Neuroprotective and Anti-Inflammatory Activity of <i>Undaria pinnatifida</i> Fucoidan <i>In Vivo</i>—A Proteomic Investigation

Undaria pinnatifida fucoidan (UPF), a bioactive sulphated polysaccharide, is widely recognised for its anti-inflammatory, antioxidant, antitumor, anticoagulant, antiviral, and immunomodulatory properties. However, the precise mechanisms by which UPF regulates inflammation and neuronal health remain unclear. This study aimed to investigate the effects of UPF supplementation on pro-inflammatory cytokines in skeletal muscle, small intestine, and the hypothalamus, as well as plasma cytokine levels. Additionally, a brain proteomic investigation in the nucleus accumbens (NAc) was performed to assess UPF’s impact on neuronal protein expression in mice. A total of 64 C57BL/6J mice were administered either a standard chow or high fat diet (HFD) with or without UPF (400 mg/kg/day) for 10 weeks. In HFD-fed mice, UPF significantly reduced the expression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in skeletal muscle, small intestine, and hypothalamus, while also lowering circulating IL-1α and IL-6 levels. Proteomic analysis of the NAc revealed that UPF modulated proteins involved in oxidative stress, neuroinflammation, neurotransmitter regulation, and endoplasmic reticulum stress. In contrast, in chow-fed mice, UPF had no effect on the neuroinflammatory-oxidative stress markers but influenced the abundance of proteins associated with immune response and innate immunity. These findings highlight diet-dependent effects of UPF, suggesting an adaptive role in modulating stress-response pathways under different metabolic conditions and highlighting its potential neuroprotective support for inflammation-related disorders and brain health.