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Open AccessArticle
A New Application for Cenicriviroc, a Dual CCR2/CCR5 Antagonist, in the Treatment of Painful Diabetic Neuropathy in a Mouse Model
by
Aleksandra Bober
Aleksandra Bober ,
Anna Piotrowska
Anna Piotrowska *,
Katarzyna Pawlik
Katarzyna Pawlik ,
Katarzyna Ciapała
Katarzyna Ciapała ,
Magdalena Maciuszek
Magdalena Maciuszek ,
Wioletta Makuch
Wioletta Makuch and
Joanna Mika
Joanna Mika *
Department of Pain Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Krakow, Poland
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2024, 25(13), 7410; https://doi.org/10.3390/ijms25137410 (registering DOI)
Submission received: 20 June 2024
/
Revised: 2 July 2024
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Accepted: 3 July 2024
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Published: 5 July 2024
Abstract
The ligands of chemokine receptors 2 and 5 (CCR2 and CCR5, respectively) are associated with the pathomechanism of neuropathic pain development, but their role in painful diabetic neuropathy remains unclear. Therefore, the aim of our study was to examine the function of these factors in the hypersensitivity accompanying diabetes. Additionally, we analyzed the analgesic effect of cenicriviroc (CVC), a dual CCR2/CCR5 antagonist, and its influence on the effectiveness of morphine. An increasing number of experimental studies have shown that targeting more than one molecular target is advantageous compared with the coadministration of individual pharmacophores in terms of their analgesic effect. The advantage of using bifunctional compounds is that they gain simultaneous access to two receptors at the same dose, positively affecting their pharmacokinetics and pharmacodynamics and consequently leading to improved analgesia. Experiments were performed on male and female Swiss albino mice with a streptozotocin (STZ, 200 mg/kg, i.p.) model of diabetic neuropathy. We found that the blood glucose level increased, and the mechanical and thermal hypersensitivity developed on the 7th day after STZ administration. In male mice, we observed increased mRNA levels of Ccl2, Ccl5, and Ccl7, while in female mice, we observed additional increases in Ccl8 and Ccl12 levels. We have demonstrated for the first time that a single administration of cenicriviroc relieves pain to a similar extent in male and female mice. Moreover, repeated coadministration of cenicriviroc with morphine delays the development of opioid tolerance, while the best and longest-lasting analgesic effect is achieved by repeated administration of cenicriviroc alone, which reduces pain hypersensitivity in STZ-exposed mice, and unlike morphine, no tolerance to the analgesic effects of CVC is observed until Day 15 of treatment. Based on these results, we suggest that targeting CCR2 and CCR5 with CVC is a potent therapeutic option for novel pain treatments in diabetic neuropathy patients.
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MDPI and ACS Style
Bober, A.; Piotrowska, A.; Pawlik, K.; Ciapała, K.; Maciuszek, M.; Makuch, W.; Mika, J.
A New Application for Cenicriviroc, a Dual CCR2/CCR5 Antagonist, in the Treatment of Painful Diabetic Neuropathy in a Mouse Model. Int. J. Mol. Sci. 2024, 25, 7410.
https://doi.org/10.3390/ijms25137410
AMA Style
Bober A, Piotrowska A, Pawlik K, Ciapała K, Maciuszek M, Makuch W, Mika J.
A New Application for Cenicriviroc, a Dual CCR2/CCR5 Antagonist, in the Treatment of Painful Diabetic Neuropathy in a Mouse Model. International Journal of Molecular Sciences. 2024; 25(13):7410.
https://doi.org/10.3390/ijms25137410
Chicago/Turabian Style
Bober, Aleksandra, Anna Piotrowska, Katarzyna Pawlik, Katarzyna Ciapała, Magdalena Maciuszek, Wioletta Makuch, and Joanna Mika.
2024. "A New Application for Cenicriviroc, a Dual CCR2/CCR5 Antagonist, in the Treatment of Painful Diabetic Neuropathy in a Mouse Model" International Journal of Molecular Sciences 25, no. 13: 7410.
https://doi.org/10.3390/ijms25137410
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