An inhibitor of claudin-5 interactions, M01, alleviates neuroinflammation and vasogenic edema after blood–spinal cord barrier dysfunction

Abstract

Molecular docking modeling has confirmed that M01 (C30H28N4O5) acts as a potent inhibitor of claudin-5. Our prior data indicated that claudin-5 is essential to the structural integrity of the blood–spinal cord barrier (BSCB). The aim of this study was to investigate the effect of M01 on the integrity of the BSCB and its effect on neuroinflammation and vasogenic edema after blood–spinal cord barrier dysfunction in in-vitro and in-vivo models. Transwell chambers were used to construct an in-vitro model of the BSCB. Fluorescein isothiocyanate (FITC)-dextran permeability and leakage assays were performed to validate the reliability of the BSCB model. Semiquantitative analysis of inflammatory factor expression and nuclear factor-κB signaling pathway protein levels was performed using western blotting. The transendothelial electrical resistance of each group was measured, and the expression of a tight junction protein ZO-1 was determined via immunofluorescence confocal microscopy. Rat models of spinal cord injury were established by the modified Allen’s weight-drop method. Histological analysis was carried out by hematoxylin and eosin staining. Locomotor activity was evaluated with Footprint analysis and the Basso–Beattie–Bresnahan scoring system. The M01 (10 μM) reduced the release of inflammatory factors and degradation of ZO-1 and improved the integrity of the BSCB by reversing vasogenic edema and leakage. M01 may represent a new strategy for the treatment of diseases related to BSCB destruction.