Oxytocin Alleviates the Cognitive and Memory Dysfunction Caused by Neuroinflammation through Blocking the TLR4/NLRP3/NF-κB Signaling Pathway

Lipopolysaccharide (LPS)-induced systemic inflammation is associated with cognitive and memory impairments, neuroinflammation, and synaptic dysfunction. The neuropeptide oxytocin has anti-inflammatory and neuromodulatory properties; however, the underlying molecular mechanisms remain poorly understood. This study aimed to investigate the role of oxytocin in LPS-induced deficits in spatial learning, memory, and social recognition and explore the underlying mechanisms related to neuroinflammatory suppression and synaptic restoration. Adult male C57BL/6 mice were intraperitoneally injected with LPS, with or without oxytocin and the oxytocin receptor antagonist atosiban, and subjected to behavioral assessments, including the Morris water maze, three-chamber social interaction test, open field test, and elevated plus maze. LPS administration impaired social and spatial memory without affecting anxiety-related behaviors. These impairments were associated with elevated levels of pro-inflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α) in the serum and hippocampus, increased microglial activation, and downregulated synaptic proteins (postsynaptic density protein 95 (PSD-95), synaptosomal-associated protein 25 (SNAP-25), and synaptophysin). LPS decreased circulating oxytocin levels and the number of oxytocinergic neurons in the hypothalamus while upregulating hippocampal oxytocin receptor expression. Exogenous oxytocin administration ameliorated LPS-induced cognitive deficits, reduced neuroinflammation, and restored synaptic protein expression, which were reversed by atosiban co-administration. Pharmacological inhibition of the nucleotide-binding oligomerization domain-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome using MCC950 mimicked the protective effects of oxytocin, whereas its activation using nigericin abolished them. These findings suggest that oxytocin alleviates LPS-induced cognitive and synaptic impairments by suppressing NLRP3 inflammasome-mediated neuroinflammation, highlighting its therapeutic potential in inflammation-associated cognitive dysfunction. • Oxytocin improves LPS-induced spatial and social memory deficits • OXT reduces neuroinflammation and microglial activation in hippocampus • OXT restores synaptic protein expression via NLRP3 inflammasome suppression • OXTR blockade attenuates the neuroprotective effects of oxytocin • NLRP3 activation reverses OXT-mediated cognitive improvement