Targeting the HMGB1–TLR4 Axis Alleviates Neuropathic Pain-Associated Cognitive Deficits

Cognitive deficits associated with chronic pain pose a significant burden on a patient's quality of life. Emerging evidence indicates that Toll-like receptor 4 (TLR4), a pattern recognition receptor implicated in neuroinflammatory signaling, can disrupt synaptic plasticity and memory processes. However, the specific involvement of TLR4 in the development of neuropathic pain-related cognitive deficits has not been fully elucidated. In this investigation, we observed an upregulation of TLR4 expression within hippocampal neurons in male mice subjected to chronic constriction injury (CCI) relative to the sham group. Notably, in separate experimental cohorts, TLR4 knock-out and neuron-specific TLR4 knockdown mice exhibited improved cognitive function compared with wild-type controls, alongside attenuated neuroinflammatory responses, reduced neuronal apoptosis, and enhanced preservation of hippocampal neuroplasticity. Concurrently, elevated concentrations of high-mobility group box 1 (HMGB1), a damage-associated molecular pattern molecule, were detected in the sciatic nerve, serum, and hippocampal tissues following CCI. Furthermore, increased colocalization of HMGB1 with TLR4 was evident in the hippocampus. Exogenous administration of HMGB1 augmented HMGB1 and TLR4 levels in the hippocampus and worsened memory functions that depend on hippocampal integrity. Conversely, inhibition of HMGB1 with glycyrrhizin, which subsequently attenuates TLR4 activation, ameliorated cognitive impairments induced by CCI. Collectively, these results support a model in which HMGB1, elevated during chronic neuropathic pain, contributes to cognitive deficits via a TLR4-dependent mechanism, triggering downstream inflammatory and apoptotic cascades and impairing synaptic plasticity.