Desloratadine as the selective 5HT2AR antagonist suppresses neutrophil extracellular traps formation to ameliorate diabetic peripheral neuropathy pathology

Diabetic peripheral neuropathy (DPN) is a common diabetic complication with a obscure and complicated pathogenesis. Here, we determined that 5-hydroxytryptamine receptor 2 A (5HT2AR) is selectively and pathologically elevated in the sciatic nerve (SN) tissues of late-stage DPN patients and the SN/dorsal root ganglion (DRG) tissues of late-stage DPN model mice (both type 1 and 2 diabetic mice) compared with the other 13 subtypes of 5HTR, and desloratadine (DLT) as a discovered selective antagonist of 5HT2AR ameliorated the DPN-like pathology in mice. To elucidate the underlying mechanisms, proteomic analysis was performed against the SN tissues of DPN mice and verified by assays against both the SN tissues from DPN patients and the DPN mice with specific 5HT2AR knockdown in the SN and DRG tissues by injection of the adeno-associated virus php.s-5HT2AR-RNAi. We determined the activation of the neutrophil extracellular traps (NETs) that is tightly linked to the vascular dysfunction and neuroinflammation in DPN pathology. NETs regulated vascular dysfunction through NE/TF/HIF-1α/MMP-9/2 pathway, and DLT-mediated 5HT2AR inhibition suppressed NETs activation through PKC/NADPH/ROS pathway. Collectively, our findings revealed that 5HT2AR associates with NETs activation in DPN pathology and supported that pharmacological inhibition of 5HT2AR shows promising as a therapeutic strategy for DPN and DLT exhibits high potential in treating the disease. • 5HT2AR-mediated neutrophil extracellular traps (NETs) is tightly linked to the vascular dysfunction and neuroinflammation activation in DPN pathology. • NETs exacerbates vascular dysfunction through NE/TF/HIF-1α/MMP-9/2 pathway and inflammation activation through NF-κB/NLRP3 pathway. • DLT targets 5HT2AR to suppress NETs in amelioration of DPN-like pathology in mice through PKC/NADPH/ROS pathway. • Antagonism of 5HT2AR shows promise as a therapeutic strategy for DPN and DLT exhibits potential in treating this disease. NETs exacerbates vascular dysfunction through NE/TF/HIF-1α/MMP-9/2 pathway and inflammation through NF-κB/NLRP3 pathway, while the DLT-mediated 5HT2AR inhibition suppressed NETs activation through PKC/NADPH/ROS pathway.