Effects of CXCR1/2 Blockade with Ladarixin on Streptozotocin-Induced Type 1 Diabetes Mellitus and Peripheral Neuropathy and Retinopathy in Rat.

Abstract

Background: 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).

Methods: 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.

Results: 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.

Conclusion: 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.