Synergistic Inhibition of Acetylcholinesterase by Alkaloids Derived from Stephaniae Tetrandrae Radix, Coptidis Rhizoma and Phellodendri Chinensis Cortex

Abstract

Alkaloids having acetylcholinesterase (AChE) inhibitory activity are commonly found in traditional Chinese medicine (TCM); for example, berberine from Coptis chinensis, galantamine from Lycoris radiata, and huperzine A from Huperzia serrata. In practice of TCM, Stephaniae Tetrandrae Radix (STR) is often combined with Coptidis Rhizoma (CR) or Phellodendri Chinensis Cortex (PCC) as paired herbs during clinical application. Fangchinoline from STR and coptisine and/or berberine from CR and/or PCC are active alkaloids in inhibiting AChE. The traditional usage of paired herbs suggests the synergistic effect of fangchinoline-coptisine or fangchinoline-berberine pairing in AChE inhibition. HPLC was applied to identify the main components in herbal extracts of STR, CR, and PCC, and the AChE inhibition of their main components was determined by Ellman assay. The synergism of herb combination and active component combination was calculated by median-effect principle. Molecular docking was applied to investigate the underlying binding mechanisms of the active components with the AChE protein. It was found that fangchinoline showed AChE inhibitory potency; furthermore, fangchinoline-coptisine/berberine pairs (at ratios of 1:5, 1:2, 1:1, and 2:1) synergistically inhibited AChE; the combination index (CI) at different ratios was less than one when Fa = 0.5, suggesting synergistic inhibition of AChE. Furthermore, the molecular docking simulation supported this enzymatic inhibition. Therefore, fangchinoline-coptisine/berberine pairs, or their parental herbal mixtures, may potentially be developed as a possible therapeutic strategy for Alzheimer's patients.

Facile and Low-Cost SPE Modification Towards Ultra-Sensitive Organophosphorus and Carbamate Pesticide Detection in Olive Oil

“…Furthermore, the % inhibition of AChE was found to be higher in pretreated spiked olive oil samples than the inhibition of the enzyme in standard solutions of the same concentration, even though the inhibition exerted by the matrix itself had already been accounted for and subtracted. Oujji et al observed a similar behavior when spiked samples were studied [ 46 ] and it is a phenomenon that should be further investigated to evaluate the possibility that the pesticides along with the fatty acids remaining in the extract upon filtration exert a synergetic and additive inhibitory effect on AChE, as it has already been demonstrated for a number of chemical compounds [ 51 , 52 ]. Despite the fact, therefore, that considerably lower concentrations of the two pesticides could be detected in spiked olive oil samples in comparison to standard solutions, it would not be valid to report lower LoDs than the ones achieved in buffer ( Figure 7 ) due to the uncertainty as to the underlying causative reason for the observed inhibition.…”

Anti-Cholinesterase Combination Drug Therapy as a Potential Treatment for Alzheimer’s Disease

“…The use of ChEIs for the treatment and management of AD may be improved through the use of dual-drug combinations or multi-drug targeting approaches [ 45 , 46 , 47 , 48 ]. The FDA approved concomitant use of memantine and ChEIs has primarily proved clinical efficacious and comparable to monotherapies, and for some studies provided additional benefit of reduced neurobehavioral symptoms [ 48 ].…”

The Cholinesterase Inhibitory Properties of Stephaniae Tetrandrae Radix

“…TCMs have been used in treating mental and emotional problems for years, and the TCM prescription Fangji Dihuang Tang (described in “Jingui Yaolve”) has been used in treating emotional diseases for years [ 29 , 30 ]. Our preliminary study showed that the alkaloid-containing herbal medicine STR in Fangji Dihuang Tang has a certain degree of AChE inhibition [ 22 , 29 ]. To reveal the material basis of STR on cholinesterase, the cholinesterase inhibitory properties of STR, as well as its main active ingredients, were studied systematically.…”

“…The synergistic effect between fangchinoline and huperzine A or donepezil was calculated by the median-effect principle [ 22 , 33 , 34 ]. The median-effect equation ( F a / F u = ( D / D m ) m ) was used to calculate the dose of fangchinoline, huperzine A, and donepezil contributing to AChE-specific inhibition according to the dose–effect curve.…”

“…Stephaniae tetrandrae radix (STR; the root of Stephania tetrandra S. Moore) is a common TCM herb in treating edema, dysuria, and rheumatism. The main components of STR are alkaloids, i.e., tetrandrine and fangchinoline, which show beneficial effects on brain disease by regulating the synthesis, expression, and metabolism of neurotransmitters [ 22 , 23 , 24 , 25 ]. However, there are very few systematic studies on the cholinesterase regulation of STR, as well as its active components.…”