Thrombin-mediated increased permeability of blood-brain barrier in diquat poisoning: Mechanistic insights and potential therapeutic targets.

Diquat (DQ), a commonly used herbicide alternative to paraquat, poses significant threats to the environment, ecosystems and human health. Central nervous system adverse effects induced by DQ may be related to the disruption of the blood-brain barrier (BBB). This study investigated the mechanisms and therapeutic targets of DQ-induced BBB damage through clinical research, rat models, and in vitro experiments. Our findings indicated that DQ induced an increase in BBB permeability, as evidenced by the disruption of F-actin cytoskeleton integrity and tight junctions in brain microvascular endothelial cells, particularly in the hippocampal CA1 region associated with cognitive function. The elevated levels of thrombin and PAI-1 in the blood of both patients and rats with DQ poisoning suggest abnormal coagulation function. Thrombin exposure in vitro exacerbated DQ-induced BBB damage. Mechanistically, thrombin-mediated DQ exposure further upregulated PAI-1 levels and induced calcium imbalance associated with endoplasmic reticulum stress. This process elevated cytoplasmic Ca2 + levels, activating MLCK/MLC2 signaling pathway to impair the BBB, which were mitigated by the endoplasmic reticulum stress inhibitor 4-PBA. In conclusion, DQ increased BBB permeability, with thrombin involvement. These findings offer valuable insights into the mechanisms underlying DQ-induced neurological damage, highlighting potential therapeutic targets for alleviating these effects.