Natural Products in Alzheimer’s Disease Therapy: Would Old Therapeutic Approaches Fix the Broken Promise of Modern Medicines?
Round 1
Reviewer 1 Report
This review gives an interesting insight into the pathology of Alzheimer’s disease (AD) and common pharmacological targets of this disease. Only a few drugs are on the market for the treatment of AD and most of them are AChE inhibitors. The review describes several potential pharmacological targets to treat AD and it is suggested in the review that novel drug discovery for treating AD should be based on a multitargeting approach through activation of the antioxidant defense system (phase II enzymes) and anti-inflammatory mechanisms coupled with specific receptor and/or enzyme mediated effects in for example neuroprotection and neuroregeneration. The manuscript is well written and relatively clear in its presentation, except of section 10 Multitarget approach – Lessons from natural products. In this section, a more detailed discussion of the pharmacological targets of natural products is clearly needed. For example, there are many types of natural products that induce the production of phase II enzymes (endogenous antioxidants); thus acting as indirect antioxidants due to their ability to undergo Michael-type addition reactions with amino acids such as cysteine. Such natural products include for example chalcones, sesquiterpene lactones, diterpenoids and curcuminoids. Many of these compounds also show anti-inflammatory activity. Furthermore, semisynthetic drugs such as rifampicin and aspirin are mentioned in this section but they are not natural products but are derivatives of natural products, which is not clear from the discussion. The neuroprotective effects of many traditional medicines such as ginseng is mentioned but not discussed in any detail. How does the active compounds in ginseng such as ginsenosides exert their neuroprotective effects? The same is true for gingkolides from Ginkgo biloba. Finally chemical structures of specific natural products discussed in this section should be shown in a figure. In conclusion, an interesting manuscript where especially the discussion line 296-324 regarding the antioxidant and anti-inflammatory effects of natural products in relation to their potential in the treatment of AD needs to be elaborated and discussed in more detail.
Author Response
This review gives an interesting insight into the pathology of Alzheimer’s disease (AD) and common pharmacological targets of this disease. Only a few drugs are on the market for the treatment of AD and most of them are AChE inhibitors. The review describes several potential pharmacological targets to treat AD and it is suggested in the review that novel drug discovery for treating AD should be based on a multitargeting approach through activation of the antioxidant defense system (phase II enzymes) and anti-inflammatory mechanisms coupled with specific receptor and/or enzyme mediated effects in for example neuroprotection and neuroregeneration. Thanks – No action required for this section.
The manuscript is well written and relatively clear in its presentation, except of section 10 Multitarget approach – Lessons from natural products. In this section, a more detailed discussion of the pharmacological targets of natural products is clearly needed. For example, there are many types of natural products that induce the production of phase II enzymes (endogenous antioxidants); thus acting as indirect antioxidants due to their ability to undergo Michael-type addition reactions with amino acids such as cysteine. Such natural products include for example chalcones, sesquiterpene lactones, diterpenoids and curcuminoids. Many of these compounds also show anti-inflammatory activity. Yes, the reviewer is correct in on this mode of action displayed by natural products:
The title is so broad – a rather text book title – It was chosen to provide perspective for all the detailed contribution to be made on the various heighted areas of the special issue. Hence, it is not possible to go to the detail of each topic mentioned.
The reviewer is correct in this mode of action of antioxidant defense induction by natural products. That is why a specific statement was given “Even some monoterpenes that lack the basic phenolic structural moieties for direct ROS scavenging, display antioxidant effects in vivo by inducing antioxidant defenses [ Reference 85].
Many studies including ours have highlighted the role of Michael-type addition reactions in antioxidant and anti-inflammatory mechanisms but this is more relevant to other therapies such as cancer. Perhaps the best mechanism that will address the referees concern here is the nrf2/HO-1 axis of antioxidant/antiinflammatorty mechanisms of natural products that is of direct relevance to AD. This is now added (line 318-326) as well as several reference to substantiate this fact.
Furthermore, semisynthetic drugs such as rifampicin and aspirin are mentioned in this section but they are not natural products but are derivatives of natural products, which is not clear from the discussion. Thank you – now removed
The neuroprotective effects of many traditional medicines such as ginseng is mentioned but not discussed in any detail. How does the active compounds in ginseng such as ginsenosides exert their neuroprotective effects? The same is true for gingkolides from Ginkgo biloba. As mentioned above, it is not possible to go such detail for each compound but this is already extensively reviewed and appropriate reference for review article is already given. Exemplary segments with reference is also provided for their effect on the above comment related to nrf2/HO-1 antioxidant/anti-inflammatory mechanism. For gingkolides from Ginkgo biloba and compounds, specific review articles addressing this topic is provided (e.g., Ref 98, 99)
Regarding the antioxidant and anti-inflammatory effects of natural products in relation to their potential in the treatment of AD needs to be elaborated and discussed in more detail. This is done and now even one more figure depicting the whole process is included.
Finally chemical structures of specific natural products discussed in this section should be shown in a figure. In conclusion, an interesting manuscript where especially the discussion line 296-324. Now included – Thank you.
Reviewer 2 Report
The author prepared a well-organized and well-written review on potential effectiveness of natural products in the treatment of Alzheimer's disease (AD). He adequately highlighted the shortcomings and failures of mono therapy using few available modern medicines. He particularly provided two well-designed cartoons to better explain the subject of his manuscript. I found the manuscript informative and interesting for a wide range of readers. The minor shortcoming I found with this manuscript is lack of a short paragraph for the role of nutraceuticals which are considered natural products in AD. For example Omega-3 fatty acids , carotenoids, alpha-linolenic acid are among those natural products for AD.
Moreover, the author can update the list of clinical trail failures with modern medicines (based on Abeta hypothesis) with a very recent one announced on March 21, 2019. The failure of the drug called Aducanumab by Pharmaceutical giant Biogen and its Japanese partner Eisai (https://www.cnn.com/2019/03/21/health/alzheimers-drug-trial-failure-aducanumab-bn/index.html).
Although the manuscript in the existing form is interesting but I think updating with the recently failed clinical trial and adding a short paragraph will enhance the quality of this review.
Author Response
The author prepared a well-organized and well-written review on potential effectiveness of natural products in the treatment of Alzheimer's disease (AD). He adequately highlighted the shortcomings and failures of mono therapy using few available modern medicines. He particularly provided two well-designed cartoons to better explain the subject of his manuscript. I found the manuscript informative and interesting for a wide range of readers. The minor shortcoming I found with this manuscript is lack of a short paragraph for the role of nutraceuticals which are considered natural products in AD. For example Omega-3 fatty acids , carotenoids, alpha-linolenic acid are among those natural products for AD. Thank you for this valuable comment. This is now addressed and line 355-362. Structures of these compounds are also included.
Moreover, the author can update the list of clinical trail failures with modern medicines (based on Abeta hypothesis) with a very recent one announced on March 21, 2019. The failure of the drug called Aducanumab by Pharmaceutical giant Biogen and its Japanese partner Eisai (https://www.cnn.com/2019/03/21/health/alzheimers-drug-trial-failure-aducanumab-bn/index.html). Although the manuscript in the existing form is interesting but I think updating with the recently failed clinical trial and adding a short paragraph will enhance the quality of this review.
Thank you for this valuable information – I actually read the news but refrained from citing it as it was not a traditional source of info to quote. I have now included it however – Line 121-124. I am sure you would agree that there is no need to include the newspaper source.
Reviewer 3 Report
Natural Products in Alzheimer’s Disease Therapy: Would Old Therapeutic Approaches Fix the Broken Promise of Modern Medicines?
Solomon Habtemariam
As a review it is very well written and very easy to follow. The list of references provided is relevant and up to date. The topic discussed is timely and the multi target therapeutic approach for complex diseases such AD is showing much interests among many scientists. Therefore I believe this article would be a good resource for those involved in drug discovery.
Author Response
As a review it is very well written and very easy to follow. The list of references provided is relevant and up to date. The topic discussed is timely and the multi target therapeutic approach for complex diseases such AD is showing much interests among many scientists. Therefore I believe this article would be a good resource for those involved in drug discovery. Thank you – No action required here
Reviewer 4 Report
Dear Editor in Chief,
The manuscript entitled “Natural Products in Alzheimer’s disease Therapy: Would Old Therapeutic Approaches Fix the Broken Promise of Modern Medicines” has been reviewed. There are ample of typographical, spacing and alignment errors throughout the manuscript. And also, the reference formatting of manuscript is very poor. Since, these are the basic things that authors should considered first, I strongly recommend to go through the guideline and correct it thoroughly. I have listed comments below for author’s convenience:
Comments
Though the mentioned hypotheses are the most accepted one for the pathology of Alzheimer’s disease, however, other possible approach are also researched which could be mentioned in the manuscript. Since this is the review article every possible approach will aid its value. These could also contribute for the multi-target therapy. A few to be listed as for example: hypometabolism of glucose [Reference: Daulatzai MA. Cerebral hypoperfusion and glucose hypometabolism: key pathophysiological modulators promote neurodegeneration, cognitive impairment, and Alzheimer's disease. J Neurosci Res. 2017;95(4):943–972], Bacteria-derived metabolites [Reference: Zhao Y, Dua P, Lukiw WJ. Microbial sources of amyloid and relevance to Amyloidogenesis and Alzheimer's disease (AD) J Alzheimers Dis Parkinsonism 2015;5(1):177].
The review only mentioned about the few terrestrial crude drug and compound. However marine natural products are also found to be potent neuroprotective agents which could be included in the review.
There are plenty of spacing, alignment and spelling error throughout the manuscript.
The formatting for the caption mentioned for the Figures are not in accordance with the guidelines. Go through the guidelines and make necessary corrections.
Line 39; tacrine’s instead of tacrin’s
The full for of the abbreviation should be mentioned wherever it is first listed in the manuscript. Eg: Line 90; AICD, Line 219; APOJ, SORL and so on.
Line 244; “For the variety of reasons, neuronal cells are…….”. It’s better to mention of give reference for this.
Line 303-304; Aspirin is not an antibiotic. Correct the sentence.
Line 348; there is no reference 120 in reference section. Correct this.
References:
The references are not aligned properly.
There are a lot of spelling errors in the references.
Use punctuations (comma, period and semicolon).
Check for the title of the study and make it in uniform pattern (either all words capital or small). Eg: reference 7, 19, 20, and so on.
And so is the case of the abbreviated journal name. Make it uniform all over and italic.
The issue is mentioned in some places while missing in some. Follow journal guideline and do according. Make it uniform.
The page number range is missing. Check and correct it.
I would suggest you to go along with the journal’s reference guideline. Check and correct.
Author Response
Though the mentioned hypotheses are the most accepted one for the pathology of Alzheimer’s disease, however, other possible approach are also researched which could be mentioned in the manuscript. Since this is the review article every possible approach will aid its value. These could also contribute for the multi-target therapy. A few to be listed as for example: hypometabolism of glucose [Reference: Daulatzai MA. Cerebral hypoperfusion and glucose hypometabolism: key pathophysiological modulators promote neurodegeneration, cognitive impairment, and Alzheimer's disease. J Neurosci Res. 2017;95(4):943–972], Bacteria-derived metabolites [Reference: Zhao Y, Dua P, Lukiw WJ. Microbial sources of amyloid and relevance to Amyloidogenesis and Alzheimer's disease (AD) J Alzheimers Dis Parkinsonism 2015;5(1):177].
The reviewer is correct in the assertion that numerous areas of AD could be added to enrich the review. The title of this article is so broad – a rather text book title – and was chosen to provide perspective for all the detailed contribution to be made on the various heighted areas of the special issue. Hence, it is not possible to go to the detail of each topics mentioned. I have added several new areas as with recommendations by the other reviewers and also below. The references are increased from 112 to 132. Line 318-326 are new addition … The above additions however appears to be not feasible as it is not aligned with the broad nature of perspective to be presented herein. Carbohydrate dysregulation as rightly mentioned are common in Ad as with diabetes is one validated model of memory impairment study. There is no scope to include all this…
The review only mentioned about the few terrestrial crude drug and compound. However marine natural products are also found to be potent neuroprotective agents which could be included in the review. Now added with references as well as other natural products such as carotenoids and fatty acids…Line 355-362.
All the minor comments below are looked at – some are very general notes on final presentations – Thank you.
There are plenty of spacing, alignment and spelling error throughout the manuscript. This is due to the justified formatting that will be addressed one we have the final version of contents …
The formatting for the caption mentioned for the Figures are not in accordance with the guidelines. Go through the guidelines and make necessary corrections. Thanks – This might still need professional touch from the production eam end.
Line 39; tacrine’s instead of tacrin’s. Corrected
The full for of the abbreviation should be mentioned wherever it is first listed in the manuscript. Eg: Line 90; AICD, Line 219; APOJ, SORL and so on. Thank you - added
Line 244; “For the variety of reasons, neuronal cells are…….”. It’s better to mention of give reference for this. Now added – ref 65.
Line 303-304; Aspirin is not an antibiotic. Correct the sentence. Removed
Line 348; there is no reference 120 in reference section. Correct this. Corrected- References now expanded as well.
References:
The references are not aligned properly. Now realigned – may need further adjustment as required.
There are a lot of spelling errors in the references. References are entered as they appear in the original sources.
Use punctuations (comma, period and semicolon). Thanks
Check for the title of the study and make it in uniform pattern (either all words capital or small). Eg: reference 7, 19, 20, and so on. Thanks – done.
And so is the case of the abbreviated journal name. Make it uniform all over and italic. Thanks.
Round 2
Reviewer 1 Report
The author has revised his manuscript according to the reviewers comments. Hence, the manuscript is acceptable for publication in its present form, although minor editorial editing is required.
