Garcinoic acid prevents β-amyloid (Aβ) deposition in the mouse brain

Abstract

<jats:p>Garcinoic acid (GA or δ-T3-13’COOH), is a natural vitamin E metabolite that has preliminarily been identified as a modulator of nuclear receptors involved in β-amyloid (Aβ) metabolism and progression of Alzheimer’s disease (AD). In this study, we investigated GA’s effects on Aβ oligomer formation and deposition. Specifically, we compared them with those of other vitamin E analogs and the soy isoflavone genistein, a natural agonist of peroxisome proliferator–activated receptor γ (PPARγ) that has therapeutic potential for managing AD. GA significantly reduced Aβ aggregation and accumulation in mouse cortical astrocytes. Similarly to genistein, GA up-regulated PPARγ expression and apolipoprotein E (ApoE) efflux in these cells with an efficacy that was comparable to that of its metabolic precursor δ-tocotrienol and higher than those of α-tocopherol metabolites. Unlike for genistein and the other vitamin E compounds, the GA-induced restoration of ApoE efflux was not affected by pharmacological inhibition of PPARγ activity, and specific activation of pregnane X receptor (PXR) was observed together with ApoE and multidrug resistance protein 1 (MDR1) membrane transporter up-regulation in both the mouse astrocytes and brain tissue. These effects of GA were associated with reduced Aβ deposition in the brain of TgCRND8 mice, a transgenic AD model. In conclusion, GA holds potential for preventing Aβ oligomerization and deposition in the brain. The mechanistic aspects of GA’s properties appear to be distinct from those of other vitamin E metabolites and of genistein.</jats:p>

Garcinoic Acid Is a Natural and Selective Agonist of Pregnane X Receptor

“…25 Our in vivo data unequivocally demonstrate that both intestinal and liver PXR respond to the agonist activity of GA thus providing mechanistic support for the investigation of this natural compound in PXR-related diseases of the liver and gut. Furthermore, in a recent study we demonstrated a PXR agonist effect of GA in the mouse brain as well as in isolated astrocytes, 32 compatible with the role of this NR in Apo-mediated detoxification of Alzheimer disease related molecule A peptide.…”

“…In view of other important roles of GA and its vitamin E-derived analogues as allosteric inhibitor of 5-lipooxygenase, 34,49 and PPAR- and CYP450 activators, 13,46,32 our findings suggest that GA can be exploited as a valuable chemical probe and lead compound for medicinal chemistry explorations to disclose novel therapeutic agents for the prevention and treatment of lipotoxicity and chronic inflammatory diseases, such as atherosclerosis, 34 and non-alcoholic fatty liver disease and steatohepatitis. 50,51 Current studies are directed towards the preparation of GA (1) derivatives with improved potency, properties and metabolic stability whose results will be reported in due course.…”

Regulation of Membrane Phospholipid Homeostasis in Neurodegenerative Diseases

“…Altogether, the molecular activities of vitamin E and its derivatives in the brain in reducing oxidative stress renders it a major participant in combating neuroinflammation [194,199]. Translating the molecular activities of vitamin E into in vivo animal studies, a recent study demonstrated another vitamin E metabolite, garcinoic acid (GA), was effective in preventing β-amyloid deposition in the mouse brain [200]. Therefore, it is also worth noting that, vitamin E metabolites instead of the parent form, also exhibit neuroprotective activities.…”

Molecular Mechanism of Vitamin K2 Protection against Amyloid-β-Induced Cytotoxicity

“…These include green tea extracts [ 23 ], sinapic acids [ 24 ], curcumin [ 25 ], and S-nitrosoglutathione [ 26 ]. As well, Aβ-induced apoptosis can be inhibited by several vitamins, such as vitamin A [ 27 ], vitamin C [ 28 ], and vitamin E [ 29 ].…”