Scientists have previously reported that Gypenoside LXXV, a novel natural PPARγ agonist isolated from Gynostemma pentaphyllum, ameliorated cognitive deficits in db/db mice. Gynostemma pentaphyllum is used in folk medicine, typically as an herbal tea.
Peroxisome proliferator-activator receptors (PPARs) regulate lipid and glucose metabolism, control inflammatory processes, and modulate several brain functions. Peroxisome proliferator-activated receptor γ agonist regulates neural plasticity in various neurodegenerative disorders. A well known drug in this class is pioglitazone.
Plant based PPAR agonists includes flavonoids, fatty acids, cannabinoids, curcumin, genistein, capsaicin, and piperine. Gypenosides are triterpenoid saponins derived from Gynostemma pentaphyllum, a climbing plant in the family Cucurbitaceae. Cucurbitaceae are generally herbaceous plants, annual or perennial, with a creeping or climbing habit, with stems provided with tendrils, and more rarely shrubs. Saponins are bitter-tasting usually toxic plant-derived organic chemicals that have a foamy quality when agitated in water.
Many Cucurbitaceae species are cultivated for their edible fruits (gourds, courgettes, cucumbers, pickles, buttermilk, melons, watermelons, chayotes, etc.) and sometimes for their seeds (oil gourd, African pistachio). Their domestication dates back thousands of years,
In this study, the authors further investigated the beneficial effects on cognitive impairment in APP/PS1 mice and a mouse model of diabetic Alzheimer's disease.
Intragastric administration of Gypenoside-75 for 3 months significantly attenuated cognitive deficits in APP/PS1 and APP/PS1xdb/db mice. Gypenoside-75 treatment markedly reduced the levels of glucose, HbA1c and insulin in serum and improved glucose tolerance and insulin sensitivity in APP/PS1xdb/db mice. It also decreased the β-amyloid burden, as measured by C-PIB PET imaging.
Importantly, Gypenoside-75 treatment increased brain glucose uptake as measured by F-FDG PET imaging. Moreover, Gypenoside-75 treatment upregulated PPARγ and increased phosphorylation of Akt and GLUT4 expression levels but decreased phosphorylation of IRS-1 in the hippocampi of both APP/PS1 and APP/PS1xdb/db mice.
Furthermore, Gypenoside-75-induced increases in GLUT4 membrane translocation in primary hippocampal neurons from APP/PS1xdb/db mice was abolished by cotreatment with the selective PPARγ antagonist GW9662 or the PI3K inhibitor LY294002.
In summary, Gypenoside-75 ameliorated cognitive deficits in APP/PS1 and APP/PS1xdb/db mice by enhancing glucose uptake via activation of the PPARγ/Akt/GLUT4 signaling pathways.