Ouabain Relieves Sleep Deprivation-Induced Anxiety-Like Behavior in Mice by Suppressing Hippocampal Neuroinflammation...

Sleep insufficiency has become a global public health challenge and is closely associated with the onset of mood and anxiety disorders. Neuroinflammation and oxidative stress are considered key pathological substrates underlying these conditions. Ouabain is a prototypical cardiotonic glycoside and an endogenous ligand of Na⁺/K⁺-ATPase. In recent years, ouabain has been reported to exert anti-inflammatory and neuroprotective effects; however, whether it can ameliorate sleep deprivation (SD)-associated affective abnormalities remains unclear.

Using a 72-h modified multiple-platform SD model in male ICR mice, we investigated whether low-dose ouabain administration (3 µg/kg, i.p.) alleviates anxiety-like behaviors, as assessed by the open field test, and mitigates hippocampal inflammatory (cytokine TNF-α, IL-1β, IL-4, and IL-10) and redox disturbances (T-AOC, SOD, GPx, MDA, and CAT), as measured by ELISA. In parallel, PLX5622 and pathway-specific modulators were employed to explore the potential mechanisms underlying the beneficial effects of ouabain.

In this study, SD reduced center zone time in the open field by 56.05% without changing locomotor activity, increased hippocampal TNF-α, IL-1β, and MDA by 105.11%, 82.50%, and 89.82%, respectively, and decreased IL-4, IL-10, SOD, GPx, CAT, and T-AOC by 54.28%, 47.22%, 44.96%, 51.95%, 52.14%, and 46.20%, respectively. Administration of low-dose ouabain significantly reversed these changes. PLX5622-mediated microglial depletion produced a partially similar protective profile, and pharmacological interference with Src/p38 MAPK/NF-κB-associated signaling attenuated the effect of ouabain.

Collectively, these findings suggest that low-dose ouabain mitigates acute SD-induced anxiety-like behavior, at least in part by suppressing hippocampal neuroinflammation and oxidative stress, and identify a potential signaling axis for further investigation.