Inhibition of tPA-NMDAR interaction prevents neurovascular and functional deficits induced by organophosphorus nerve agents.

Organophosphorus compounds (OP), including pesticides and nerve agents such as sarin, soman and Novichok, irreversibly inhibit cholinesterases (ChE), resulting in excessive cholinergic signaling, excitotoxicity, and neuroinflammation. Although current countermeasures provide partial protection, OP exposure remains associated with central nervous system (CNS) damage, including blood-brain barrier (BBB) disruption and cognitive impairments. In this study, we identify a critical role for tissue-type plasminogen activator (tPA)-a serine protease that modulates neuronal and endothelial N-methyl-D- aspartate receptor (NMDAR) signaling-in mediating OP-induced brain injury. Using a murine model exposed to soman or the nerve agent surrogate 4-nitrophenyl isopropylmethylphosphonate (NIMP), we show that OP exposure elevates circulating tPA levels, exacerbating neuroinflammation, BBB leakage, and neurovascular coupling impairment. Notably, blockade of the tPA-NMDAR interaction using Glunomab, a monoclonal antibody, prevents these effects. Our findings identify tPA-NMDAR signaling as a key mediator of OP-induced CNS damage and a promising therapeutic target.