Role of Oxidative Stress on the Etiology and Pathophysiology of Amyotrophic Lateral Sclerosis (ALS) and Its Relation with the Enteric Nervous System

Round 1

Reviewer 1 Report

This manuscript can be accepted after revisions.

Here are the points:

-(with the glutaminergic inhibitor rulizol as the active ingredient) is wrong. It must be riluzole

-Riluzole® must be Rilutek (because riluzole is active ingredient and marketed names are different).

-“Immunosuppressive treatments with cyclosporine or azathioprine, and immunotherapy with plasmapheresis or immunoglobulins, have been tested for patients in advanced stages”. This indication is not adequate because most of the treatment options were on trials. I should recommend authors to check this manuscript “Int J Mol Sci. 2022 Feb 22;23(5):2400. doi: 10.3390/ijms23052400.) Due to lots of similarities, authors also should cite this paper.

-Currently, Riluzole® (with the glutaminergic inhibitor rulizol as the active ingredient) is the only available drug that slightly delays the clinical course, and seems to extend the survival of ALS patients by about 3 months. This meaning is also wrong because edaravone is also FDA approved.

-There must be “Future and Remarks” part.

Author Response

Response to Reviewer 1 Comments

Dear Reviewer 1, thank you very much for all your suggestions such appropriate. We show you all the changes made in this document:

 

Comments and Suggestions for Authors:

This manuscript can be accepted after revisions.

Here are the points:

Point 1: -(with the glutaminergic inhibitor rulizol as the active ingredient) is wrong. It must be riluzole.

Response 1: Thank you for this correction-we have changed it in the line 144.

 

Point 2: -Riluzole® must be Rilutek (because riluzole is active ingredient and marketed names are different).

Response 2: We fully agree with this point-it has been corrected in line 144.

 

Point 3: -“Immunosuppressive treatments with cyclosporine or azathioprine, and immunotherapy with plasmapheresis or immunoglobulins, have been tested for patients in advanced stages”. This indication is not adequate because most of the treatment options were on trials. I should recommend authors to check this manuscript “Int J Mol Sci. 2022 Feb 22;23(5):2400. doi: 10.3390/ijms23052400.) Due to lots of similarities, authors also should cite this paper.

Response 3: We appreciate your comment and we have changed this sentence to state a therapy in a more advanced phase of study based on the manuscript that you have recommended, among others. The modification appears on lines 138-143. We also add the recommended reference.

Point 4: -Currently, Riluzole® (with the glutaminergic inhibitor rulizol as the active ingredient) is the only available drug that slightly delays the clinical course, and seems to extend the survival of ALS patients by about 3 months. This meaning is also wrong because edaravone is also FDA approved.

Response 4: thank you for your comment. Due to edaravone is approved in several countries of Asia, USA, Canada and in Switzerland, and still pending approval in several countries of the European Union), we consider this important fact and include it in the text in line 145-147.

Point 5: - -There must be “Future and Remarks” part.

Response 5: In response to your requirement, we have added one paragraph more, included in the conclusion paragraph, to maintain the template structure. In which we state the importance of obtaining new evidences focused on each of the different mechanisms of action for the treatment of this disease. We also highlight, in our opinion, the interest of preventing the possible precipitating factors of ALS, specifically the growing clinical interest of possible gene therapy, as well as the need to implement genetic studies in predisposed individuals.

Thank you very much for your indications. Your comments have really improved this manuscript.

Author Response File: Author Response.docx

Reviewer 2 Report

An interesting review article. Typical poings of pathophysiology, genetic findings, risk factors are developed. And the presenting knowledge are mostly deeper than most of other review articles. I have some comments:

There are some pathomechanisms only suggested and not really presented -toxic products of astrocytes, altered intestinal proteins (SMMHC, GFAP), sustained neuronal excitability, etc And these hypothesis should be more implemented into the patomechanisms - if it is possible.

The role of increased physical activity - it is also mentioned in the conclusion, but is not sufficiently strong evaluated.

The conclusion - I mean, too many adjectives and factors, that the reader should pick up the real one by himself.

Though the enteric nervous system dysfunction is mentioned at the conclusion, there is very little written about it in the text.

Author Response

Response to Reviewer 2 Comments

Comments and Suggestions for Authors:

An interesting review article. Typical poings of pathophysiology, genetic findings, risk factors are developed. And the presenting knowledge are mostly deeper than most of other review articles. I have some comments:

Point 1: There are some pathomechanisms only suggested and not really presented -toxic products of astrocytes, altered intestinal proteins (SMMHC, GFAP), sustained neuronal excitability, etc And these hypothesis should be more implemented into the patomechanisms - if it is possible.

Response 1: Thank you very much for such interesting appreciation. In our opinion, it is precisely in these items where there are a very extensive field of study. We have expanded this information in the corresponding parts, adding several more references to justify it.

-In line 471-75, we added a new reference [40] to justify the involvement of TNF-α and IL-1 in inflammation-mediated toxicity to motor neurons of spinal cord.

-In line 594, we further analyse the role of Fibroblast growth factor-1 (FGF-1) that can be released by motor neurons in response to damage to induce astrocyte activation, and stimulates nerve growth factor (NGF) expression and secretion. Prolonged stimulation with FGF-1 or SOD-mediated oxidative stress in astrocytes may disrupt the normal neuron-glia interactions and lead to progressive neuronal degeneration [54].

-The hypothesis about altered intestinal proteins is indicated in more detail in line 646-55.

-In relation to “neuronal excitability”, we have added a paragraph for better explaining it in line 421-428

Point 2: The role of increased physical activity - it is also mentioned in the conclusion, but is not sufficiently strong evaluated.

Response 2: We considered this comment and have removed it in the conclusion, as this role of increased physical activity needs to be further studied in the future.

Point 3: The conclusion - I mean, too many adjectives and factors, that the reader should pick up the real one by himself.

Response 3: Thank you for this comment. We have considered it, and modified the conclusions, suppressing so many details, trying to give more general information.

Point 4: Though the enteric nervous system dysfunction is mentioned at the conclusion, there is very little written about it in the text.

Response 4: This section has been enriched (line 658-65) with a new reference: “pTDP-43 aggregates accumulate in non-central nervous system tissues prior to symptom onset in amyotrophic lateral sclerosis: a case series linking archival surgical biopsies with clinical phenotypic data”. In this manuscript, there are valuous information that aseverates that pTDP-43 aggregation within the myenteric plexus could be detected many years prior to neurological involvement.

Thank you very much for your indications. Your comments have really improve this manuscript.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

This manuscript is suitable for publication.