Peripheral and Central Administration of Soluble Glycoprotein 130 Improves Cognitive Outcomes Following Controlled...

Traumatic brain injury (TBI) initiates complex immune responses, including upregulation of interleukin (IL)-6, a cytokine associated with clinical outcomes after injury. IL-6 trans-signaling, via the solubilized IL-6 receptor, drives pro-inflammatory cascades and is selectively inhibited by soluble glycoprotein 130 (sgp130). Although chronic intermittent sgp130Fc fusion protein (sgp130Fc) treatment after TBI has shown benefits across species, optimal dosing remains unclear. This study evaluated the effects of a single sgp130Fc dose (2 μg intrahippocampally or 10 μg intraperitoneally) in male mice on day three following controlled cortical impact or sham procedures. Cognitive performance was assessed using the Morris water maze, and histological assessment included lesion volume and microglia quantification. Intrahippocampal sgp130Fc improved spatial memory during probe trials, decreasing latency to the platform zone (p < 0.05) and enhanced spatial swim strategy selection (p < 0.05). Intraperitoneal sgp130Fc improved spatial learning (p < 0.05) and reduced anxiety-like behavior, indicated by increased target zone time during probe trials and decreased peripheral zone time (p < 0.05). Neither route significantly altered lesion volume or thalamic ionized calcium-binding adaptor molecule 1+ cell counts versus vehicle-treated injured animals; however, intrahippocampal sgp130Fc reduced major histocompatibility complex class II+ cells. These findings demonstrate that a single subacute sgp130Fc dose confers modest behavioral benefits when administered post-TBI, without worsening outcomes. The results underscore the effects of IL-6 trans-signaling inhibition on TBI outcomes and highlight the need for further research into dose, timing, and sex-specific responses. Overall, these data add to emerging support that selective IL-6 blockade with sgp130Fc may represent a translatable strategy to modulate post-TBI inflammation and support cognitive recovery, in part, via reducing anxiety-associated dysfunction.