Undaria pinnatifida fucoidan (UPF), a sulphated polysaccharide derived from brown seaweed, has attracted scientific and clinical interest for its wide-ranging anti-inflammatory and neurodegenerative properties. A growing body of research shows that UPF inhibits NF-κB and MAPK signalling pathways, reduces pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), decreases ROS production, and suppresses iNOS and COX-2 activity, thereby mitigating oxidative and inflammatory damage in vitro. In vivo studies confirm these actions, demonstrating reduced systemic inflammation, promoted antioxidant defence, modulated gut microbiota composition, and improved production of beneficial microbial metabolites. In parallel, emerging evidence highlights UPF’s neuroprotective potential, characterised by protection against neuroinflammation and oxidative stress, the attenuation of amyloid-beta deposition, and improvement in neuronal function. Importantly, low- to medium-molecular-weight and highly sulphated UPF fractions consistently exhibit stronger bioactivities, suggesting a structural basis for its therapeutic potential. This review integrates mechanistic evidence from cellular, preclinical, and emerging clinical studies, highlighting UPF as a versatile marine-derived agent with therapeutic relevance for inflammatory and neurodegenerative diseases, and outlines future research directions toward clinical translation.

Undaria pinnatifida fucoidan (UPF), a sulphated polysaccharide derived from brown seaweed, has attracted increasing scientific interest for its wide-ranging anti-inflammatory and neuroprotective properties. Previous studies have demonstrated that UPF exerts significant anti-inflammatory effects through the downregulation of pro-inflammatory cytokines, inhibition of key signalling pathways such as NF-κB and MAPKs, suppression of oxidative stress, and modulation of immune mediators and gut microbiota. In parallel, emerging evidence highlights UPF's neuroprotective potential, characterised by reduced neuroinflammation, oxidative damage, and amyloid-beta accumulation, alongside enhanced antioxidant defence and neuronal function. Current investigations reinforce these findings, suggesting that UPF may serve as a valuable adjunct in managing inflammation-related disorders and neurodegenerative conditions. This review summarises the current knowledge on UPF’s mechanisms of action, with a particular focus on its anti-inflammatory and neuroprotective pathways and implications for brain health, while also identifying gaps for future research and clinical translation.

Post-traumatic stress disorder (PTSD) is characterized by persistent threat-related memories for which there are limited effective treatment options. The N-methyl-D-aspartate (NMDA) receptor-dependent extracellular signal-regulated kinase (ERK) pathway in the lateral amygdala (LA) is necessary for synaptic plasticity, threat memory consolidation and reconsolidation. Disruption of these memories during the reconsolidation window has been proposed as a therapeutic strategy for PTSD, however, no current therapies using this strategy are available. To disrupt reconsolidation, memories must first be brought into a labile state. We investigated the effect of the NMDA receptor partial agonist D-cycloserine (DCS) and the ketamine-like non-competitive antagonist MK801 on threat memory reconsolidation in mice. Using auditory threat conditioning, DCS, or saline vehicle, was administered one hour before memory reactivation to facilitate labilization of a recalled threat memory, followed by MK801 or a saline vehicle after reactivation. Experimental groups included vehicle, DCS 15 mg/kg, MK801 0.06 mg/kg, and MK801 0.12 mg/kg alone and in combination. The effect of behavioural and drug interventions on phospho-ERK-expressing neurons in the LA was analysed using neuron counting and topographical mapping in the LA. MK801 alone and in combination with DCS reduced the number of pERK neurons in the LA across all doses. Freezing behaviour was reduced by high-dose MK801 when combined with DCS. These findings suggest that DCS and MK801 together effectively disrupt threat memory reconsolidation in the LA and offer an NMDA-based combined drug and behavioural treatment strategy for PTSD.

Strong fear memories resistant to modification are a key hallmark of trauma disorders such as post-traumatic stress disorder (PTSD). However, the neural mechanisms behind the encoding of these memories, and how these may differ in terms of strength, remain poorly understood. In this study, 36 male C57BL/6 mice were divided into four treatment groups (strong fear memory, weak fear memory, unpaired strong control, unpaired weak control) and underwent a classical auditory aversive memory reconsolidation paradigm. Brains were stained using immunohistochemistry (IHC) for pERK expression in the medial prefrontal cortex (mPFC) and basolateral amygdala (BNC) to show active principal neurons recruited to the fear memory engram. Behavioural data showed significantly higher expression of freezing behaviour in the strong fear group on Day 3 compared to all other groups F(3,32) = 4.83, p = 0.0069. In line with behavioural data, the IHC analysis indicated that the strong fear group showed significantly higher levels of activated pERK principal neurons in the prelimbic (PL) and infralimbic cortices (IL), and the dorsolateral (LaDL), ventrolateral (LaVM), and posterior basomedial subnuclei (BMP) of the basolateral amygdala, compared to the low fear group and unpaired controls. Furthermore, it was found that specific populations of neurons within these subnuclei differentially encoded different memory strengths. These findings indicate that the memory strength encoding is localised to subnuclei and neuronal populations within these subnuclei, rather than the entire nucleus. This has implications for the identification of the physical site of the engrams involved in conditioned fear memory.

The basolateral amygdala complex (BNC) plays an important role in learning, memory, motivation, and social behaviour, with its dysfunction implicated in a wide variety of psychiatric disorders. Despite being one of the most intensely researched areas of the brain, much is still unknown about its microanatomical structure and function, relationships and evolutionary origins. In this review, we offer a multidisciplinary approach through the lens of comparative anatomy and evolutionary developmental studies to provide a better understanding of the anatomical and functional relationship between the amygdala and cortex in memory, learning, and social behaviour. Particular attention is paid to the evolutionary origin of pallial areas across amniotes, as well as homology between principal neurons, cortical layers, BNC nuclei, and connectivity between these areas. We argue that the basolateral amygdala complex functions as an early form of the mammalian neocortex. This theory will help to further the understanding of amygdala and cortex function in both health and psychiatric disease.