Illustrating the Pathogenesis and Therapeutic Approaches of Epilepsy by Targeting Angiogenesis, Inflammation, and Oxidative Stress

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript: Neuroglia-3644387 entitled "Illustrating the Pathogenesis and Therapeutic Approaches of Epilepsy by Targeting Angiogenesis, Inflammation and Oxidative Stress" by Mohapatra & coll. is reviewing  the current literature on the causes of epilepsy and its possible prevention and treatment. The review is well organized and clearly written. The literature cited is adequate. A mention to neural ephaptic coupling in epilepsy (https://doi.org/10.1111/epi.16903) would complete the overview of the mechanisms involved in this disease.

Author Response

The manuscript: Neuroglia-3644387 entitled "Illustrating the Pathogenesis and Therapeutic Approaches of Epilepsy by Targeting Angiogenesis, Inflammation and Oxidative Stress" by Mohapatra & coll. is reviewing the current literature on the causes of epilepsy and its possible prevention and treatment. The review is well organized and clearly written. The literature cited is adequate. A mention to neural ephaptic coupling in epilepsy (https://doi.org/10.1111/epi.16903) would complete the overview of the mechanisms involved in this disease.

Reply: Thank you for your valuable and praiseworthy comments. Neural ephaptic coupling in epilepsy has been mentioned as point 3.4 and highlighted as yellow. The suggested reference (https://doi.org/10.1111/epi.16903) has also been cited [38] in reference section.

Reviewer 2 Report

Comments and Suggestions for Authors

1. In abstract line “Cellular changes in the brain……..21-22”, all the mentioned cellular conditions contribute to neurodegeneration therefore it is a consequential last event in the life cycle of a neuron. Therefore, cannot be mentioned as par with other cellular changes, please rectify.
2. Epilepsy is a common abnormal brain activity but not a common neurodegenerative disorder; also citing a review article to claim epilepsy is neurodegenerative is not appropriate.
3. Lines 54-58; citation missing to conclude on gender specificity of epilepsy prevalence.
4. Line 132-34; 26 months or percent…..?
5. Lines 173-75; citation missing?
6. There is a disconnect in presenting various ideas; this can be sensed clearly while reading this manuscript; authors are also suggested to present their arguments more clearly.
7. According to the above suggested comments please update the manuscript. Also look for other potential minor errors such as typos etc. along with improving the picture quality especially for the clarity of respective depicted concepts.

Comments on the Quality of English Language

mentioned in the comments.

Author Response

Reviewer’s comment

1. In abstract line “Cellular changes in the brain……..21-22”, all the mentioned cellular conditions contribute to neurodegeneration therefore it is a consequential last event in the life cycle of a neuron. Therefore, cannot be mentioned as par with other cellular changes, please rectify.

Reply 1: It has been rectified as per reviewer’s suggestion in the Abstract section.

2. Epilepsy is a common abnormal brain activity but not a common neurodegenerative disorder; also citing a review article to claim epilepsy is neurodegenerative is not appropriate.

Reply 2: It has been rectified as per reviewer’s suggestion in the Introduction section. Neurodegenerative disorder has been rectified as neurological conditions as per suggestion.

3. Lines 54-58; citation missing to conclude on gender specificity of epilepsy prevalence.

Reply 3: Relevant Citation has been added [3] in reference section.

4. Line 132-34; 26 months or percent…..?

Reply 4: It would be 26 months only. This sentence has been modified for better understanding of the readers and highlighted yellow.

5. Lines 173-75; citation missing?

Reply 5: Citation [17] has been added.

6. There is a disconnect in presenting various ideas; this can be sensed clearly while reading this manuscript; authors are also suggested to present their arguments more clearly.

Reply 6: The review has been through several changes as per reviewer’s suggestion and now the review is more readable and connected as per our knowledge.

7. According to the above suggested comments please update the manuscript. Also look for other potential minor errors such as typos etc. along with improving the picture quality especially for the clarity of respective depicted concepts.

Reply 7: The manuscript has been updated. Typographic errors have been rectified along with that the better picture quality of figures has been provided.

Reviewer 3 Report

Comments and Suggestions for Authors

This article by Mohaparta et al reviewed the pathogenesis and therapeutic strategies of epilepsy by targeting angiogenesis, inflammation and oxidative stress.

The information provided in the second half of this paper (in particular, therapies) is interesting. However, the reviewer sees many issues, some major and others minor:

1. Section 2 (Contributing Etiology of Epilepsy), as well as Figure 1, could be deleted or shortened since it provides little information on the molecular pathophysiology of epilepsy.
2. The title of Figure 1, as well as the legend, is lacking. The shown title and legend are for Figure 2. This figure may be unnecessary because it concerns only with CNS infection.
3. Figure 3 is excessively conceptual.
4. Figure 4: GABAmatergic -> Glutamatergic (the middle presynaptic nerve ending). The connection of a GABAergic nerve terminal to a glutamatergic neuron appears peculiar.
5. The paper by Iwasa et al is not included in the references (Line 324-326).
6. Table 1, Examination of CSF, Application: What does the first sentence (in particular, “in the case of infants younger than six months”) mean?
7. Table 2, Tocilizumab, Effects on certain markers: Does tocilizumab really decrease Interleukin-6?
8. Abbreviations should be spelt out where they first appear; MI (Line 107), SBI (Line 109), ECP (Line 186), VEc (Line 210), and CSF (Line 310).
9. Grammatically imperfect sentences and phrases: Astrocytes and …TNF-alpha (Line 313), remain survive (Line 359), … is now researched advanced kidney related tumor patients (Lines 465-466), The expression … one theory (Lines 290-292), and Astrocytes … TNF-alpha (line 313).
10. Typographic and other errors: Brain Tumors and Epilepsy -> Brain Tumors, Injury and Epilepsy (Line 100), PDGF-beta -> Greek (Line 222), Blood-brain barrier-> BBB (Line 235), Convulsions-> Seizures (Line 235), enviro -> environment (Line 348), and few -> a few (Line 461).
11. The space between “micro” and (-vascular” (Line 165), period between “features” and “as” (Line 258), parenthesis after “injury” (Line 283), parenthesis before and after “TLR 1, 2, and 3”(Line 334), and parenthesis after “death” (Line 413) are all  unnecessary.

Comments on the Quality of English Language

This manuscript contains many sentences or phrases that are grammatically imperfect.

Author Response

Reviewer 

This article by Mohaparta et al reviewed the pathogenesis and therapeutic strategies of epilepsy by targeting angiogenesis, inflammation and oxidative stress.

The information provided in the second half of this paper (in particular, therapies) is interesting. However, the reviewer sees many issues, some major and others minor:

Reviewer’s comment

1. Section 2 (Contributing Etiology of Epilepsy), as well as Figure 1, could be deleted or shortened since it provides little information on the molecular pathophysiology of epilepsy.

Reply 1: This section has been modified. Figure 1 was mainly meant to represent section 2.3 Infection & Epilepsy as Figure 1 was cited in that section only. As infection is one of the major etiological factors associated with epilepsy the figure 1 was created. So, we have kept Figure 1 in Section 2.3 to make it more relevant. Some sentences in this section have been deleted.

2. The title of Figure 1, as well as the legend, is lacking. The title and legend are shown in Figure 2. This figure may be unnecessary because it concerns only with CNS infection.

Reply 2: This section has been modified. Figure 1 Title and legend have been added. Figure 1 was mainly meant to represent section 2.3 Infection & Epilepsy as Figure 1 was cited in that section only. As infection is one of the major etiological factors associated with epilepsy the figure 1 was created. So, we have inserted Figure 1 in Section 2.3 to make it more relevant. Few irrelevant sentences in this section have been deleted to make it more precise.

3. Figure 3 is excessively conceptual.

Reply 3: Figure 3 demonstrates the basic mechanism of glial cells and different chemokines that leads to the progression of neuroinflammation ultimately causing epilepsy. Neuroinflammation is one of the key mechanisms involved during epilepsy so figure 3 is necessary for the readers to know the basic alterations related to neuroinflammation associated with epileptic conditions.

4. Figure 4: GABAergic -> Glutamatergic (the middle presynaptic nerve ending). The connection of a GABAergic nerve terminal to a glutamatergic neuron appears peculiar.

Reply 4: Chloride ions are moving through the GABAergic terminal channel as depicted in figure 3 and arrow has been added in figure to increase its understandability. Figure 3 has been modified.

5. The paper by Iwasa et al is not included in the references (Line 324-326).

Reply 5: Iwasa et al has been included as citation [31] in reference list.

6. Table 1, Examination of CSF, Application: What does the first sentence (in particular, “in the case of infants younger than six months”) mean?

Reply 6: It means infants of age less than six-month-old.

7. Table 2, Tocilizumab, Effects on certain markers: Does tocilizumab really decrease Interleukin-6?

Reply 7: Tocilizumab is a humanized monoclonal antibody designed to target the IL-6 receptor, So, yes Tocilizumab decreases IL-6 level to treat several pathological conditions here in case of epilepsy it has also been utilized for its treatment by decreasing IL-6 level as evident with provided reference [62].

8. Abbreviations should be spelt out where they first appear; MI (Line 107), SBI (Line 109), ECP (Line 186), VEc (Line 210), and CSF (Line 310).

Reply 8: Abbreviations have been spelt wherever applicable as per reviewer’s suggestion.

9. Grammatically imperfect sentences and phrases: Astrocytes and …TNF-alpha (Line 313), remain survive (Line 359), … is now researched advanced kidney related tumor patients (Lines 465-466), The expression … one theory (Lines 290-292), and Astrocytes … TNF-alpha (line 313).

Reply 9: Grammatical errors have been corrected as per the reviewer’s suggestions.

10. Typographic and other errors: Brain Tumors and Epilepsy -> Brain Tumors, Injury and Epilepsy (Line 100), PDGF-beta -> Greek (Line 222), Blood-brain barrier-> BBB (Line 235), Convulsions-> Seizures (Line 235), enviro -> environment (Line 348), and few -> a few (Line 461).

Reply 10: Typographic and other errors have been rectified as suggested by the reviewer.

11. The space between “micro” and (-vascular” (Line 165), period between “features” and “as” (Line 258), parenthesis after “injury” (Line 283), parenthesis before and after “TLR 1, 2, and 3” (Line 334), and parenthesis after “death” (Line 413) are all unnecessary.

Reply 11: All the errors have been corrected in the relevant sections as suggested by the reviewer.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

• 4. Astrocytic terminals are depicted as neuronal; this needs to be distinguished. There are subtle differences between neuronal and astrocytic terminals; both structurally and functionally. Moreover, the orientation they are shown in the figure is also not physiological. Please look into it.
• Section 3.4, lines 439-40, please review your conclusion for clarity of your idea.
• Lines 451-54, provide the background of computational model used to study& depict the neuronal recruitment?
• Why have authors reviewed this information (ephaptic coupling); there is no context provided about the original proposed idea in the review i.e. neuroinflammation?
• Authors are advised to trim and simplify the information provided in table.1.
• It is suggested that if authors wish to review the electric properties of neurons in Epileptic phase, then first a background of functional read-out should be provided and then the review should unfold to information relevant to inflammation related mechanisms.
• If authors choose to review electric coupling, then please provide the most relevant inflammatory – players that directly corelates to epileptic pathophysiology, also it is expected that functional read-outs are reviewed in this context. Furthermore, original research must be cited depicting the functional read-outs.
• Overall, it is suggested that authors stick to original proposed ideas and review the most relevant neuro-inflammatory mechanisms and markers; such that a more refined view about epileptic pathophysiology can be presented through this review.
• Nowhere in the review is the significance of doing this review attributed in a more convincing fashion?
• Authors are further advised to improve on figures; they can’t be accepted in present form.
• Recheck the citations of Table 2-3.

Comments on the Quality of English Language

Re-review for minor issues such as sentence structure and clarity of the message.

Author Response

Reviewer’s Comment

1. Figure 4. Astrocytic terminals are depicted as neuronal; this needs to be distinguished. There are subtle differences between neuronal and astrocytic terminals; both structurally and functionally. Moreover, the orientation they are shown in the figure is also not physiological. Please look into it.

Reply 1: Structurally astrocyte has been modified making it different from neuronal terminals in Figure 4 as per reviewers suggestion and quality of the same has also been improved.

2. Section 3.4, lines 439-40, please review your conclusion for clarity of your idea.

Reply 2: Section 3.4. has been removed as per the reviewer’s suggestion as it was added due to the optional suggestion of another reviewer 1 to include this topic but we also find it irrelevant to our review.

3. Lines 451-54, provide the background of computational model used to study & depict the neuronal recruitment?

Reply 3: Section 3.4 has been removed as per the reviewer’s suggestion.

4. Why have authors reviewed this information (ephaptic coupling); there is no context provided about the original proposed idea in the review i.e. neuroinflammation?

Reply 4: It was done as per one of the reviewer’s suggestion (Reviewer-1) who suggested us to add this section to our review but it was optional at their end. As per your suggestion we have removed this Section 3.4 as we also find it irrelevant to our topic.

5. Authors are advised to trim and simplify the information provided in table.1.

Reply 5: Table 1 has been trimmed as per the suggestion of the reviewer.

6. It is suggested that if authors wish to review the electric properties of neurons in Epileptic phase, then first a background of functional read-out should be provided and then the review should unfold to information relevant to inflammation related mechanisms.

Reply 6: Section 3.4 has been removed as per the reviewer’s suggestion as it seems irrelevant to the topic of our review.

7. If authors choose to review electric coupling, then please provide the most relevant inflammatory – players that directly corelates to epileptic pathophysiology, also it is expected that functional read-outs are reviewed in this context. Furthermore, original research must be cited depicting the functional read-outs.

Reply 7: Section 3.4 has been removed as per the reviewer’s suggestion as it seems irrelevant to the topic of our review.

8. Overall, it is suggested that authors stick to original proposed ideas and review the most relevant neuro-inflammatory mechanisms and markers; such that a more refined view about epileptic pathophysiology can be presented through this review.

Reply 8: We have sticked to our original idea of our review and removed the Section 3.4 as it seems irrelevant.

9. Nowhere in the review is the significance of doing this review attributed in a more convincing fashion?

Reply 9: As per your suggestion we have improved the significance and relevance of our review.

10. Authors are further advised to improve on figures; they can’t be accepted in present form.

Reply 10: We have further improved the figures as per suggestion to best our ability to make it acceptable. We could provide it separately as well when asked. During the pdf conversion the figure quality might reduce but at our end all the figures are of high quality.  

11. Recheck the citations of Table 2-3.

Reply 11: Citation of Table 2-3 has been rechecked and they are okay.

Reviewer 3 Report

Comments and Suggestions for Authors

In this revised version, many of the issues in the original version are duly addressed.

Comments on the Quality of English Language

Many of the syntax and typographic errors have been corrected.

Author Response

Comments and Suggestions for Authors

In this revised version, many of the issues in the original version are duly addressed.

Reply: Thank you for your valuable comments for the improvement of this review article.