Effects of CXCR1/2 Blockade with Ladarixin on Streptozotocin-Induced Type 1 Diabetes Mellitus and Peripheral Neuropathy and Retinopathy in Rat (Diabetes Metab J 2025;49:990-1005)

Serena Boccella; Andrea Maria Morace; Cristina Giorgio; Francesca Guida; Michela Perrone; Iolanda Manzo; Carmela Belardo; Meghan Jones; Sabatino Maione; Andrea Aramini; Marcello Allegretti; Livio Luongo; Laura Brandolini

doi:10.4093/dmj.2025.0927

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Response Effects of CXCR1/2 Blockade with Ladarixin on Streptozotocin-Induced Type 1 Diabetes Mellitus and Peripheral Neuropathy and Retinopathy in Rat (Diabetes Metab J 2025;49:990-1005): Serena Boccella^1*, Andrea Maria Morace^2*, Cristina Giorgio^1*, Francesca Guida², Michela Perrone², Iolanda Manzo², Carmela Belardo², Meghan Jones³, Sabatino Maione², Andrea Aramini⁴, Marcello Allegretti⁴, Livio Luongo², Laura Brandolini⁴; Diabetes & Metabolism Journal 2025;49(6):1356-1357.
DOI: https://doi.org/10.4093/dmj.2025.0927
Published online: November 1, 2025

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¹Research & Early Development (R&D), Dompé Farmaceutici SpA, Naples, Italy

²Pharmacology Division, Department of Experimental Medicine, University of Campania “L. Vanvitelli”, Naples, Italy

³R&D, Dompé US, San Mateo, CA, USA

⁴R&D, Dompé Farmaceutici SpA, L’Aquila, Italy

Corresponding author: Laura Brandolini

R&D, Dompé Farmaceutici SpA, Via Campo di Pile, 67100 L’Aquila, Italy E-mail: Laura.Brandolini@dompe.com

*Serena Boccella, Andrea Maria Morace, and Cristina Giorgio contributed equally to this study as first authors.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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See the letter "Effects of CXCR1/2 Blockade with Ladarixin on Streptozotocin-Induced Type 1 Diabetes Mellitus and Peripheral Neuropathy and Retinopathy in Rat (Diabetes Metab J 2025;49:990-1005)" on page 1351.

We thank Dr. Heung Yong Jin for their interest in our work and their thoughtful comments regarding our recent article, ‘Effects of CXCR1/2 blockade with ladarixin on streptozotocin-induced type 1 diabetes mellitus and peripheral neuropathy and retinopathy in rat’ [1]. We appreciate the opportunity to briefly share some thoughts.

First, Dr. Jin makes a meaningful contribution to the interpretation and larger context of our results by emphasizing the diversity/heterogeneity of diabetic peripheral neuropathy (DPN). While our data contribute an initial proof-of-concept that CXC motif chemokine receptor 1/2 (CXCR1/2) blockade has therapeutic potential for DPN to the current literature [2-4], how different DPN patients with unique underlying type 1 diabetes mellitus (T1DM) endotypes or patients with type 2 diabetes mellitus (T2DM) might respond to ladarixin (LDX) treatment for their DPN symptoms remains to be elucidated. Interestingly, the letter highlights that in T2DM, unlike in T1DM, initial DPN symptoms can appear unrelated to hyperglycemia levels. Based on this observation, we fully agree that extending our findings to T2DM is an essential step.

As Dr. Jin correctly emphasized, streptozotocin (STZ) has both diabetogenic and potential direct neurotoxic effects. We acknowledge that it might represent a limitation of the current model and we are considering complementary approaches in future studies, including genetic models of autoimmune diabetes, to better define the relative contributions of hyperglycemia and direct toxicity.

Moreover, we agree that evaluating different doses of LDX and various STZ protocols could provide important information regarding the therapeutic window and mechanism of action. Future studies will be designed to explore whether different dosing strategies influence both glycemic control and peripheral nerves and retinal structures.

We would also like to discuss the preferential protection of LDX on small or large nerve fibers that is also highly relevant [5-7]. In our ongoing experiments, we are including more detailed neurophysiological and morphological analysis to address this issue. These data may be helpful in clarifying the role of LDX in affecting pain versus motor components of neuropathic phenotypes.

Finally, the idea of establishing chemokine thresholds for DPN diagnosis and monitoring is persuasive. We plan to expand our chemokine profiling in both serum and neural tissues to investigate whether these molecules could serve as diagnostic or predictive tools.

In conclusion, we are grateful for Dr. Jin’s expert evaluation, which underscores the importance of continuing to investigate the interleukin-8–CXCR1/2 axis not only in β-cell preservation but also in the prevention of diabetic complications. We believe that this line of research, combined with precision medicine approaches, may contribute to the development of new disease-modifying therapies for diabetes.

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CONFLICTS OF INTEREST

Serena Boccella, Cristina Giorgio, Andrea Aramini, Marcello Allegretti, Meghan Jones, and Laura Brandolini are Dompé Farmaceutici SpA employees and Andrea Maria Morace, Francesca Guida, Michela Perrone, Iolanda Manzo, Carmela Belardo, Sabatino Maione, and Livio Luongo are University of Vanvitelli in Naples employees. The authors declare no competing interests in relation to the contents of this work. The authors declare that this study received funding from Dompé Farmaceutici SpA.

REFERENCES

1. Boccella S, Morace AM, Giorgio C, Guida F, Perrone M, Manzo I, et al. Effects of CXCR1/2 blockade with ladarixin on streptozotocin-induced type 1 diabetes mellitus and peripheral neuropathy and retinopathy in rat. Diabetes Metab J 2025;49:990-1005.PubMed PMC
2. Fousteri G, Jones M, Novelli R, Boccella S, Brandolini L, Aramini A, et al. Beyond inflammation: the multifaceted therapeutic potential of targeting the CXCL8-CXCR1/2 axis in type 1 diabetes. Front Immunol 2025;16:1576371.Article PubMed PMC
3. Staats Pires A, Heng B, Tan VX, Latini A, Russo MA, Santarelli DM, et al. Kynurenine, tetrahydrobiopterin, and cytokine inflammatory biomarkers in individuals affected by diabetic neuropathic pain. Front Neurosci 2020;14:890.PubMed PMC
4. Baldimtsi E, Papadopoulou-Marketou N, Jenmalm MC, Wahlberg J. The role of chemokines in type 1 diabetes-associated neuropathy. Endocrinol Diabetes Metab 2023;6:e419.Article PubMed PMC
5. Cao DL, Zhang ZJ, Xie RG, Jiang BC, Ji RR, Gao YJ. Chemokine CXCL1 enhances inflammatory pain and increases NMDA receptor activity and COX-2 expression in spinal cord neurons via activation of CXCR2. Exp Neurol 2014;261:328-36.Article PubMed
6. Moraes TR, Elisei LS, Malta IH, Galdino G. Participation of CXCL1 in the glial cells during neuropathic pain. Eur J Pharmacol 2020;875:173039.Article PubMed
7. Carreira EU, Carregaro V, Teixeira MM, Moriconi A, Aramini A, Verri WA Jr, et al. Neutrophils recruited by CXCR1/2 signalling mediate post-incisional pain. Eur J Pain 2013;17:654-63.PubMed

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Effects of CXCR1/2 Blockade with Ladarixin on Streptozotocin-Induced Type 1 Diabetes Mellitus and Peripheral Neuropathy and Retinopathy in Rat (Diabetes Metab J 2025;49:990-1005)

Diabetes Metab J. 2025;49(6):1356-1357. Published online November 1, 2025

DOI: https://doi.org/10.4093/dmj.2025.0927

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Effects of CXCR1/2 Blockade with Ladarixin on Streptozotocin-Induced Type 1 Diabetes Mellitus and Peripheral Neuropathy and Retinopathy in Rat (Diabetes Metab J 2025;49:990-1005)

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Boccella S, Morace AM, Giorgio C, Guida F, Perrone M, Manzo I, Belardo C, Jones M, Maione S, Aramini A, Allegretti M, Luongo L, Brandolini L. Effects of CXCR1/2 Blockade with Ladarixin on Streptozotocin-Induced Type 1 Diabetes Mellitus and Peripheral Neuropathy and Retinopathy in Rat (Diabetes Metab J 2025;49:990-1005). Diabetes Metab J. 2025;49(6):1356-1357.

DOI: https://doi.org/10.4093/dmj.2025.0927.

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