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

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript titled "Ghrelin/GHSR System in Depressive Disorder: Pathologic Roles and Therapeutic Implications" provides a literature review on the pathological roles of the Ghrelin/GHSR system in depressive disorder and its potential therapeutic implications. While I think the review provides significant insights, it also has several major shortcomings. Key issues include misconceptions regarding the current model for the central action of ghrelin, the omission of information regarding LEAP2, and a lack of discussion on controversies in the field. I identified several major points that should be addressed:

 

1. There are two major flaws in the introduction regarding the descriptions of the central actions of ghrelin:

   - The article states that ghrelin has been found in various organs, including the hypothalamus, pituitary, and hippocampus. However, it is well established that ghrelin is not produced in the central nervous system (10.3390/ijms18030638).

   - The text argues that ghrelin can cross the blood–brain barrier (BBB). The notion that ghrelin crosses the BBB in a blood-to-brain direction is incorrect. Seminal studies by Banks and colleagues show that mouse ghrelin does not access the mouse brain (10.1124/jpet.102.034827). Further studies using fluorescent ghrelin confirm these findings, demonstrating that the accessibility of plasma ghrelin to the brain is strikingly low and depends on blood-cerebrospinal fluid transport (as reviewed in 10.3390/ijms18040859 and 10.1111/jne.12677). The review presents a misconception about the central effects of ghrelin.

 

2. The review lacks inclusion of the identification of LEAP2, a recently recognized GHSR ligand that blocks ghrelin action and acts as an inverse agonist of GHSR (10.1016/j.cmet.2017.10.016 and 10.1021/acs.jmedchem.8b01644). Additionally, the ligand-independent actions of GHSR should be addressed.

 

3. The manuscript does not align with the current consensus nomenclature for the ghrelin system (10.1111/jne.13224). For example, it should avoid using the redundant expression "acyl ghrelin."

 

4. The molecular events regulated by ghrelin-evoked GHSR activity should include a detailed discussion of the mechanisms involving presynaptic calcium channels and the regulation of neurotransmitter release (e.g., 10.1085/jgp.201511383).

 

5. The review should more thoroughly address the role of ghrelin as a modulator of the HPA axis (10.1371/journal.pone.0031462, 10.1016/j.psyneuen.2016.01.027, 10.1016/j.biopsych.2012.03.010, 10.1210/en.2016-1306), given the well-established link between HPA axis dysfunctions and mood disorders.

Comments on the Quality of English Language

None

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This review focuses on the role of Ghrelin/GHSR in depressive disorders. Pan et al., discuss ghrelin's role in neuritogenesis, astrocyte protection, inflammatory factor production, and endocrine disruption in depression. The authors also highlight the signaling pathways including cAMP/CREB/BDNF, PI3K/Akt, Jak2/STAT3, and p38-MAPK, which may have antidepressant effects that are activated by Ghrelin/GHSR activates, making it a potential therapeutic target for depression treatment. The review is comprehensive and well written. I have some minor concerns:

1. The transition between the paragraphs are very abrupt.  

2. Some sentences are long and confusing: For example:

The expression of these monoamine neurotransmitters may be involved in the neuropathologic process of ghrelin. 

Moreover, the reduced mRNA expression of dopaminergic receptors in the amygdala and the dorsal nucleus of the middle suture was found in studies in GHSR1a-/- mice [32], suggesting the potential regulation of dopamine neuron production by the ghrelin/GHSR system.

Ghrelin also directly induces the proliferation and differentiation of adult neural progenitor cells in the 174 hippocampal subgranular zone, and in the case of ghrelin receptor-knock-out mouse(GHSR1a-/-) systemic administration, it was found that the number of progenitor cells was reduced compared with the wild-type controls [55]. 

Serum ghrelin concentrations have been reported to increase in inflammatory bowel 113 disease (IBD) and are associated with the degree of activity [38]. 

 

Comments on the Quality of English Language

No major issues in English language noted.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have satisfactorily addressed the concerns I raised in my previous revision