Inhibition of the TRPM4 channel by 9-PH attenuates hippocampal endothelial injury induced by sleep deprivation and the subsequent neuroinflammation and neurological dysfunction

Sleep deprivation (SD) is a significant public health concern and a recognized risk factor for cognitive impairment. While both vascular dysfunction and neuroinflammation are implicated, the mechanistic link between them remains elusive. Here, we identify a pathogenic positive feedback loop centered on endothelial transient receptor potential melastatin 4 (TRPM4) as a core driver of SD-induced pathology. We demonstrate that SD triggers an early and specific upregulation of TRPM4 in hippocampal endothelial cells, which in turn induces blood-brain barrier (BBB) disruption, characterized by tight junction loss and perivascular edema. This endothelial injury promotes the release of high-mobility group box 1 (HMGB1), which activates microglial TLR4-NF-κB signaling and neuroinflammation. Crucially, we provide direct evidence that microglia-derived inflammatory mediators feed back to upregulate endothelial TRPM4 expression in an NF-κB-dependent manner, thereby establishing a self-sustaining TRPM4-HMGB1-NF-κB loop. Pharmacological inhibition of TRPM4 with 9-phenanthrol (9-PH) following SD onset effectively disrupted this cycle, preserving BBB integrity, suppressing microglial activation and neuronal Apoptosis, and rescuing hippocampal-dependent cognitive function. These protective effects were associated with concurrent downregulation of the HMGB1-TLR4-NF-κB axis. Our findings establish endothelial TRPM4 as a master initiator and amplifier of SD-induced neurovascular unit injury, revealing the TRPM4-HMGB1-NF-κB loop as a promising therapeutic target for mitigating the cognitive consequences of sleep loss.