- Huperzine A ameliorates obesity-related cognitive performance impairments involving neuronal insulin signaling pathway in mice. [Journal Article]
- APActa Pharmacol Sin 2019 Jun 18
- Type 2 diabetes (T2D) and Alzheimer's disease (AD) share several common pathophysiological features. Huperzine A (Hup A), a Lycopodium alkaloid extracted from the Chinese herb moss Huperzia serrata, …
Type 2 diabetes (T2D) and Alzheimer's disease (AD) share several common pathophysiological features. Huperzine A (Hup A), a Lycopodium alkaloid extracted from the Chinese herb moss Huperzia serrata, is a specific and reversible inhibitor of acetylcholinesterase, which is clinically used for the treatment of AD. In this study, we investigated whether Hup A improved the metabolic and cognitive functions in the high fat-induced (HFD) obese mice and genetic ob/ob mice. HFD and ob/ob mice were treated with Hup A (0.1, 0.3 mg · kg-1 · d-1, ig) for 3 months. Body weight was monitored and glucose tolerance tests were performed. Novel object recognition test and Morris water maze assay were conducted to evaluate the cognitive functions. We found that the Hup A treatment had no significant effect on peripheral metabolism of obese mice, whereas Hup A (0.1, mg · kg-1 · d-1) improved both the abilities of object recognition and spatial memory in HFD-fed mice, but not in ob/ob mice. Furthermore, Hup A treatment significantly upregulated the insulin and phosphorylated Akt levels in the cortex of HFD-fed mice, but not ob/ob mice. In addition, Hup A (0.3, mg · kg-1 · d-1) significantly decreased cortical β-secretase (BACE1) expression. In conclusion, these results demonstrate that treatment with Hup A (0.1, mg · kg-1 · d-1) can effectively improve the cognitive functions, at least in diet-induced obese mice.
- Decahydroquinoline Ring 13C NMR Spectroscopic Patterns for the Stereochemical Elucidation of Phlegmarine-Type Lycopodium Alkaloids: Synthesis of (-)-Serralongamine A and Structural Reassignment and Synthesis of (-)-Huperzine K and (-)-Huperzine M (Lycoposerramine Y). [Journal Article]
- JNJ Nat Prod 2019 Jun 05
- Analysis of 13C NMR spectroscopic data of the phlegmarine subset of Lycopodium alkaloids revealed spectral patterns that allowed the stereochemical arrangement of the four stereogenic carbons in the …
Analysis of 13C NMR spectroscopic data of the phlegmarine subset of Lycopodium alkaloids revealed spectral patterns that allowed the stereochemical arrangement of the four stereogenic carbons in the decahydroquinoline core to be established. A relatively simple predictive set of chemical shift combinations is reported, providing a tool for the challenging stereochemical assignment of phlegmarine-type alkaloids. Based on the chemical shifts in their NMR spectroscopic profiles, the alkaloids huperzine K and huperzine M, formally reported as cis derivatives, were structurally reassigned as trans-decahydroquinolines. The NMR spectroscopic data for huperzine M were identical to those reported for lycoposerramine Y and, hence, also implied the configurational reassignment of the latter. The revised structures of the above alkaloids were confirmed by enantioselective total synthesis. Additionally, the synthesis of (-)-serralongamine A via a common intermediate precursor is reported.
- The potential role of human multidrug resistance protein 1 (MDR1) and multidrug resistance-associated protein 2 (MRP2) in the transport of Huperzine A in vitro. [Journal Article]
- XXenobiotica 2019 Jun 09; :1-9
- 1. More than 30% of epilepsy patients suffer pharmacoresistance. Transport of antileptic drugs by P-glycoprotein (P-gp) and MRP2 plays an important role in drug-resistant epilepsy. Huperzine A (Hup-A…
1. More than 30% of epilepsy patients suffer pharmacoresistance. Transport of antileptic drugs by P-glycoprotein (P-gp) and MRP2 plays an important role in drug-resistant epilepsy. Huperzine A (Hup-A) is a natural compound, which might have potential in treating neurological disorders including epilepsy and Alzheimer's disease. In this study, we investigated whether human P-gp and MRP2 transport Hup-A. 2. LLC-PK1 and MDCKII cells transfected with human P-gp or MRP2 were used to establish concentration equilibrium transport assays (CETAs) and determine the transport profile of Hup-A. The expression of P-gp and MRP2 was detected by qPCR and western blotting. The transport function of P-gp and MRP2 was measured by Rho123 and CDFDA cell uptake assay. 3. In CETAs, Hup-A at concentrations of 10 ng/mL or 2 µg/mL was transported by MDR1 and MRP2 from basolateral to apical sides of the cell monolayers. P-gp and MRP2 inhibitors completely blocked the efflux of Hup-A. There was no efflux of Hup-A in LLC-PK1 or MDCKII wild-type (WT) cells. 4. We demonstrate that Hup-A is a substrate of P-gp and MRP2. These results imply the efflux of Hup-A across the blood-brain barrier (BBB) in vivo, suggesting potential drug resistance of Hup-A.
- Production and enhancement of the acetylcholinesterase inhibitor, huperzine A, from an endophytic Alternaria brassicae AGF041. [Journal Article]
- AMAppl Microbiol Biotechnol 2019 May 22
- Huperzine A (HupA) is a potent acetylcholinesterase (AChE) inhibitor of a great consideration as a prospective drug candidate for Alzheimer's disease treatment. Production of HupA by endophytes offer…
Huperzine A (HupA) is a potent acetylcholinesterase (AChE) inhibitor of a great consideration as a prospective drug candidate for Alzheimer's disease treatment. Production of HupA by endophytes offers an alternative challenge to reduce the massive plant harvest needed to meet the increasing demand of HupA. In the current study, some endophytic fungal and actinobacterial isolates from the Chinese herb, Huperzia serrata, underwent liquid fermentation, alkaloid extraction, and screening for AChE inhibition and HupA production. Among these isolates, Alternaria brassicae AGF041 strain was the only positive strain for HupA production with the maximum AChE inhibition of 75.5%. Chromatographic analyses verified the identity of the produced HupA. The HupA production was efficiently maximized up to 42.89 μg/g of dry mycelia, after optimization of thirteen process parameters using multifactorial statistical approaches, Plackett-Burman and central composite designs. The statistical optimization resulted in a 40.8% increase in HupA production. This is the first report to isolate endophytic actinobacteria with anti-AChE activity from H. serrata, and to identify an endophytic fungus A. brassicae as a new promising start strain for a higher HupA yield.
- Pharmacokinetic Studies of Three Alkaloids in Rats After Intragastrical Administration of Lycopodii Herba Extract by LC-MS/MS. [Journal Article]
- MMolecules 2019 May 19; 24(10)
- Lycopodii Herba is a widely used traditional medicinal herb, and contains diverse fascinating alkaloids. In this study, a fast and sensitive LC-MS/MS method for the simultaneous determination of lyco…
Lycopodii Herba is a widely used traditional medicinal herb, and contains diverse fascinating alkaloids. In this study, a fast and sensitive LC-MS/MS method for the simultaneous determination of lycodoline, α-obscurine, and N-demethyl-α-obscurine from Lycopodii Herba in rat plasma and brain tissue was developed and validated. Biological samples were extracted via a protein precipitation procedure using methanol as the extraction solvent and Huperzine B as the internal standard. Chromatographic separation was carried out using a Thermo Syncronis-C18 column (50 mm × 2.1 mm, 5 μm) and a gradient mobile phase containing methanol and water with 0.05% formic acid. The three alkaloids were detected by positive electrospray ionization in selective reaction monitoring mode. The selectivity, crosstalk, carryover effect, linearity, accuracy, precision, extraction recovery, matrix effect, and stability of the current method were validated. Then, using the validated method, the plasma pharmacokinetics and brain tissue distribution of the alkaloids in rats were investigated after intragastrical administration of Lycopodii Herba extract. The three alkaloids were shown to be rapidly absorbed into the blood (Tmax, 0.79-1.58 h), and then also eliminated rapidly (t1/2, 1.27-2.24 h). All of them could pass through the blood-brain barrier. The method provides a new research approach to expand preclinical studies of Lycopodii Herba.
- Asymptotic analysis of quasielastic neutron scattering data from human acetylcholinesterase reveals subtle dynamical changes upon ligand binding. [Journal Article]
- JCJ Chem Phys 2019 Apr 28; 150(16):161104
- In this paper, we show that subtle changes in the internal dynamics of human acetylcholinesterase upon ligand binding can be extracted from quasielastic neutron scattering data by employing a nonexpo…
In this paper, we show that subtle changes in the internal dynamics of human acetylcholinesterase upon ligand binding can be extracted from quasielastic neutron scattering data by employing a nonexponential relaxation model for the intermediate scattering function. The relaxation is here described by a stretched Mittag-Leffler function, which exhibits slow power law decay for long times. Our analysis reveals that binding of a Huperzine A ligand increases the atomic motional amplitudes of the enzyme and slightly slows down its internal diffusive motions. This result is interpreted within an energy landscape picture for the motion of the hydrogen atoms.
- [Efficacy and safety of huperzine A in treating patients with mild cognitive impairment: a systematic review and Meta-analysis]. [Journal Article]
- ZZZhongguo Zhong Yao Za Zhi 2019; 44(3):582-588
- To evaluate the efficacy and safety of huperzine in treating patients with mild cognitive impairment. The randomized controlled trials(RCT) were retrieved from EMbase, Cochrane Library, PubMed, CNKI,…
To evaluate the efficacy and safety of huperzine in treating patients with mild cognitive impairment. The randomized controlled trials(RCT) were retrieved from EMbase, Cochrane Library, PubMed, CNKI, Wanfang and VIP. The methodology quality of the included studies was evaluated, and a Meta-analysis was performed using RevMan 5.3 software. A total of nine RCTs were included. The Meta-analysis results showed that compared with placebo, Huperzine significantly increased the scores of memory quotient(MQ) and mini-mental state examination(MMSE). However, there was no statistical difference between oral tablet and capsule. Compared with placebo, huperzine A was superior in the scores of MQ and MMSE. Huperzine is safe with mild side effects. Due to the low quality of original studies, more high-quality studies are needed to verify its efficacy.
- Lycofargesiines A-F, further Lycopodium alkaloids from the club moss Huperzia fargesii. [Journal Article]
- PPhytochemistry 2019; 162:183-192
- Six undescribed Lycopodium alkaloids (LAs) comprising four lycodine-type (lycofargesiines A-D), one lycopodine-type (lycofargesiine E), and a phlegmarine-type (lycofargesiine F), together with 16 kno…
Six undescribed Lycopodium alkaloids (LAs) comprising four lycodine-type (lycofargesiines A-D), one lycopodine-type (lycofargesiine E), and a phlegmarine-type (lycofargesiine F), together with 16 known ones were isolated from the club moss Huperzia fargesii. Their structures and absolute configurations were determined by extensive spectroscopic methods, electronic circular dichroism (ECD) analysis, and density functional theory (DFT) calculations. (7S,8R,12R,13R)-Lycofargesiine A is a rare naturally occurring LA possessing an exocyclic double bond between C-15 and C-16, with ring A being a rare 2,3-dihyropyridone motif. Lycofargesiine D is an uncommon lycodine-type alkaloid featuring a unique N-acetylated tetrahydropyridinyl segment (ring A), whereas lycofargesiine F is the first phlegmarane-type LA bearing two nitrone moieties. In addition to the isolated huperzine A in this study, another two isolates (lycofargesiine C and 16-hydroxyhuperzine A) were also found to show inhibitory activities against acetylcholinesterase (AChE), with IC50 values of 8.63 and 5.18 μM, respectively.
- Donepezil, a drug for Alzheimer's disease, promotes oligodendrocyte generation and remyelination. [Journal Article]
- APActa Pharmacol Sin 2019 Mar 27
- Myelin sheaths play important roles in neuronal functions. In the central nervous system (CNS), the myelin is formed by oligodendrocytes (OLs), which are differentiated from oligodendrocyte precursor…
Myelin sheaths play important roles in neuronal functions. In the central nervous system (CNS), the myelin is formed by oligodendrocytes (OLs), which are differentiated from oligodendrocyte precursor cells (OPCs). In CNS demyelinating disorders such as multiple sclerosis (MS), the myelin sheaths are damaged and the remyelination process is hindered. Small molecule drugs that promote OPC to OL differentiation and remyelination may provide a new way to treat these demyelinating diseases. Here we report that donepezil, an acetylcholinesterase inhibitor (AChEI) developed for the treatment of Alzheimer's disease (AD), significantly promotes OPC to OL differentiation. Interestingly, other AChEIs, including huperzine A, rivastigmine, and tacrine, have no such effect, indicating that donepezil's effect in promoting OPC differentiation is not dependent on the inhibition of AChE. Donepezil also facilitates the formation of myelin sheaths in OPC-DRG neuron co-culture. More interestingly, donepezil also promotes the repair of the myelin sheaths in vivo and provides significant therapeutic effect in a cuprizone-mediated demyelination animal model. Donepezil is a drug that has been used to treat AD safely for many years; our findings suggest that it might be repurposed to treat CNS demyelinating diseases such as MS by promoting OPC to OL differentiation and remyelination.
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- Huperzine-A response to cognitive impairment and task switching deficits in patients with Alzheimer's disease. [Journal Article]
- JCJ Chin Med Assoc 2019; 82(1):40-43
- CONCLUSIONS: Huperzine-A is effective in reducing cognitive and task switching deficits in patients with AD.