Boccella Serena, Morace Andrea Maria, Giorgio Cristina, Guida Francesca, Perrone Michela, Manzo Iolanda, Belardo Carmela, Jones Meghan, Maione Sabatino, Aramini Andrea, Allegretti Marcello, Luongo Livio, Brandolini Laura
Research & Early Development (R&D), Dompé Farmaceutici SpA, Naples, Italy.
Pharmacology Division, Department of Experimental Medicine, University of Campania "L. Vanvitelli", Naples, Italy.
Diabetes Metab J. 2025 Mar 12. doi: 10.4093/dmj.2024.0504.
The CXC motif chemokine ligand 8 (CXCL8)-CXC motif chemokine receptor 1/2 (CXCR1/2) axis has been implicated in type 1 diabetes mellitus (T1DM). Its actions on non-immune cells may also contribute to T1DM-associated complications, including painful diabetic peripheral neuropathy (DPN) and diabetic retinopathy (DR).
We assessed the efficacy of early (4-8 weeks) or late (8-12 weeks) daily ladarixin (LDX) for the treatment of streptozotocin (STZ)-induced T1DM and the related complications of DPN or DR in male rats.
Early LDX mitigated STZ-induced dysmetabolism (i.e., blood glucose, insulin), inflammation in dorsal root ganglion/ sciatic nerve (interleukin-1β and tumor necrosis factor-α expression) and mechanical allodynia and thermal hyperalgesia, indicative of DPN. Moreover, vitreous citrullinated histone H3 (CitH3) and plasma GRO/CINC1 (CXCL8) increase were attenuated. Late LDX failed to reverse STZ-induced changes in metabolic parameters (i.e., blood glucose, insulin, C-peptide, pancreatic β-cell number and function). Strikingly, even in the absence of an effect on glycemic control, late LDX mitigated STZ-induced mechanical allodynia and thermal hyperalgesia and vitreous (CXCL8, CitH3) and retinal (CXCL8, CXCR1/2, myeloperoxidase, CitH3) inflammatory/pro-angiogenic (vascular endothelial growth factor, CD34) signs of DR.
These data confirm the efficacy of LDX in STZ-induced T1DM and provide evidence of a protective effect also against DPN and onset of DR which is independent of its effect on β-cell functionality preservation and glycemic control.
CXC基序趋化因子配体8（CXCL8）-CXC基序趋化因子受体1/2（CXCR1/2）轴与1型糖尿病（T1DM）有关。其对非免疫细胞的作用也可能导致T1DM相关并发症，包括疼痛性糖尿病周围神经病变（DPN）和糖尿病视网膜病变（DR）。
我们评估了早期（4 - 8周）或晚期（8 - 12周）每日给予拉达瑞辛（LDX）对链脲佐菌素（STZ）诱导的雄性大鼠T1DM及其相关并发症DPN或DR的治疗效果。
早期给予LDX可减轻STZ诱导的代谢紊乱（即血糖、胰岛素）、背根神经节/坐骨神经炎症（白细胞介素-1β和肿瘤坏死因子-α表达）以及机械性异常性疼痛和热痛觉过敏，这些均提示DPN。此外，玻璃体中瓜氨酸化组蛋白H3（CitH3）和血浆GRO/CINC1（CXCL8）的增加也得到缓解。晚期给予LDX未能逆转STZ诱导的代谢参数变化（即血糖、胰岛素、C肽、胰腺β细胞数量和功能）。令人惊讶的是，即使对血糖控制无影响，晚期给予LDX仍可减轻STZ诱导的机械性异常性疼痛和热痛觉过敏，以及玻璃体（CXCL8、CitH3）和视网膜（CXCL8、CXCR1/2、髓过氧化物酶、CitH3）的炎症/促血管生成（血管内皮生长因子、CD34）迹象，这些迹象提示DR。
这些数据证实了LDX对STZ诱导的T1DM的疗效，并提供了其对DPN和DR发病具有保护作用的证据，且该保护作用与其对β细胞功能保存和血糖控制的影响无关。
