The NK-1 Receptor Signaling: Distribution and Functional Relevance in the Eye

Round 1

Reviewer 1 Report

It is a good review on “The NK-1 receptor signaling: distribution and functional relevance in the eye”. In this review, the roles of substance P (SP) and neurokinin-1 receptors (NK1R) in the pathophysiology of eye disorders are discussed. Moreover, the therapeutic benefits of NK1R antagonists in the treatment of ocular diseases are reviewed.

 

However, there are some issues.

 

Major point

 

- Page 5. Line 158-162. It says: Further, it was demonstrated that blocking SP led to downregulation of γH2AX, inhibition of the mammalian target of the rapamycin (mTOR) pathway and induced senescence of corneal epithelium. However, it should say: The overexpression of SP is associated with limbal stem cell deficiency (LSCD) and results in accelerated senescence and exhaustion of residual stem cells. By contrast, treatment with NK1R antagonist ameliorates clinical signs associated with LSCD.

 

- One of the ocular diseases is retinoblastoma. It is the most common primary malignant intraocular tumors of childhood. Moreover, retinoblastoma tumors and cells express SP and NK1R. Moreover, SP at nanomolar concentration elicits retinoblastoma cells proliferation. By contrast, the NK-1R antagonists (L-732,138, L-733,060 and aprepitant drug) inhibit retinoblastoma cells proliferation and at certain concentration induces retinoblastoma cells apoptosis (Ophthalmic Res. 1983;15(6):300-6; Invest Ophthalmol Vis Sci. 2005 Jul;46(7):2567-70; Invest Ophthalmol Vis Sci. 2007 Jun;48(6):2775-81; Invest New Drugs. 2010 Apr;28(2):187-93). This section as well as the references should be included and discuss in the manuscript.

 

Minor points

 

- In the abstract should be include substance P (SP) in the pathophysiology of eye disorders.

- Once NK1R or SP has been entered in the text, only this abbreviation should be used throughout the text. Check the text and change NK-1 receptor for NK1R and Substance P for SP

 

- TAC1KO should be in italics TAC1KO

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

The manuscript written by Ibrahim Halil Demirsoy et al. focuses on SP-NK1R signaling in eye disease. The authors summarized the expression and biological roled of NK1R in the eye, as well as its involution with the physiopathology of eye disorders. Despite the relevance of the study, this article should make improvements before publication.

1. Line 41-43: The lack of C-terminal of NK1R led to the absence of interaction with both β-arrestin and G-protein.

2. Line 57-60: long sentences and grammar mistakes should be revised.

3. The authors listed NK1R mediated multiply signaling pathways in a textbook style in section 1.3. I may suggest that they could describe them according the cell types in which the original investigations were performed, as well as the related biological effects such as inflammation, cell migration, etc. The original references should be cited.

4. They summarized the functions of NK1R in pathophysiology of corneal epithelial wound healing, ocular surface inflammation and pain, however, the details about how NK1R exerted these functions were not fully provided. Such as:

1) Blocking SP was beneficial for corneal transparency and wounding healing. Is any study reported SP concentration of improving corneal epithelial wound healing while SP concentration was necessary for the destiny of SP function? Line158-161

2) The meaning of pathogen clearance should be explained in a detail. Line189

3) The author should discuss the role of NK1R in AMD model in detail.

4) Author should elaborate on the cytokines involved in ocular inflammation in part of 1.5.2 section. The publications about cytokines regulated inflammation of eye diseases should be cited.

5) In the section 1.5.3, the activity of NK1R in ocular pain is not well characterized, especially about the effect of NK1R antagonists. (Topical administration of the NK1R antagonist fosaprepitant effectively reduces ocular surface nociception by decreasing SP release in the tear fluid and TG, and corneal leukocyte infiltration. Fosaprepitant repurposing shows promise for the treatment of ocular pain)

6) The author should summarize the potential of NK1R as a target in ocular infectious and inflammatory conditions or graft host eye. (PMID: 36067981) (PMID: 35644287) (PMID: 32058829)

5. Extensive editing of English language and style are required to improve the manuscript.

Author Response

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Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Page 7 line 258 : delete reference 128 in the manuscript and in the references line 695-696.

Page 7 line 259 to add " and aprepitant after to L-733,060"

Page 8 line 321 L-732,138 is repeted, delete one .Check and change to L-732,138 always in the text

Page 9 line 336 delete the reference 154 in this paragraf and in the references line 763-765.

Then Check the references both the manuscript and the references

Author Response

Please see the attachment.

Author Response File: Author Response.pdf