Neuroprotection in Diabetes Retinal Disease: An Unmet Medical Need
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsIn this paper, the authors present a comprehensive review of neuroprotective strategies in diabetic retinopathy, focusing on mechanisms such as oxidative stress, inflammation, neurovascular unit dysfunction, glutamate excitotoxicity, and neurotrophic signaling. The review is well-structured and includes critical mechanistic insights, supported by appropriate figures (can be improved) and references. I have some suggestions for improvements before the manuscript can be considered for publication.
- Lack of some newly published literatures from 2024-2025, suggest adding these ones: https://doi.org/10.36283/ziun-pjmd14-2/063,
https://doi.org/10.1007/s40200-025-01604-w
https://doi.org/10.1007/s10792-025-03584-5 -
No Summary Table. A table listing neuroprotective agents, pathways, and trial status would be a great addition.
Author Response
In this paper, the authors present a comprehensive review of neuroprotective strategies in diabetic retinopathy, focusing on mechanisms such as oxidative stress, inflammation, neurovascular unit dysfunction, glutamate excitotoxicity, and neurotrophic signaling. The review is well-structured and includes critical mechanistic insights, supported by appropriate figures (can be improved) and references. I have some suggestions for improvements before the manuscript can be considered for publication.
- Lack of some newly published literatures from 2024-2025, suggest adding these ones:
https://doi.org/10.36283/ziun-pjmd14-2/063
https://doi.org/10.1007/s40200-025-01604-w
https://doi.org/10.1007/s10792-025-03584-5
Answer: We thank the reviewer for suggesting to add the above papers to the revised manuscript. We have now included these references (References 49, 74 and 125). For each reference, we have added a corresponding paragraph that summarizes the key message of the article and its relevance. Specifically, the role of endoplasmic reticulum stress in diabetic retinopathy and its association with early neurodegeneration has been incorporated into Section 2.2 (Lines 173–179). The suggested systematic review on BDNF physiology in diabetic retinopathy has been added to Section 2.5 to highlight the discussion on neurotrophic factor deficiency and its relevance to early retinal neurodegeneration (Lines 240–248). Finally, additional information on the pleiotropic effects of GLP-1R agonists has been included in Section 4.1.5.
- No Summary Table. A table listing neuroprotective agents, pathways, and trial status would be a great addition.
Answer: We thank the reviewer for pointing out that a summary table will help illustrate all the neuroprotective agents discussed. In the revised version of the manuscript we have included the summary table listing all the aspects mentioned by the reviewer (Lines 424-426).
All changes made to the manuscript are highlighted in red.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsThe manuscript is interesting and it contains overview of diabetes and retinal disease.
Several comments will increase the manuscript's impact.
It is important to discuss the contribution of each pathologic mechanism in diabetic retinopathy. Authors suggested protein kinase C (PKC), hexosamine, polyol and advanced glycation end-products (AGEs). Percentage of the progression contribution is required.
How about oxidative stress and mitochondrial function? Which cell types are more affected in diabetic retinopathy? This information is missing.
Inflammation and microglial activation are important topics but there is no clear evidence in this manuscript. More studies should be collected including genetic studies and pharmacologic studies.
In this study, neovascularization and ischemic stress are missing in diabetic retinopathy. In this disease, this form is severe and it is related to vision impairments. Therefore, this should be discussed with novel therapies.
Author Response
The manuscript is interesting and it contains overview of diabetes and retinal disease.
Several comments will increase the manuscript's impact.
- It is important to discuss the contribution of each pathologic mechanism in diabetic retinopathy. Authors suggested protein kinase C (PKC), hexosamine, polyol and advanced glycation end-products (AGEs). Percentage of the progression contribution is required.
Answer: We thank the reviewer for this comment. The involvement of hyperglycemia-driven pathways, including protein kinase C (PKC), hexosamine, polyol, and advanced glycation end-products (AGEs) pathways, in diabetic retinopathy is well-established in the literature and is not a novel proposal from our group. These pathways have been consistently described as major contributors to the metabolic and oxidative stress that underlie the development and progression of diabetic retinopathy (PMID: 40048937; PMID: 38790699; PMID: 33302369; PMID: 37172821; PMID: 35911994; PMID: 33248932).
Importantly, there is currently no experimental or clinical evidence that allows a quantitative estimation of the relative contribution (e.g., percentage) of each of the aforementioned pathways to the disease development or progression. These mechanisms are highly interconnected and act in parallel rather than independently, which limits the assignation of specific quantitative contributions. To address this, we have added a paragraph to the manuscript explicitly clarifying that the relative contribution of these pathways cannot be defined in quantitative terms based on the available evidence (Lines 133-139).
- How about oxidative stress and mitochondrial function? Which cell types are more affected in diabetic retinopathy? This information is missing.
Answer: We thank the reviewer for highlighting the need for further clarification in Section 2.2, where oxidative stress and mitochondrial dysfunction are introduced and discussed. We agree that these mechanisms play a central role in the pathogenesis of retinal neurodegeneration, and because of that, we have extended the section, identifying the most vulnerable retinal cell types (Lines 143–147).
- Inflammation and microglial activation are important topics but there is no clear evidence in this manuscript. More studies should be collected including genetic studies and pharmacologic studies.
Answer: We thank the reviewer for this comment about the key role of inflammation and microglial activation. In response, we have expanded Section 2.4 to explicitly include experimental genetic and pharmacologic evidence showing that the modulation of inflammatory pathways is able to reduce microglial activation, oxidative stress, and neuronal dysfunction in diabetic models (Lines 217–225). These findings support the fact that inflammation is an active contributor to early retinal neurodegeneration.
- In this study, neovascularization and ischemic stress are missing in diabetic retinopathy. In this disease, this form is severe and it is related to vision impairments. Therefore, this should be discussed with novel therapies.
Answer: Thank you for pointing out that neovascularization and ischemic stress are not addressed in the current version of the manuscript. We fully agree that ischemic stress and pathological neovascularization are critical components of advanced diabetic retinopathy and major contributors to vision loss. However, the primary focus of this review is on the earliest stages of diabetic retinopathy, specifically the underlying neurodegenerative process, which precedes both ischemic stress and neovascularization.
As the main objective of this review is to comprehensively analyse experimental therapeutic strategies conferring neuroprotection during the initial stages of the disease, we deliberately focused on the early pathogenic mechanisms triggering retinal neurodegeneration, in order to avoid overlap with the extensive literature addressing ischemia-driven and neovascular stages of diabetic retinopathy. To further clarify this scope, we have added a sentence to the Introduction clearly stating that the review focuses on the early, non-proliferative stages of diabetic retinopathy (Lines 66-68).
All changes made to the manuscript are highlighted in red
Author Response File: Author Response.pdf
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsThe raised comments have been addressed.
