Traumatic Brain Injury, Sleep, and Melatonin—Intrinsic Changes with Therapeutic Potential

Round 1

Reviewer 1 Report

u1.       It is well documented that melatonin is synthesized in the mitochondria and the majority of its neuronal protective effects may occur at the level of mitochondria, particular mediated by melatonin membrane receptor 1 (MT1) located in the mitochondrial outer membrane (Suofu, et al. Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release. Proc Natl Acad Sci U S A. 2017  114(38): E7997–E8006. doi: 10.1073/pnas.1705768114). This novel information should be discussed in detail to improve the quality of the report.

 

2.       In humans, it is believed that the insomnia is more or less associated to the disrupted melatonin circadian rhythm. It is speculated that the CSF melatonin circadian rhythm is dominated to the sleep regulation and brain protection over to the blood melatonin circadian rhythm (Dun-Xian Tan, Russel J. Reiter, Scott Zimmerman, Ruediger Hardeland Melatonin: Both a Messenger of Darkness and a Participant in the Cellular Actions of Non-Visible Solar Radiation of Near Infrared Light Biology (Basel) 2023 Jan; 12(1): 89.  doi: 10.3390/biology12010089). This important issue directly related to this review should be discussed.

3.       It would be better to add a paragraph as to the safety and side effects of melatonin compared to other compounds used in the traumatic brain injury and evaluate their risk/benefit properties.   

 

Author Response

We would like to thank the reviewers for their consideration, time, thoughtful comments, and insightful recommendations. Please, find our incorporation of these suggestions in the attached document, which we feel have strengthened the paper significantly.

 

REVIEWER 1:

 

u1.       It is well documented that melatonin is synthesized in the mitochondria and the majority of its neuronal protective effects may occur at the level of mitochondria, particular mediated by melatonin membrane receptor 1 (MT1) located in the mitochondrial outer membrane (Suofu, et al. Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release. Proc Natl Acad Sci U S A. 2017  114(38): E7997–E8006. doi: 10.1073/pnas.1705768114). This novel information should be discussed in detail to improve the quality of the report.

• Thank you for the helpful feedback on this and for including the references! We have added information and citation to lines 338, 452-455 [83].

2. In humans, it is believed that the insomnia is more or less associated to the disrupted melatonin circadian rhythm. It is speculated that the CSF melatonin circadian rhythm is dominated to the sleep regulation and brain protection over to the blood melatonin circadian rhythm (Dun-Xian Tan, Russel J. Reiter, Scott Zimmerman, Ruediger Hardeland Melatonin: Both a Messenger of Darkness and a Participant in the Cellular Actions of Non-Visible Solar Radiation of Near Infrared Light Biology (Basel) 2023 Jan; 12(1): 89. doi: 10.3390/biology12010089). This important issue directly related to this review should be discussed.

• Thank you for the feedback and reference! We appreciate your time in helping us strengthen our manuscript!!  We have added information from article [87] to lines 348-360.
• Added information from reference 93 [84] found in article to line 339-340.
  • Added additional information from references found within article to lines 360-367.
  • Added additional figure from reference found within article (Figure 5) with permission from the author.
• Added information from reference 190 [147] found in article to line 771-773.
  • Also updated Figure 3 with information about melatonin’s influence on M2 polarization.

3. It would be better to add a paragraph as to the safety and side effects of melatonin compared to other compounds used in the traumatic brain injury and evaluate their risk/benefit properties.

• Added paragraph–lines 839-855.

 

 

Reviewer 2 Report

Abstract

The authors say that TBI is one of the most prevalent causes of death in the U.S. This is not true. It is not among the 10 leading causes of death in any age category.

Introduction

Line 46. “chronicity of injury” is not clear. Do you mean the severity and long-term effect of the injury?

Lines 63-64. Which authors?

Lines 70-72. Reference(s)?

Perhaps start a new paragraph at line 72, beginning with “Despite …”

Methods

Line 87. A non-systematic literature review is informative (versus all encompassing) on a topic. However, your search appears to be comprehensive. I’m just curious about the use of the word non-systematic.

Results

Line 115. “1, 2” Also capitalize “appendix”

The placement of “Continued” for the tables is odd, appearing mid pages.

Discussion

Line 171-175. Missing reference(s).

Author Response

We would like to thank the reviewers for their consideration, time, thoughtful comments, and insightful recommendations. Please, find our incorporation of these suggestions in the attached document, which we feel have strengthened the paper significantly.

 

REVIEWER 2:

 

Abstract

The authors say that TBI is one of the most prevalent causes of death in the U.S. This is not true. It is not among the 10 leading causes of death in any age category.

• Changed mortality to morbidity.

Introduction

Line 46. “chronicity of injury” is not clear. Do you mean the severity and long-term effect of the injury?

• Changed to the “chronicity since injury”

Lines 63-64. Which authors?

• Changed to the “the authors of this paper”

Lines 70-72. Reference(s)?

• Added reference to 29.

Perhaps start a new paragraph at line 72, beginning with “Despite …”

• Thank you, we started a new paragraph here as you recommended.

Methods

Line 87. A non-systematic literature review is informative (versus all encompassing) on a topic. However, your search appears to be comprehensive. I’m just curious about the use of the word non-systematic.

• We did not pre-define/pre-plan a method for researching and incorporating the literature for the article. However, we did attempt to be all-encompassing.

Results

Line 115. “1, 2” Also capitalize “appendix”

•  

The placement of “Continued” for the tables is odd, appearing mid-pages.

• Added spacing to correct odd placement.

Discussion

Line 171-175. Missing reference(s).

• Added citation to reference 73.

Round 2

Reviewer 1 Report

This is a sound timely review. It summarized majority of the development of melatonin on traumatic brain injury, sleep and melatonin. There is only one suggestion from this review. Recently it was hypothesized that neurophysiology including the sleep may have been impacted by the circulation of neural glymphatic system which may wash the brain to clean the neuronal debride, especially after TBI and melatonin promotes its circulation (Bitar, R.D., Torres-Garza, J.L., Reiter, R.J. and Phillips, W.T. 2021. Neural glymphatic system: Clinical implications and potential importance of melatonin. Melatonin Research. 4, 4 (Dec. 2021), 551-565. doi.10.32794/mr112500111.). In addition, pineal gland is a source of CSF formation to promote the CSF circulation (Tan DX, Manchester LC, Reiter RJ. CSF generation by pineal gland results in a robust melatonin circadian rhythm in the third ventricle as an unique light/dark signal. Med Hypotheses. 2016, 86:3-9. doi: 10.1016/j.mehy.2015.11.018). Its injury may also worse the TBI. Additional paragraph on this information would strengthen the argument.  

Author Response

Thank you again for your time, consideration, and insightful recommendations. We incorporated information from the two articles (lines 419-437) and corrected/added information to a separate paragraph (lines 608-682).