Review Reports

Round 1

Reviewer 1 Report

Article entitled ’’ A quinoline tetrahydro-6-hydroxy derivative alleviates oxidative stress and NF-κB-mediated inflammation in rats with experimental Parkinson's disease”

is very interesting and issues in the field of Parkinson's disease and inflammation, or oxidative stress as the cause of this disease are important and timely. However, the work needs refinement.

1.       Under Figures 2 and 4, authors should provide the number n.

2.       In the introduction, it would be worthwhile to detail the link between oxidative stress and NF-kappaB and inflammation. For a better understanding, it would be useful to present it on a diagram. The authors presented this issue too superficially and it may be incomprehensible to the reader why antioxidant compounds may have anti-inflammatory effects or affect the transcription factor NF-kappaB.

3.       It would also be worth explaining the importance of 8-isoprostane and lipid peroxidation products. What role do these factors play and why were they marked?

4.       However, my main complaint is the need to perform additional experiments. Considering the work done on animals, definitely more research should be done to clarify all aspects. In addition to the analysis of gene expression, the authors should determine the level of proteins, i.e. interleukins, COX, as well as the level of active NF-kappaB penetrating the cell nucleus and activating the expression of factors, e.g. pro-inflammatory.

 

Author Response

Dear Editors and Reviewers,

Thank you for your conscientious review of this article and for providing insightful feedback. We have made every effort to consider all of your comments. Our responses to each of the comments are outlined below, with all changes to the text highlighted in yellow. On the suggestion of Ms Linnie Yin, we have selected Khidmet S. Shikhaliev as the correspondent author.

Kind regards, the authors.

 

Reviewer 1

Article entitled ’’ A quinoline tetrahydro-6-hydroxy derivative alleviates oxidative stress and NF-κB-mediated inflammation in rats with experimental Parkinson's disease”

is very interesting and issues in the field of Parkinson's disease and inflammation, or oxidative stress as the cause of this disease are important and timely. However, the work needs refinement.

1. Under Figures 2 and 4, authors should provide the number n.

The number n has been added to the captions of the figures.

2. In the introduction, it would be worthwhile to detail the link between oxidative stress and NF-kappaB and inflammation. For a better understanding, it would be useful to present it on a diagram. The authors presented this issue too superficially and it may be incomprehensible to the reader why antioxidant compounds may have anti-inflammatory effects or affect the transcription factor NF-kappaB.

In the introduction, we have elaborated on the NF-kappaB factor and its relationship to oxidative stress. The graphical abstract will encompass the mechanisms of NF-kappaB regulation, and the remaining findings obtained during the study.

3. It would also be worth explaining the importance of 8-isoprostane and lipid peroxidation products. What role do these factors play and why were they marked?

We have extended the discussion regarding the role of oxidation molecule processes and oxidation products in the pathogenesis of PD (lane 377).

4. However, my main complaint is the need to perform additional experiments. Considering the work done on animals, definitely more research should be done to clarify all aspects. In addition to the analysis of gene expression, the authors should determine the level of proteins, i.e. interleukins, COX, as well as the level of active NF-kappaB penetrating the cell nucleus and activating the expression of factors, e.g. pro-inflammatory.

To obtain data on NF-kappaB levels, we analysed the activated form of the p65 subunit of this factor (p65 phospho S276) [doi: 10.3390/cells5010012]. We outlined this point in the Methods section. To provide precise numerical values of the results, we counted the number of cells positive for NF-kappaB p65 phospho S276 and represented the data in a diagram.

In terms of cytokines, our hypothesis was that NF-kappaB activation in rats with PD is linked to heightened transcription of this factor's target genes, particularly proinflammatory genes. We confirmed cytokine gene transcription activation by analysing their mRNA levels by qPCR. As a result of inflammatory gene activation, the inflammatory response was triggered along with the induction of the immune system, which we verified by measuring the total immunoglobulin G level in animals. HTHQ, owing to its capacity for protection and antioxidant qualities, lowered the level of active NF-kappaB. This effect corresponded with a decrease in proinflammatory gene transcription intensities and degree of immune system activation.   

Reviewer 2 Report

The authors report synthesis of a known compound, 6-hydroxy-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline (HTHQ), and its influence on motor-coordination scores, brain tissue morphology, expression of tyrosine hydroxylase, severity of oxidative stress parameters, levels of the p65 subunit of NF-κB factor, and the inflammatory response in rats during the development of rotenone-induced parkinsonism. The reported results might add knowledge to the ongoing worldwide search for the remedy for Parkinson disease. There are several revisions that shoul dbe done before the manuscript may be accepted for publication.

-          Lines 110-114: The description of the synthesis of the investigated compound needs improvement. First of all, the compound used in the study is known. The search conducted on September 1, 2023 in SciFinder indicated 32 references related to this compound and showed 45 commercial suppliers for it. Thus, the first question is whether the synthesis procedure used by the authors in new. If it isn’t, then such information should be provided in the text and reference should be provided. If the authors used a new path for the synthesis of this compound, the Experimental part is needed where the general information for the synthesis would be provided and the statement about the melting point and at least ¹H NMR spectral data being in accordance with the reported ones is needed.  

-          Since just one quinoline compound is used in the study, my advice would be to use its full chemical name in the title and just abbreviation everywhere in the text instead of such unclear name as "hydroxy derivative of quinoline".

-          Institutional Review Board Statement is missing

-          The references should be revised to meet the style of the journal as indicated in the template:  Author 1, A.B.; Author 2, C.D. Title of the article. Abbreviated Journal Name Year, Volume, page range.

-          Line 101: the index 3 in CH3 should be in subscript

-          Line 105: what do authors mean by „saturated compound“?

Line 21: my suggestion would be to write “comparative” instead of “comparator”

Line 41: “electron leakage“ would sound better as “electron transfer“

Line 52: “a” before “means” should be deleated

Line 65: my suggestion would be to write etc. instead of “and so on”.

Line 71: please, check the meaning of the sentence – whether “leads” should be for singular.

Line 85: “what” instead of “which”?

Author Response

Dear Editors and Reviewers,

Thank you for your conscientious review of this article and for providing insightful feedback. We have made every effort to consider all of your comments. Our responses to each of the comments are outlined below, with all changes to the text highlighted in yellow. On the suggestion of Ms Linnie Yin, we have selected Khidmet S. Shikhaliev as the correspondent author.

Kind regards, the authors.

Reviewer 2

The authors report synthesis of a known compound, 6-hydroxy-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline (HTHQ), and its influence on motor-coordination scores, brain tissue morphology, expression of tyrosine hydroxylase, severity of oxidative stress parameters, levels of the p65 subunit of NF-κB factor, and the inflammatory response in rats during the development of rotenone-induced parkinsonism. The reported results might add knowledge to the ongoing worldwide search for the remedy for Parkinson disease. There are several revisions that shoul dbe done before the manuscript may be accepted for publication.

-          Lines 110-114: The description of the synthesis of the investigated compound needs improvement. First of all, the compound used in the study is known. The search conducted on September 1, 2023 in SciFinder indicated 32 references related to this compound and showed 45 commercial suppliers for it. Thus, the first question is whether the synthesis procedure used by the authors in new. If it isn’t, then such information should be provided in the text and reference should be provided. If the authors used a new path for the synthesis of this compound, the Experimental part is needed where the general information for the synthesis would be provided and the statement about the melting point and at least ¹H NMR spectral data being in accordance with the reported ones is needed.  

We synthesized HTHQ using the established methodology. References were included in the synthesis description as necessary.

-          Since just one quinoline compound is used in the study, my advice would be to use its full chemical name in the title and just abbreviation everywhere in the text instead of such unclear name as "hydroxy derivative of quinoline".

In the title of the article, the exact name of the tested compound was specified. Additionally, in the text, we clearly indicate which compounds are being discussed (line 101 and line 122).

-          Institutional Review Board Statement is missing

Institutional Review Board Statement has been added to the article.

-          The references should be revised to meet the style of the journal as indicated in the template:  Author 1, A.B.; Author 2, C.D. Title of the article. Abbreviated Journal Name Year, Volume, page range.

The references have been corrected.

-          Line 101: the index 3 in CH3 should be in subscript

Indices at chemical substituents have been corrected (line 122, 399).

-          Line 105: what do authors mean by „saturated compound“?

An unfortunate phrase has been concretised: «a compound with a saturated quinoline ring» (line 126)

Line 21: my suggestion would be to write “comparative” instead of “comparator”

The word has been replaced.

Line 41: “electron leakage“ would sound better as “electron transfer“

The phrase has been changed

Line 52: “a” before “means” should be deleated

"a" was deleted.

Line 65: my suggestion would be to write etc. instead of “and so on”.

The change has been made.

Line 71: please, check the meaning of the sentence – whether “leads” should be for singular.

Yes, it is correct to write in the singular.

Line 85: “what” instead of “which”?

Yes (line 106)

Round 2

Reviewer 1 Report

Dear Authors

Thank you for your answer. Determining cytokines would complete the whole, but ultimately I accept it in this form.

Reviewer 2 Report

The authors have revised the manusript. It can be accepted for publishing.