Background and purpose We focused on the, yet undescribed, therapy effect of the stable gastric pentadecapeptide BPC 157 in hippocampal ischemia/reperfusion injuries, after bilateral clamping of the common carotid arteries in rats. The background is the proven therapy effect of BPC 157 in ischemia/reperfusion injuries in different tissues. Furthermore, there is the subsequent oxidative stress counteraction, particularly when given during reperfusion. The recovering effect it has on occluded vessels, results with activation of the alternative pathways, bypassing the occlusion in deep vein thrombosis. Finally, the BPC 157 therapy benefits with its proposed role as a novel mediator of Roberts' cytoprotection and bidirectional effects in the gut-brain axis. Materials and Methods Male Wistar rats underwent bilateral clamping of the common carotid arteries for a 20-min period. At 30 s thereafter, we applied medication (BPC 157 10 mu g/kg; or saline) as a 1 ml bath directly to the operated area, that is, trigonum caroticum. We documented, in reperfusion, the resolution of the neuronal damages sustained in the brain, resolution of the damages reflected in memory, locomotion, and coordination disturbances, with the presentation of the particular genes expression in hippocampal tissues. Results In the operated rats, at 24 and 72 hr of the reperfusion, the therapy counteracted both early and delayed neural hippocampal damage, achieving full functional recovery (Morris water maze test, inclined beam-walking test, lateral push test). mRNA expression studies at 1 and 24 hr, provided strongly elevated (Egr1, Akt1, Kras, Src, Foxo, Srf, Vegfr2, Nos3, and Nos1) and decreased (Nos2, Nfkb) gene expression (Mapk1not activated), as a way how BPC 157 may act. Conclusion Together, these findings suggest that these beneficial BPC 157 effects may provide a novel therapeutic solution for stroke.
The effect of pentadecapeptide BPC 157 on hippocampal ischemia/reperfusion injuries in rats
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Decision Letter
2020/05/2828-May-2020
Dear Dr. Vukojević:
It is a pleasure to accept your manuscript entitled "The effect of pentadecapeptide BPC 157 on hippocampal ischemia/reperfusion injuries in rats" in its current form for publication in Brain and Behavior. If there were further comments from the reviewer(s) who read your manuscript, they will be included at the foot of this letter.
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Author Response
2020/05/27Zagreb, 27th May 2020
Dear Editor,
Thank you very much for your kind letter and comments given by your respected reviewers. We also apologize for all problems produced by technical mistakes that unfortunately appear to be due to inappropriate use of the referencing software program.
We hope you will see that the manuscript is considerably improved in accordance with the suggestions and comments given by both of the reviewers.
To the comments given by the reviewers, see our arguments and reply:Reviewer: 1
Comments to the Author
Thank you for revising your manuscript. I recommend acceptance but I saw an error in references. please correct it when you receive a proof.
reference 2 is wrong
corrected reference: Amani, Hamed, Rouhollah Habibey, Fereshteh Shokri, Seyed Javad Hajmiresmail, Omid Akhavan, Alireza Mashaghi, and Hamidreza Pazoki-Toroudi. 2019. 'Selenium nanoparticles for targeted stroke therapy through modulation of inflammatory and metabolic signaling', Scientific Reports, 9: 1-15.
Ad Reviewer 1. Acknowledged and corrected.Reviewer: 2
Comments to the Author
The manuscript entitled as “The effect of pentadecapeptide BPC 157 on hippocampal ischemia/reperfusion injuries in rats” could have written well.
Although, it was edited but still the language of the research manuscript is not upto the mark, typo, grammatical and syntax errors throughout the paper and need special attention.
Strikingly, Abstract is quite difficult to understand e.g Together, these findings provide a strong indication these beneficial BPC 157 effects may provide a novel therapeutic solution for stroke
- , bypassing the occlusion in deep vein thrombosis.?
A standard GLP?
number of the studie,
Although author (s) have been published numerous papers but there is no clear basis and rationale of the study.Ad Reviewer 2. Acknowledged and corrected. To be sure that the English is now adequate, we used the Grammarly software and consulted an office of our Medical Faculty. We hope that the rationale is now better explained, and the changes can be seen in the Background section and in the Abstract.
Reference should be in Standard Format as per journal guidelines..and be in the same manner
Kang et al., 2018; Seiwerth et al., 2014, 2018; P Sikiric et al., 2012; Predrag Sikiric et al., 2018, 2017, 2016, 2011, 2013, 2014).
They must be written in sequence if so.. Predrag Sikiric et al., 2018, 2010, 2017, 2016, 2011, 2013, 2014)
The statement must be rephrases as confusing ………….
Also cite only recent references?
It was prepared as a peptide with 99% (HPLC) purity (1-des-Gly peptide was the main impurity; manufactured by Diagen, Ljubljana, Slovenia, GEPPPGKPADDAGLV, M.W. 1419) (in dose and application regimens as described before)(Kang et al., 2018; Seiwerth et al., 2014, 2018; P Sikiric et al., 2012; Predrag Sikiric et al., 2018, 2017, 2016, 2011, 2013, 2014)
P Sikiric et al., 2012; Predrag Sikiric et al., 2018?
Why, the reference not in same style ?....
(Amani, Kazerooni, Hassanpoor, Akbarzadeh, & Pazoki-Toroudi, 2019; Amani, Kazerooni, Hassanpoor, Akbarzadeh, Pazoki-Toroudi, et al., 2019).Ad Reviewer 2. As mentioned before, we apologize for all the problems produced by technical mistakes that, unfortunately, appear to be due to inappropriate use of the referencing software program. Changes have been made throughout the manuscript and highlighted accordingly.
Training took place over five consecutive days before stroke inducing surgery, and there was a final assessment 24 h after surgery
Pathology………?
Heading must be clear
with hypoxic changes….What does it mean?
The therapeutic focus was on significant reperfusion-induced hippocampal lesions, memory, and motor coordination failure after bilateral carotid artery occlusion.
Statement needs to be changed..Ad Reviewer 2. Acknowledged and corrected. The explications were made; the headings are now clear (the changes have been made in the Methodology and Results section).
Nevertheless, the mRNA expression analyses provide insight into events in the rats after removal of the bilateral carotid artery ligation, similar to that before in rats with occlusion of the inferior caval vein and left ovarian vein recruitment to bypass occlusion of the inferior caval vein
Ad Reviewer 2. Acknowledged and corrected. The additional explication is done. The relevance of these findings, for the presented results, seems to be better underlined and explained now. (see corresponding paragraphs in Discussion).
All authors have seen the updated version of the manuscript and approved this submission.
In summary, we hope that all of the requests of the reviewers were adequately accepted and solved and that you will find our manuscript in the revised, improved version, suited for the final presentation in your distinguished journal.Sincerely,
Jaksa Vukojevic, MD
Cite this author response
- pre-publication peer review (ROUND 2)
Decision Letter
2020/04/2727-Apr-2020
We recognise that the impact of the COVID-19 pandemic may affect your ability to return your revised manuscript to us within the requested timeframe. If this is the case, please let us know.
Dear Dr. Vukojević:
Manuscript ID BRB3-2019-08-0508.R1 entitled "The effect of pentadecapeptide BPC 157 on hippocampal ischemia/reperfusion injuries in rats" which you submitted to Brain and Behavior, has been reviewed. Some revisions to your manuscript have been recommended. Therefore, I invite you to respond to the comments appended below and revise your manuscript.
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Once again, thank you for submitting your manuscript to Brain and Behavior and I look forward to receiving your revision.
Sincerely,
Dr. Nutan Sharma
Editor in Chief, Brain and Behavior
nsharma@partners.orgAssociate Editor Comments to Author:
Reviewer(s)' Comments to Author:
Reviewer: 1
Comments to the Author
Thank you for revising your manuscript. I recommend acceptance but I saw an error in references. please correct it when you receive a proof.
reference 2 is wrong
corrected reference: Amani, Hamed, Rouhollah Habibey, Fereshteh Shokri, Seyed Javad Hajmiresmail, Omid Akhavan, Alireza Mashaghi, and Hamidreza Pazoki-Toroudi. 2019. 'Selenium nanoparticles for targeted stroke therapy through modulation of inflammatory and metabolic signaling', Scientific Reports, 9: 1-15.Reviewer: 2
Comments to the Author
The manuscript entitled as “The effect of pentadecapeptide BPC 157 on hippocampal ischemia/reperfusion injuries in rats” could have written well.
Although, it was edited but still the language of the research manuscript is not upto the mark, typo, grammatical and syntax errors throughout the paper and need special attention.
Strikingly, abstract is quite difficult to understand e.g Together, these findings provide a strong indication these beneficial BPC 157 effects may provide a novel therapeutic solution for stroke
- , bypassing the occlusion in deep vein thrombosis.?
A standard GLP?
number of the studie,
Although author (s) have been published numerous papers but there is no clear basis and rationale of the study.Reference should be in Standard Format as per journal guidelines..and be in the same manner
Kang et al., 2018; Seiwerth et al., 2014, 2018; P Sikiric et al., 2012; Predrag Sikiric et al., 2018, 2017, 2016, 2011, 2013, 2014).
They must be written in sequence if so.. Predrag Sikiric et al., 2018, 2010, 2017, 2016, 2011, 2013, 2014)
The statement must be rephrases as confusing ………….
Also cite only recent references?
It was prepared as a peptide with 99% (HPLC) purity (1-des-Gly peptide was the main impurity; manufactured by Diagen, Ljubljana, Slovenia, GEPPPGKPADDAGLV, M.W. 1419) (in dose and application regimens as described before)(Kang et al., 2018; Seiwerth et al., 2014, 2018; P Sikiric et al., 2012; Predrag Sikiric et al., 2018, 2017, 2016, 2011, 2013, 2014)
P Sikiric et al., 2012; Predrag Sikiric et al., 2018?
Why, the reference not in same style ?....
(Amani, Kazerooni, Hassanpoor, Akbarzadeh, & Pazoki-Toroudi, 2019; Amani, Kazerooni, Hassanpoor, Akbarzadeh, Pazoki-Toroudi, et al., 2019).
Training took place over five consecutive days before stroke inducing surgery, and there was a final assessment 24 h after surgery
Pathology………?
Heading must be clear
with hypoxic changes….What does it mean?
The therapeutic focus was on significant reperfusion-induced hippocampal lesions, memory, and motor coordination failure after bilateral carotid artery occlusion.
Statement needs to be changed..
Nevertheless, the mRNA expression analyses provide insight into events in the rats after removal of the bilateral carotid artery ligation, similar to that before in rats with occlusion of the inferior caval vein and left ovarian vein recruitment to bypass occlusion of the inferior caval veinThis manuscript in its current form not ready to be published.
Decision letter by
Cite this decision letter
Reviewer report
2020/03/12The manuscript entitled as “The effect of pentadecapeptide BPC 157 on hippocampal ischemia/reperfusion injuries in rats” could have written well.
Although, it was edited but still the language of the research manuscript is not upto the mark, typo, grammatical and syntax errors throughout the paper and need special attention.
Strikingly, abstract is quite difficult to understand e.g Together, these findings provide a strong indication these beneficial BPC 157 effects may provide a novel therapeutic solution for stroke
- , bypassing the occlusion in deep vein thrombosis.?
A standard GLP?
number of the studie,
Although author (s) have been published numerous papers but there is no clear basis and rationale of the study.Reference should be in Standard Format as per journal guidelines..and be in the same manner
Kang et al., 2018; Seiwerth et al., 2014, 2018; P Sikiric et al., 2012; Predrag Sikiric et al., 2018, 2017, 2016, 2011, 2013, 2014).
They must be written in sequence if so.. Predrag Sikiric et al., 2018, 2010, 2017, 2016, 2011, 2013, 2014)
The statement must be rephrases as confusing ………….
Also cite only recent references?
It was prepared as a peptide with 99% (HPLC) purity (1-des-Gly peptide was the main impurity; manufactured by Diagen, Ljubljana, Slovenia, GEPPPGKPADDAGLV, M.W. 1419) (in dose and application regimens as described before)(Kang et al., 2018; Seiwerth et al., 2014, 2018; P Sikiric et al., 2012; Predrag Sikiric et al., 2018, 2017, 2016, 2011, 2013, 2014)
P Sikiric et al., 2012; Predrag Sikiric et al., 2018?
Why, the reference not in same style ?....
(Amani, Kazerooni, Hassanpoor, Akbarzadeh, & Pazoki-Toroudi, 2019; Amani, Kazerooni, Hassanpoor, Akbarzadeh, Pazoki-Toroudi, et al., 2019).
Training took place over five consecutive days before stroke inducing surgery, and there was a final assessment 24 h after surgery
Pathology………?
Heading must be clear
with hypoxic changes….What does it mean?
The therapeutic focus was on significant reperfusion-induced hippocampal lesions, memory, and motor coordination failure after bilateral carotid artery occlusion.
Statement needs to be changed..
Nevertheless, the mRNA expression analyses provide insight into events in the rats after removal of the bilateral carotid artery ligation, similar to that before in rats with occlusion of the inferior caval vein and left ovarian vein recruitment to bypass occlusion of the inferior caval veinThis manuscript in its current form not ready to be published.
Reviewed by
Cite this review
Reviewer report
2020/02/18Thank you for revising your manuscript. I recommend acceptance but I saw an error in references. please correct it when you receive a proof.
reference 2 is wrong
corrected reference: Amani, Hamed, Rouhollah Habibey, Fereshteh Shokri, Seyed Javad Hajmiresmail, Omid Akhavan, Alireza Mashaghi, and Hamidreza Pazoki-Toroudi. 2019. 'Selenium nanoparticles for targeted stroke therapy through modulation of inflammatory and metabolic signaling', Scientific Reports, 9: 1-15.Reviewed by
Cite this review
Author Response
2020/02/10Jakša Vukojević, MD
University Psychiatric Hospital Vrapče,
University of Zagreb,
Bolnička cesta 32
10000 Zagreb, Croatia
Phone: 385-91-156-1989
e-mail: jaksa.vukojevic@bolnica-vrapce.hrZagreb, 10th February 2020
Respected reviewer,Once again, thank you for your time and comments regarding the manuscript. All of your comments have been acknowledged and incorporated in the final version as follows:
1. The title has been changed to be more precise. The new title is:
The effect of pentadecapeptide BPC 157 on hippocampal ischemia/reperfusion injuries in rats. The title now conveys the exact region of the brain that is investigated as well the species the experiment is performed on (changes made on the title page)
2. Elsevier language editing services revised the whole paper, and as such, the paper should now be more natural to read and comprehend. The proof of language editing is uploaded within your system. (changes made throughout the manuscript)
3. The abstract was altered according to your comments. We additionally explained where we applied the drug, and in which anatomical region the drug was applied. The part of the abstract pertaining to colitis ischemia injuries was changed to a more broad statement as BPC 157 has been proven to ameliorate ischemia injuries in different tissues. The premise behind this effect of BPC 157 is that there are similar, if not same, cellular and molecular responses in all of the tissues, and thereby cells when confronted with ischemia. This notion is a pivotal element of Roberts cytoprotection theory, which states that all cells have similar responses when confronted with the same noxa. Moreso this explains why BPC 157 has a similar effect in different tissues as well as that it triggers specific mechanisms that are similar in various models and tissues and thereby gives more proof to the cytoprotection theory. (changes have been made in the abstract, page 2)
4. The Table for primers was added to the text, as a bracket indicating that the table is in additional material, and uploaded as additional material. The primers were provided directly from the manufacturer as, and such will allow everyone to reproduce the experiment if needed. (changes made on page 10)
5. New references were added, ones you have proposed as well as some updated references regarding stroke and inflammation as well as growth factors. Although there hasn’t been a lot of changes in the manuscript, the updated references make this paper up to date regarding knowledge in this field. All of the added references are highlighted in the reference list. (small changes made throughout the text, several sentences added or changed on page 3 and 20)
All authors have seen the updated version of the manuscript and approved this submission. We strongly hope that you will find this revised manuscript suited for your readers and deserving of the presentation in your distinguished journal.Yours Sincerely,
Jakša Vukojević, MDCite this author response
- pre-publication peer review (ROUND 1)
Decision Letter
2019/12/2323-Dec-2019
Dear Dr. Vukojević:
Manuscript ID BRB3-2019-08-0508 entitled "The effect of pentadecapeptide BPC 157 on ischemia/reperfusion injuries in rat brains" which you submitted to Brain and Behavior, has been reviewed. Some revisions to your manuscript have been recommended. Therefore, I invite you to respond to the comments appended below and revise your manuscript.
Before submitting your revisions:
Prepare a response to the reviewer comments appended below in point-by-point fashion. In order to expedite the processing of the revised manuscript, please be as specific as possible in your response and indicate the page numbers in the manuscript where you have addressed each comment.
Prepare a revised manuscript (word document), highlighting the changes you’ve made. Save this new document on your computer as you will be asked to upload it during the revision submission process. NOTE: Please be sure to keep in mind reviewer comments and incorporate your responses within the manuscript. There may well be areas where you disagree; for example, you may want to write, "A reviewer suggests that... However, I disagree because...". In any case, please try to address all of the concerns that are raised within the manuscript.
In addition to your revised manuscript with changes highlighted, please also save a “clean” copy where the changes are not marked.
To submit your revised manuscript:
- Log in by clicking on the link below
PLEASE NOTE: This is a two-step process. After clicking on the link, you will be directed to a webpage to confirm.
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OR
Log into https://mc.manuscriptcentral.com/brainandbehavior and click on Author Center. Under author resources, use the button “Click here to submit a revision”. PLEASE DO NOT SUBMIT YOUR REVISIONS AS A NEW MANUSCRIPT.
Follow the on-screen instructions. First you will be asked to provide your “Response to Decision Letter”—this is the response to reviewer comments that you prepared earlier.
Click through the next few screens to verify that all previously provided information is correct.
File Upload: Delete any files that you will be replacing (this includes your old manuscript). Upload your new revised manuscript file with changes highlighted, a “clean” copy of your revised manuscript file, any replacement figures/tables, or any new files. Once this is complete, the list of files in the “My Files” section should ONLY contain the final versions of everything. REMEMBER: figures/tables should be in jpeg, tiff, or eps format. We hope that you will designate one of the figures in your paper to be considered for our online covers and potential publication on our blog.
Review and submit: please be sure to double-check everything carefully so that your manuscript can be processed as quickly as possible.
Deadlines:
Because we are trying to facilitate timely publication of manuscripts submitted to Brain and Behavior,your revised manuscript should be uploaded as soon as possible. If it is not possible for you to submit your revision in 2 months, we may have to consider your paper as a new submission. If you feel that you will be unable to submit your revision within the time allowed please contact me to discuss the possibility of extending the revision time.If you feel that your paper could benefit from English language polishing, you may wish to consider having your paper professionally edited for English language by a service such as Wiley’s at http://wileyeditingservices.com. Please note that while this service will greatly improve the readability of your paper, it does not guarantee acceptance of your paper by the journal.
Once again, thank you for submitting your manuscript to Brain and Behavior and I look forward to receiving your revision.
Sincerely,
Dr. Nutan Sharma
Editor in Chief, Brain and Behavior
nsharma@partners.orgAssociate Editor Comments to Author:
Reviewer(s)' Comments to Author:
Reviewer: 1
Comments to the Author
comment1: the title is not suitable. please state type of ischemia. cerebral ischemia?
comment 2: The manuscript should be meticulously revised by a native English speaker. There are several problems with grammar, orthography and both textual cohesion and coherence (mandatory).
comment3: what did you want to say in background of abstract? why did you statecolitis ischemia/reperfusion injuries??
where did you inject drug? it is vague
comment 4) the authors should provide a table including primer sequences for all the genes
comment 5)many references are old. please add some related works (https://doi.org/10.1038/s41598-019-42633-9 and https://doi.org/10.1080/21691401.2019.1639723 ) to enrich your work.Decision letter by
Cite this decision letter
Reviewer report
2019/09/28comment1: the title is not suitable. please state type of ischemia. cerebral ischemia?
comment 2: The manuscript should be meticulously revised by a native English speaker. There are several problems with grammar, orthography and both textual cohesion and coherence (mandatory).
comment3: what did you want to say in background of abstract? why did you statecolitis ischemia/reperfusion injuries??
where did you inject drug? it is vague
comment 4) the authors should provide a table including primer sequences for all the genes
comment 5)many references are old. please add some related works (https://doi.org/10.1038/s41598-019-42633-9 and https://doi.org/10.1080/21691401.2019.1639723 ) to enrich your work.Reviewed by
Cite this review
