Modulation of CNS function by natural extracts

The “amyloid cascade hypothesis” predicts that the progress for pathogenesis of Alzheimer's disease (AD) involves multiple factors such as amyloid aggregation, oxidative stress, loss of ion homeostasis and inflammation. In a transgenic C. elegans model of AD, intracellular expression of human Aβ is associated with elevated oxidative stress, accumulation of Ab aggregation and progressive paralysis behavior. Recently we demonstrated that EGb 761 stimulated neurogenesis in aged wild type mice as well as a mouse model of Alzheimer's disease, and altered neurotransmitter serotonin (5-HT) sensitivity in a transgenic Aβ-expressing C. elegans. Serotonin plays an important role in neuronal plasticity and survival. It has also been associated with behavioral deficiencies seen in AD patients. The aim of this study is to determine the mechanism of action of EGb 761 and its constituents on 5-HT transmission. Several C. elegans 5-HT system mutants were used for 5-HT-controlled behavioral test. Our results show that wild type worms treated with EGb 761 demonstrate a similar sensitivity to 5-HT as the untreated mod-1 mutants, suggesting that the effect of EGb 761 on locomotion depends on the postsynaptic 5-HT receptors. Bilobalide also had a significant inhibitory effect on the egg-laying response in the wild type animals and this effect was not blocked in mod-5 mutant worms, further confirming postsynaptic action. Moreover, combinations of compounds with different mechanisms of action exhibit potential synergistic and/or additive effects. These results may provide a rationale for more effective natural therapeutic strategies for the prevention and/or treatment of AD.