Prostaglandin analog effects on cerebrospinal fluid reabsorption via nasal mucosa

Michelle G. Pedler; J. Mark Petrash; Prem S. Subramanian

doi:10.1371/journal.pone.0248545

Peer Review History

Original SubmissionFebruary 25, 2021
17 Jun 2021 Decision Letter - Francesco Lolli, Editor PONE-D-21-06439 Prostaglandin analog effects on cerebrospinal fluid reabsorption via nasal mucosa PLOS ONE Dear Dr. Subramanian, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Aug 01 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Francesco Lolli, M.D., Ph.D. Academic Editor PLOS ONE Additional Editor Comments: The manuscript is technically sound, and the data do support the conclusions. However both reviewer had major comments, and some involve additional data requested Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. 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Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: In this article, nasal delivery of prostaglandin analogues boosted nasal recovery of a CSF fluorescent tracer, implying enhanced CSF outflow via the nasal lymphatics. Latanoprost had the most substantial impact and dose-dependent. These medicines may help lower ICP. Some section of the article needs a better presentation. The statistic section describes "Student's t-tests and ANOVA RM with Dunnet's post hoc analysis". It is not informative and should be expanded, referring to preplanned methods. The results refer to Fig.2 and Fig. 3, but it is not clear how the asterisk refers to the difference between the groups in which specific test. Fig legends refer more to methods than results. Fig. 1a and 1b should show the area of interest. Please indicate the signals within the ventricle and the injection track (Fig.1A) and the control ventricles with no staining (Fig.1B). Reviewer #2: The authors investigated the ability of ophthalmic prostaglandin F2alpha analogs to increase CSF outflow when applied to the nasal mucosa by inhalation. The idea behind this work is that no medications are available that will increase CSF outflow, and the olfactory lymphatics provide an accessible target for such a treatment. The authors utilized commercially available PGF2alpha analogues (latanoprost, bimatoprost, travoprost, latanoprostene bunod, and tafluprost) that are widely used in the treatment of open angle glaucoma. The main results is that a single nasal inhalation of the PGF2alpha analogue latanoprost resulted in an increased recovery of a CSF tracer from nasal mucosa, that suggested an increased passage of CSF through olfactory lymphatic channels, a little effect was seen with bimatoprost and tafluprost. The work is technically well done and well executed and data obtained are very promising. The identification of compounds with the potential to increase CSF outflow is of great interest. However, it is surprising that the authors fell short of performing additional experiments to validate their important observation. Indeed, time course experiments to pinpoint the duration of a single (or even more important) repeated dose regimen are missing. Also, in my opinion it is vital to address the effects of these prostaglandin analogs on the nasal mucosa such as morphology and cell infiltrate. In summary, this work is a nice piece of science portraying extremely interesting preliminary results but that requires additional work to be accepted for publication ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. 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Revision 1
26 Sep 2021 Author Response Dear Dr. Lolli: We thank you and the reviewers for your comments and suggestions to improve our manuscript. We have made the following changes and offer our responses to these comments below: Reviewer 1 In this article, nasal delivery of prostaglandin analogues boosted nasal recovery of a CSF fluorescent tracer, implying enhanced CSF outflow via the nasal lymphatics. Latanoprost had the most substantial impact and dose-dependent. These medicines may help lower ICP. RESPONSE: Thank you for your comments and your review. Some section of the article needs a better presentation. The statistic section describes "Student's t-tests and ANOVA RM with Dunnet's post hoc analysis". It is not informative and should be expanded, referring to preplanned methods. RESPONSE: We have revised the final paragraph of the Methods section (lines 109-114 of the tracked changes version) to provide additional statistical information as requested. The results refer to Fig.2 and Fig. 3, but it is not clear how the asterisk refers to the difference between the groups in which specific test. RESPONSE: We have provided clarification regarding the meaning of the asterisks in the Figure legends; comparisons in each instance are between the specific drug/dose and controls unless otherwise indicated. Fig legends refer more to methods than results. RESPONSE: Figure legends have been rewritten to more appropriately reflect and describe the results and no longer contain methodologic information. Fig. 1a and 1b should show the area of interest. Please indicate the signals within the ventricle and the injection track (Fig.1A) and the control ventricles with no staining (Fig.1B). RESPONSE: Asterisks and arrows have been added to direct the reader’s attention to the fluorescent signal in the ventricle and the injection track, respectively. Reviewer 2 The authors investigated the ability of ophthalmic prostaglandin F2alpha analogs to increase CSF outflow when vapplied to the nasal mucosa by inhalation. The idea behind this work is that no medications are available that will increase CSF outflow, and the olfactory lymphatics provide an accessible target for such a treatment. The authors utilized commercially available PGF2alpha analogues (latanoprost, bimatoprost, travoprost, latanoprostene bunod, and tafluprost) that are widely used in the treatment of open angle glaucoma. The main results is that a single nasal inhalation of the PGF2alpha analogue latanoprost resulted in an increased recovery of a CSF tracer from nasal mucosa, that suggested an increased passage of CSF through olfactory lymphatic channels, a little effect was seen with bimatoprost and tafluprost. RESPONSE: Thank you for your review and your very helpful comments. The work is technically well done and well executed and data obtained are very promising. The identification of compounds with the potential to increase CSF outflow is of great interest. However, it is surprising that the authors fell short of performing additional experiments to validate their important observation. Indeed, time course experiments to pinpoint the duration of a single (or even more important) repeated dose regimen are missing. RESPONSE: We appreciate this recommendation to look at duration of effect of dosing. As you noted, multiple dose/multiday dosing would reflect real-life use of a medication. Therefore, we undertook additional experiments with latanoprost only (given that it showed the greatest effect with single dosing) and found a sustained effect upon CSF drainage via the lymphatic pathways (new Figure 4 and text lines 164-181). Also, in my opinion it is vital to address the effects of these prostaglandin analogs on the nasal mucosa such as morphology and cell infiltrate. RESPONSE: The effect upon latanoprost and other prostaglandin analogues on the ocular/conjunctival mucosa has been studied extensively during pre-clinical and clinical studies. No concerning findings with respect to inflammation or cellular infiltrates were identified. These drugs are known to cause slight conjunctival hyperemia and other changes to goblet cells that are of no functional consequence. With limited research resources and a need to prioritize the most salient experiments because of COVID-19 pandemic-related restrictions on laboratory usage and capacity, we respectfully submit that the existing data on mucosal effects of prostaglandin analogues should be sufficient to allay any concerns regarding safety and tolerability when applied to the nasal mucosa, a tissue with similar properties. We have added a statement about the known effects of these substances on the mucosal surface (Lines 72-73) and included a new reference (12). In summary, this work is a nice piece of science portraying extremely interesting preliminary results but that requires additional work to be accepted for publication RESPONSE: We thank the reviewer again for the very helpful suggestions to improve the impact of our work. Additional Editor Comments The manuscript is technically sound, and the data do support the conclusions. However both reviewer had major comments, and some involve additional data requested RESPONSE: We believe we have addressed the requests for changes and additional data that the reviewers have helpfully suggested. Sincerely yours, Prem S. Subramanian, MD, PhD Professor of Ophthalmology, Neurology, and Neurosurgery Vice Chair for Academic Affairs Division Head, Neuro-Ophthalmology Attachments Attachment Submitted filename: CSF drainage rebuttal letter PLoS ONE.docx https://doi.org/10.1371/journal.pone.0248545.r002
14 Oct 2021 Decision Letter - Francesco Lolli, Editor PONE-D-21-06439R1Prostaglandin analog effects on cerebrospinal fluid reabsorption via nasal mucosaPLOS ONE Dear Dr. Subramanian, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Reviewing the new versions of the manuscript entitled “Prostaglandin analog effects on cerebrospinal fluid reabsorption via nasal mucosa” the points raised by the reviewers were considered and responded to. The manuscript is accordingly improved. In the present revision we noticed that certain details of animal experimental techniques, particularly a description of care/monitoring information, are absent or insufficiently described from the methods.They should be introduced. The requests for animal reasearch are found in https://journals.plos.org/plosone/s/submission-guidelines#loc-animal-research Please submit your revised manuscript by Nov 28 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Francesco Lolli, M.D., Ph.D. Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments (if provided): Reviewing the new versions of the manuscript entitled “Prostaglandin analog effects on cerebrospinal fluid reabsorption via nasal mucosa” the points raised by the reviewers were considered and responded to. The manuscript is accordingly improved. In the present revision we noticed that certain details of animal experimental techniques, particularly a description of care/monitoring information, are absent or insufficiently described from the methods.They should be introduced. The requests for animal reasearch are found in https://journals.plos.org/plosone/s/submission-guidelines#loc-animal-research [Note: HTML markup is below. Please do not edit.] Reviewers' comments: [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0248545.r003
Revision 2
2 Nov 2021 Author Response Francesco Lolli, MD, PhD Academic Editor PLoS ONE Dear Dr. Lolli: We thank you and the reviewers for your additional comments and suggestions to bring the manuscript within the PLoS ONE guidelines. We have made the following changes and offer our responses to these comments below: Comment: Reviewing the new versions of the manuscript entitled “Prostaglandin analog effects on cerebrospinal fluid reabsorption via nasal mucosa” the points raised by the reviewers were considered and responded to. The manuscript is accordingly improved. RESPONSE: Thank you very much. In the present revision we noticed that certain details of animal experimental techniques, particularly a description of care/monitoring information, are absent or insufficiently described from the methods. They should be introduced. RESPONSE: We have added more specific information describing the care and monitoring of the animals and trust that these details will fulfill the requirements (lines 69-74 and 91-92 in the tracked changes version). We used a recent article in PLoS ONE (https://doi.org/10.1371/journal.pone.0247149) as a model after reviewing overall requirements. Thank you again for consideration of our work. Sincerely yours, Prem S. Subramanian, MD, PhD Professor of Ophthalmology, Neurology, and Neurosurgery Vice Chair for Academic Affairs Division Head, Neuro-Ophthalmology Attachments Attachment Submitted filename: CSF drainage rebuttal letter PLoS ONE.docx https://doi.org/10.1371/journal.pone.0248545.r004
8 Nov 2021 Decision Letter - Francesco Lolli, Editor Prostaglandin analog effects on cerebrospinal fluid reabsorption via nasal mucosa PONE-D-21-06439R2 Dear Dr. Subramanian, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Francesco Lolli, M.D., Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): The authors added more specific information describing the animals' care and monitoring. They did meet the requirements. Reviewers' comments: https://doi.org/10.1371/journal.pone.0248545.r005
Formally Accepted
23 Dec 2021 Acceptance Letter - Francesco Lolli, Editor PONE-D-21-06439R2 Prostaglandin analog effects on cerebrospinal fluid reabsorption via nasal mucosa Dear Dr. Subramanian: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Francesco Lolli Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0248545.r006

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