ATP-Sensitive Potassium Channels in Migraine: Translational Findings and Therapeutic Potential

Round 1

Reviewer 1 Report

This review is a well-edited and detailed manuscript on the role of ATP-sensitive potassium channels in migraine. The authors collected and assessed numerous references and produced a comprehensive summary from pharmacological, preclinical and clinical perspectives. Relevant information was incorporated into the manuscript and a logical structure was used. I support the publication of this review after some minor corrections.

My suggestions:

·       Abstract, Page 1: Please, correct these mistakes (erratum): lines 18 and 20: levcromaklaim and levcromakalaim; line 23: thourough; line 28: differnces

·       1. Introduction, Page 2: ATP sensitive potassium … - in the whole text, please standardize: ATP-sensitive (with hyphen)

·       2. Molecular basis and physiological function of K_ATP channels … Page 2: In the sub-title there is a mistake: „rugulation” – please, correct it.

·       2.3.1. Vascular system, Page 5: PACAP abbreviation was used without the whole name. Please, correct it.

·       2.3.2. Neuronal function, Page 6: line 185: Ca2+ - please, standardize in the whole text the 2+ in superscript (page 8, line 246, 247). 

·       2.3.4. Analgesia, antinociception and opioid signaling, Page 7: line 214 – I think there is an erratum: NK-kappaB – please correct it (NF). In line 219 – there is a missing dot: Khanna et al.

·       2.3.5. Insulin secretion and glucose metabolism, Page 8: line 247-253 – I think there is a too long sentence („It is generally accepted…” – please, split it). Also, in this section the „loss of function „ phrase was written with and without hyphen (line 248 and 254). In the line 260 you used the WT abbreviation without the explanation (wild type).

·       3.1 K_ATP channel openers, Page 8: line 285: hyperglecamia – please, correct it.

·       4.2.2. Stimulation of CGRP release, Page 11: line 390 – singe cells (maybe single?)

·       4.2.4. In vivo mouse model, Page 11: line 410 – ICV abbreviation is unnecessary

·       4.3.1. Effect of K_ATP channel blockers in preclinical models, Page 12: line 442 – the MMA abbreviation was used before, so please change the “middle meningeal artery” to MMA; page 13, line 453 and 456: the GTN abbreviation may not be used before – please check it.

·       4.3.2. Clinical effect of … … in human migraine models, Page 13: line 489, the heart rate was abbreviated before (HR on page 10, line 345), so you can use it.

·       Discussion, page 14, line 499: there is an erratum (typo): K_TAP -please, correct it. Page 18: the FDA abbreviation is unnecessary. 

·       I think highlighting secondary captions would be useful to separate/break up the text (e.g. 4.2., because this title has several sub-titles: 4.2.1 and 4.2.2, etc). 

      I recommend to make a figure for the section of “4. K_ATP channels and headache” or the discussion, which may present the connections between migraine and ATP-sensitive potassium channels (similarities, discrepancies, targets, possible mechanisms, therapeutic perspectives – preclinical and clinical data). It would help in better understanding.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

This is an interesting and exhaustive review on K_ATP channel involvement in pathophysiology and on the possible utility of K_ATP channel as antimigraine therapeutic agents.

The paper is well written and covers a topic which is extremely interesting for the development of future migraine treatments.

1)    Migraine may occur without headache pain. This is the case of the so-called “Episodic syndromes that may be associated with migraine” (ICHD-III: 1.6) and of “Typical aura without headache” (ICHD-III: 1.2.1.2). Hence, the authors should acknowledge that K_ATP channel modulation has migraine consequences in most – but not in all – migraine patients

2)    The proportion of patients responding to antiCGRP mAbs is higher than 50%. Most prospective real-life studies document a >50% response in 60%-70% of migraine patients

3)    There are several typos in the abstract and throughout the paper

4)    Reference style should be checked (e.g., use of capital letters for authors/study title in ref #121,122, 142 and others

Author Response

Please see the attachment.

Author Response File: Author Response.pdf