punicalagin and Alzheimer-Disease

Alzheimer's disease (AD) is an irreversible, progressive brain disorder characterized by loss of memory and cognitive dysfunction in the aged. Despite remarkable advances in drug therapy, effective pharmacological interventions are rare. Punicalagin (PU) is an active antioxidant polyphenol found in pomegranates, raspberries, blueberries, and chestnuts that has attracted considerable attention owing to its strong antioxidant and anti-inflammatory properties. The current study focused on the neuroprotective effect of PU on aging mice and its potential mechanisms. In this study, we first evaluated the protective effect of PU on neuro-2a (N2a) cell damage mediated by BV2 microglia-induced neuroinflammation. The in vivo D-galactose (D-gal)-induced brain aging model demonstrated that PU ameliorated deficits in learning and memory and prevented neuroinflammation, which was evident from the decrease in microglial activation and astrocytosis. Furthermore, PU reduced the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) and inhibited NLRP3 inflammasome activation, reducing the levels of inflammatory cytokines, such as interleukin-6 (IL-6), tumor necrosis factor-a (TNF-a), interleukin-18 (IL-18), and interleukin-1 beta (IL-1β) in both accelerated aging and naturally senescent mouse models. PU effectively improved neuroinflammation, learning and memory deficits, and redox homeostasis in aging mice, and it could be a potential therapeutic agent for AD.

Topics: Alzheimer Disease; Animals; Antioxidants; Inflammation; Memory Disorders; Mice; Microglia; Neuroinflammatory Diseases; Oxidation-Reduction; Polyphenols; Pomegranate

Alzheimer disease (AD) brain is characterized by extracellular plaques of amyloid β (Aβ) peptide with reactive microglia. This study aimed to determine whether a dietary intervention could attenuate microgliosis. Memory was assessed in 12-mo-old male amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice via Barnes maze testing followed by division into either a control-fed group provided free access to normal chow and water or a treatment group provided free access to normal chow and drinking water supplemented with pomegranate extract (6.25 mL/L) for 3 mo followed by repeat Barnes maze testing for both groups. Three months of pomegranate feeding decreased the path length to escape of mice compared with their initial 12-mo values (P < 0.05) and their control-fed counterparts (P < 0.05). Brains of the 3-mo study pomegranate-fed mice had lower tumor necrosis factor α (TNF-α) concentrations (P < 0.05) and lower nuclear factor of activated T-cell (NFAT) transcriptional activity (P < 0.05) compared with controls. Brains of the 3-mo pomegranate or control mice were also compared with an additional control group of 12-mo-old mice for histologic analysis. Immunocytochemistry showed that pomegranate- but not control-fed mice had attenuated microgliosis (P < 0.05) and Aβ plaque deposition (P < 0.05) compared with 12-mo-old mice. An additional behavioral study again used 12-mo-old male APP/PS1 mice tested by T-maze followed by division into a control group provided with free access to normal chow and sugar supplemented drinking water or a treatment group provided with normal chow and pomegranate extract-supplemented drinking water (6.25 mL/L) for 1 mo followed by repeat T-maze testing in both groups. One month of pomegranate feeding increased spontaneous alternations versus control-fed mice (P < 0.05). Cell culture experiments verified that 2 polyphenol components of pomegranate extract, punicalagin and ellagic acid, attenuated NFAT activity in a reporter cell line (P < 0.05) and decreased Aβ-stimulated TNF-α secretion by murine microglia (P < 0.05). These data indicate that dietary pomegranate produces brain antiinflammatory effects that may attenuate AD progression.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Anti-Inflammatory Agents; Brain; Dietary Supplements; Disease Models, Animal; Ellagic Acid; Fruit; Hydrolyzable Tannins; Lythraceae; Male; Maze Learning; Memory; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; NFATC Transcription Factors; Phytotherapy; Plant Extracts; Plaque, Amyloid; Polyphenols; Presenilin-1; Tumor Necrosis Factor-alpha