Abstract

Depression is the most common chronic mental illness and is characterized by low mood, insomnia, and affective disorders. However, its pathologic mechanisms remain unclear. Numerous studies have suggested that the ghrelin/GHSR system may be involved in the pathophysiologic process of depression. Ghrelin plays a dual role in experimental animals, increasing depressed behavior and decreasing anxiety. By combining several neuropeptides and traditional neurotransmitter systems to construct neural networks, this hormone modifies signals connected to depression. The present review focuses on the role of ghrelin in neuritogenesis, astrocyte protection, inflammatory factor production, and endocrine disruption in depression. Furthermore, ghrelin/GHSR can activate multiple signaling pathways, including cAMP/CREB/BDNF, PI3K/Akt, Jak2/STAT3, and p38-MAPK, to produce antidepressant effects, given which it is expected to become a potential therapeutic target for the treatment of depression.

Keywords: GHSR; GPCR; cell signaling; depression; ghrelin.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1

The antidepressant potential of ghrelin, which exerts neuroprotective effects by promoting neuronal proliferation and neurotrophic factor production in the brain. Ghrelin can inhibit apoptosis, reduce inflammation, increase astrocyte production, and significantly inhibit the process of depression. Ghrelin interacts with GHSR1a to increase the proliferation of hippocampal NSCs by increasing the expression of the Jak2/STAT3 signaling pathway, which also indirectly upregulates the PI3K/Akt/mTOR pathway to jointly exert neuronal protective effects. In addition, ghrelin binding to its receptor can also increase the expression of the PI3K/Akt signaling pathway, play a pro-neural cell proliferation role by promoting the phosphorylation of downstream molecules (mTOR and p70S6K), and inactivate GSK-3β by promoting GSK-3β phosphorylation, which can further increase the nuclear translocation of β-catenin, thus decreasing cellular apoptosis, playing a role in promoting cell survival. The activation of this pathway also promotes the proliferation of astrocytes and the communication of neurons in the brain. Moreover, ghrelin treatment can inhibit the p38-MAPK signaling pathway, increase GR expression, and inhibit glucocorticoid resistance in depressed patients. Additionally, ghrelin increases CREB phosphorylation by promoting the expression of the cAMP/CREB signaling pathway, thus regulating BDNF transcription and eventually exerting neuroprotective effects to inhibit depression. Besides this, ghrelin levels increase in the regulation of inflammatory response; further, this hormone downregulates neutrophil transport and the amount of pro-inflammatory cytokines, thus reducing inflammation, and it also increases the expression of BDNF and improves neurobehavioral function. In the figure, the subtraction symbol indicates inhibitory/suppressing action, while the addition symbol indicates stimulatory action. The P labeled in the circle represents substrate phosphorylation. ↑, increase; ↓, decrease.

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