Ellagitannin component punicalin prevents cognitive impairment by inhibiting metabolic disorders, TLR4/NF-kB/NLRP3 inflammasome signaling, and mitochondrial dysfunction in high-fat diet-fed mice

Abstract

Obesity linked to overnutrition can result in metabolic dysregulation and cognitive impairment. This study aimed to explore the protective role of punicalin (PUN), an ellagitannin with various biological activities, against cognitive impairment in high-fat diet (HFD)-fed mice and to examine the underlying mechanisms. PUN was orally administered at 50, 100, and 150 mg/kg for 8 weeks, resulting in a significant reduction in body weight, restoration of glucose tolerance, and normalization of lipid profiles in the serum and liver of HFD-fed mice. PUN notably enhanced spatial memory and improved depression-like symptoms across various behavioral assessments, which were associated with improved synaptic function by boosting synaptic protein levels and excitatory postsynaptic currents, while decreasing oxidative damage, balancing amyloidogenesis, and the cholinergic system in HFD-fed mice. PUN reduced the activation of the TLR4/NF-kB/NLRP3 inflammasome, which decreased microglia overactivation, engulfment of PSD95 in microglia and mediated neuroinflammation in mouse models of HFD-induced obesity. In addition, PUN improved the activity of tricarboxylic acid cycle enzymes, including PDH, CS, and OGDH; lowered 8-OHdG levels; elevated ATP and NAD+ levels; and disrupted mitochondrial structure. PUN modulates molecular pathways by reducing phosphorylated p53 levels and upregulating PGC-1α, thereby improving mitochondrial function. Therefore, PUN could help counteract cognitive impairment in HFD-fed mice by inhibiting neuroinflammation via the TLR4/NFkB/NLRP3 inflammasome and reinstating mitochondrial capabilities through the p53/PGC-1α pathway. PUN could serve as a new nutritional strategy for preventing obesity-related cognitive dysfunction via its metabolic regulation and anti-inflammatory effects.