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Alkaloid-enriched extract of Huperzia serrata (Thunb.) Trevis (Lycopodiaceae) (HsAE) can potentially be used to manage neuronal disorders. This study determines the anti-neuroinflammatory effects of HsAE on lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and the underlying mechanisms. BV-2 cells were pre- or post-treated with different concentrations of HsAE (25-150 µg/mL) for 30 min before or after LPS induction. Cell viability was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and no cytotoxicity was found. Nitric oxide (NO) concentration was determined using Griess reagent. The levels of prostaglandin E2 (PGE2), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were determined using enzyme-linked immunosorbent assay. The levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 and the phosphorylation of mitogen-activated protein kinase (MAPK) were analyzed using western blotting. HsAE reduced LPS-induced NO production with half-maximal inhibitory concentration values of 99.79 and 92.40 µg/mL at pre- and post-treatment, respectively. Pre-treatment with HsAE at concentrations of 50, 100, and 150 µg/mL completely inhibited the secretion of PGE2, TNF-α, IL-6, and IL-1β compared to post-treatment with HsAE. This suggests that prophylactic treatment is better than post-inflammation treatment. HsAE decreased the expression levels of iNOS and COX-2 and attenuated the secretion of pro-inflammatory factors by downregulating the phosphorylation of p38 and extracellular signal-regulated protein kinase in the MAPK signaling pathway. HsAE exerts anti-neuroinflammatory effects on LPS-stimulated BV-2 cells, suggesting that it may be a potential candidate for the treatment of neuroinflammation in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

A series of arylated huperzine A (HPA) derivatives (1–24) were efficiently synthesized in good yields (45–88% yields) through the late-stage modification of structurally complex natural anti-Alzheimer's disease (AD) drug huperzine A (HPA), using the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction. The acetylcholinesterase (AChE) inhibitory activity of all synthesized compounds was evaluated to screen the potential anti-AD bioactive molecules. The results showed that introducing the aryl groups to C-1 position of HPA resulted in the unsatisfactory AChE inhibitory activity. The present study demonstrably verifies pyridone carbonyl group could be the necessary and unchangeable pharmacophore for maintaining HPA's anti-AChE potency, and provides the helpful information on the further research for developing anti-AD HPA analogues. [ABSTRACT FROM AUTHOR]

Organophosphorus nerve agents pose a global threat to both military personnel and civilian population, because of their high acute toxicity and insufficient medical countermeasures. Commonly used drugs could ameliorate the intoxication and overall medical outcomes. In this study, we tested the drugs able to alleviate the symptoms of Alzheimer's disease (donepezil, huperzine A, memantine) or Parkinson's disease (procyclidine). They were administered to mice before soman intoxication in terms of their: i) protection potential against soman toxicity and ii) influence on post-exposure therapy consisting of atropine and asoxime (also known as oxime HI-6). Their pretreatment effect was not significant, when administered alone, but in combination (acetylcholinesterase inhibitor such as denepezil or huperzine A with NMDA antagonist such as memantine or procyclidine) they lowered the soman toxicity more than twice. These combinations also positively influenced the efficacy of post-exposure treatment in a similar fashion; the combinations increased the therapeutic effectiveness of antidotal treatment. In conclusion, the most effective combination – huperzine A and procyclidine – lowered the toxicity three times and improved the post-exposure therapy efficacy more than six times. These results are unprecedented in the published literature. [ABSTRACT FROM AUTHOR]

Increasingly attention has been paid to the transdermal drug delivery systems with microneedles owing to their excellent compliance, high efficiency, and controllable drug release, therefore, become promising alternative with tremendous advantages for delivering specific drugs such as huperzine A (Hup A) for treatment of Alzheimer's disease (AD) yet with low oral bioavailability. The purpose of the present study is to design, prepare, and evaluate a dissolving microneedle patch (DMNP) as a transdermal delivery system for the Hup A, investigating its in vitro drug release profiles and in vivo pharmacokinetics as well as pharmacodynamics treating of AD. Skin penetration experiments and intradermal dissolution tests showed that the blank DMNP could successfully penetrate the skin with an adequate depth and could be quickly dissolved within 5 min. In vitro transdermal release tests exhibited that more than 80% of the Hup A was accumulatively permeated from DMNP through the skin within three days, indicating a sustained release profile. In vivo pharmacokinetic analysis demonstrated that the DMNP group resulted in longer Tmax (twofold), longer t1/2 (fivefold), lower Cmax (3:4), and larger AUC(0–∞) (twofold), compared with the oral group at the same dose of Hup A. Pharmacodynamic research showed a significant improvement in cognitive function in AD rats treated with DMNP-Hup A and Oral-Hup A, as compared to the model group without treatment. Those results demonstrated that this predesigned DMNP is a promising alternative to deliver Hup A transdermally for the treatment of AD. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of Huperzine A on memory and learning in individuals with moderate-severe traumatic brain injury (TBI). Design: Randomized, double-blind, placebo-controlled Phase II clinical trial. Methods: Subjects were randomly assigned to receive Huperzine A or placebo for 12 weeks and were assessed during in-person visits at screening/baseline, and 6, 12, 24, and 52 weeks post-injury. Changes in memory and learning scores on the California Verbal Learning Test – 2nd Edition (CVLT-II) from baseline to week 12 were assessed using permutation tests and regression analyses. Results: There was no difference between the Huperzine A and placebo groups in memory performance after 12 weeks of treatment. In the placebo group, significant improvements were noted in learning and memory scores. Both groups showed clinically important improvements in depression on the Beck Depression Index. Conclusions: The clinically important improvements in cognitive and emotional outcomes observed in both the placebo and active treatment arms of this clinical trial of Huperzine A are best understood in the context of a placebo effect. Future trials involving patients with moderate-severe TBI in the subacute to chronic phases of recovery should be designed to account for placebo effects as failure to do so may lead to spurious conclusions. [ABSTRACT FROM AUTHOR]

Huperzine A (HupA) is an acetylcholinesterase (AChE) inhibitor extracted from Huperzia Serrata, a firmoss, which has been used for various diseases in traditional Chinese medicine for fever and inflammation. More recently, it has been used in Alzheimer’s disease and other forms of dementia with a presumed mechanism of action via central nicotinic and muscarinic receptors. HupA is marketed as a dietary supplement in the U.S. This article reviews newly proposed neuroprotective and anticonvulsant HupA properties based on animal studies. HupA exerts its effects mainly via α7nAChRs and α4β2nAChRs, thereby producing a potent anti-inflammatory response by decreasing IL-1β, TNF-α protein expression, and suppressing transcriptional activation of NF-κB signaling. Thus, it provides protection from excitotoxicity and neuronal death as well as increase in GABAergic transmission associated with anticonvulsant activity. [ABSTRACT FROM PUBLISHER]

Huperzine A (HupA), a naturally occurring alkaloid in the plant family Huperziaceae, has drawn great interest for its potential application in Alzheimer disease therapy. Our primary objective was to identify alkaloid- and HupA-producing fungi from the Chinese folk herb,Huperzia serrata. We established a rapid and efficient model for screening HupA-producing endophytic fungal strains. The presence of HupA inPaecilomyces tenuisYS-13 was analysed by thin-layer chromatography, high-performance liquid chromatography and mass spectrometry. The fermentation yield of HupA was 21.0 μg/L, and the IC50of the crude extract of YS-13 fermentation broth was 1.27 ± 0.04 mg/mL. This is the first report ofP. tenuisas a HupA-producing endophyte isolated from Huperziaceae. [ABSTRACT FROM PUBLISHER]

The aim of the present study was to construct an innovative microemulsion-based patch for simultaneously transdermal delivery of huperzine A (HA) and ligustrazine phosphate (LP). The pseudo-ternary phase diagrams for microemulsion region were developed using oleic acid as oil, Cremophor RH40 as a surfactant, and ethanol as a cosurfactant. 1,8-cineole was added to the microemulsion as a penetration enhancer. The microemulsion-based transdermal patches were prepared by the lamination technique. The permeation studies were performed in vitro to evaluate the abilities of various microemulsions and transdermal patches to deliver HA and LP across the rat abdominal skin, showing that microemulsions increased the permeation rates of HA and LP compared with the control, and the penetration kinetics of the transdermal patch was in a zero order process. The results of the pharmacodynamic studies indicated that the transdermal combination therapy of HA and LP showed more benefits for fighting against amnesia in comparison with monotherapy. The anti-amnesic effects were also confirmed in scopolamine-induced amnesia rats after transdermal administration at multiple doses for 9 consecutive days, and the efficacy exhibited a dose-dependent manner. As a conclusion, the microemulsion-based transdermal patch containing HA and LP might provide a feasible strategy for the prevention of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Huperzine is a secondary metabolite in lycopods Huprzia and an inhibitor of acetylcholinesterase and antagonist of N-methyl-D-apartate receptor. Huperine is a suitable drug for the treatment of Alzheimer's disease as it is a part of traditional Chinese medicine. Currently, it undergoes clinical trials in the European Union and United States. The toxicological data about huperzine are missing and link between huperzine and oxidative stress has not been extensively investigated. For the above mentioned reasons, we organized experiment on a guinea pig model aimed at the investigation of adverse effects caused by huperzine. Guinea pigs were exposed to (-)-huperzine A in doses 5-625 µg/kg. Animals were sacrificed one day after exposure. Ferric reducing antioxidant power, thiobarbituric acid reactive substances, glutathione reductase, caspase 3 activity and selected biochemical markers (e.g. transaminases, blood urea nitrogen and glucose) were assayed. In frontal, parietal, temporal lobes and cerebellum, we found increase of antioxidants, glutathione reductase and oxidative stress markers in a dose dependent manner. Effects on liver, kidney and spleen were milder. We discuss ambivalent action of huperzine in the body and judge the huperzine action owing to recently reported experiments. [ABSTRACT FROM AUTHOR]

Context: The pharmaceutical alkaloid huperzine A (HupA), currently used in herbal supplements and medicines worldwide, is predominantly sourced from the Chinese lycopod Huperzia serrata (Thunb. ex Murray) Trev. (Lycopodiaceae), which on average contains only 0.08 mg HupA g−1 dry weight, and is experiencing a rapid decline in China due to over-harvesting. Objective: To find a high-yielding, natural source of HupA and/or the related huperzine B (HupB) that could potentially be used as the starting material in a commercial propagation program. Materials and methods: We surveyed 17 Huperzia species (15 indigenous to Australia and southeast Asia) for their foliar HupA and HupB concentrations. We also studied intra-specific variation for the huperzines in four species that were available in sufficient numbers, and determined tissue-specific accumulation in larger specimens. Results: HupA was detected in 11 Australasian and southeast Asian species, with eight also containing HupB, albeit at much lower concentrations. A H. elmeri (Herter) Holub plant from the Philippines had one of the highest HupA concentrations recorded (1.01 mg g−1 dry wt) and it also had the highest HupB content of all plants surveyed (0.34 mg g−1 dry wt). Intra-specific HupA and HupB concentrations were extremely variable, and at the intra-plant level, reproductive strobili were found to accumulate the highest HupA concentrations. Discussion and conclusion: Select Huperzia species from Australia and southeast Asia have potential as the starting material for establishing commercial HupA plantations, but the high intra-specific variability observed suggests that detailed screening is needed to isolate high huperzine-yielding individuals. [ABSTRACT FROM AUTHOR]

The green tea polyphenol (–)-epigallocatechin-3-gallate (EGCG) was investigated for its enhancement effect of huperzine A on inhibiting acetylcholinesterase (AChE). The inhibitory effect of huperzine A on acetylcholinesterase is quite weak in the whole phase. EGCG hardly inhibits the AChE activity within the range 10–300 mg/kg. However, upon addition of EGCG to the huperzine A groups, a remarkably enhanced inhibitory effect was observed. The EGCG also can largely prolong the inhibitory time. These results indicate that addition of EGCG to huperzine A can reduce the dose of huperzine A required compared with huperzine A alone. The enhancement and complementary effect of EGCG on huperzine A activity may partly be due to the antioxidant property of EGCG. One of the beneficial effects of green tea is to induce a feeling of relief. It is conceivable that this function may be regulated by EGCG in the central nervous system since EGCG is distributed in the brain after oral administration. EGCG can be used as an enhanced supplement for huperzine A to treat Alzheimer's disease. [ABSTRACT FROM AUTHOR]

A rapid, facile, and environmentally friendly process was developed for purification of huperzine A (HupA) and huperzine B (HupB) from the Chinese traditional herb Huperzia serrata . The process consisted of two steps of preparative low-pressure liquid chromatography (LPLC) on two polystyrene based resins, successively. The first step removed a large amount of impurities and captured HupA and HupB using Amberlite XAD-4 from the herbal extraction prepared by 1% aqueous H 2 SO 4 . This step was more efficient than multi-cycle liquid-liquid extraction as an initial separation step. The second step was able to separate HupA and HupB, employing a novel uniform polystyrene based porous microsphere named PST as the packing material. The PST column demonstrated a better separation and shorter run time compared with a commercial C 18 column. The mobile phases used in both LPLC's simply consisted of water and ethanol that are considered to be of low toxicity. Combination of the XAD-4 and PST chromatography and one step of crystallization enabled purification of HupA and HupB from 0.18% and 0.08% to 98.2% and 98.8%, respectively, with total recoveries of 82.8% and 84.3%. [ABSTRACT FROM AUTHOR]

To develop a long-acting injectable huperzine A-PLGA microsphere for the chronic therapy of Alzheimer's disease, the microsphere was prepared by using an o/w emulsion solvent extraction evaporation method based on a series of formulation design of the emulsion. The dialysis method was used for release analysis. The encapsulation efficiency and release amount of the microspheres were determined by a UV/VIS spectrophotometer. The morphology of the microspheres was observed by scanning electron microscopy. The distribution of the drug within microspheres was observed by a confocal laser scanning microscope. The results indicated that the PLGA 15?000 microspheres possessed a smooth and round appearance with average particle size of 50?µm or so. The encapsulation percentages of microspheres prepared from PLGA 15?000, 20?000 and 30?000 were 62.75%, 27.52% and 16.63%, respectively. The drug release percentage during the first day decreased from 22.52% of PLGA 30?000 microspheres to 3.97% of PLGA 15?000 microspheres, the complete release could be prolonged to 3 weeks. The initial burst release of microspheres with higher molecular weight PLGA could be explained by the inhomogeneous distribution of drug within microspheres. The encapsulation efficiency of the microspheres improved as the polymer concentration increased in the oil phase and PVA concentration decreased in the aqueous phase. The burst release could be controlled by reducing the polymer concentration. Evaporation temperature had a large effect on the drug release profiles. It had better be controlled under 30°C. Within a certain range of particle size, encapsulation efficiency decreased and drug release rate increased with the reducing of the particle size. [ABSTRACT FROM AUTHOR]

A new natural product, named selagoline, and two known alkaloids, huperzine A and serratidine, were isolated from Huperzia selago (Lycopodiaceae) collected in Iceland. Their structures were determined using 600 and 800MHz one- and two-dimensional NMR methods supported by Fourier-transform mass spectrometry. Possible role of selagoline as a precursor of 5,15-oxidolycopodane, a component of the classical alkaloids L28 and L31, is discussed. [ABSTRACT FROM AUTHOR]

Effects of subchronic administration of huperzine A, a cholinesterase inhibitor, on spatial memory were studied in guinea pig. Spatial memory was appreciated by the Morris water maze test. At a dose of 0.25 μg/h, inhibiting 36% of blood AChE and 14–20% of central AChE, no effect on spatial learning was found. At a dose of 1 μg/h, inhibiting 20% of blood AChE and 14–20% of central AChE, no memory impairment was found, on the other hand, a memory enhancing effect, limited to the first day was shown. It thus appears that subchronic administration of huperzine A did not induce deleterious effects on spatial memory. [ABSTRACT FROM AUTHOR]

Huperzine A-producing fungusPenicillium polonicumHy4 (CCTCC No.M2010086) was isolated fromHuperzia serrata(Thunb) Trev. The complete mitochondrial genome ofP. polonicumis 28 192 bp in length, containing 15 protein-encoding genes, 27 tRNA genes and two rRNA genes. The whole mitogenome is high in AT content (74.40%) and low in GC content (25.60%). The mitochondrial gene order and arrangement ofP. polonicumare identical to those of otherPenicillium. Phylogenetic analysis based on 14 concatenated protein-encoding genes showed thatP. polonicumwas close toP. solitum. This study reports the complete mitogenome ofP. polonicumfor the first time and provides valuable information for further exploration of mitochondrial evolution. [ABSTRACT FROM PUBLISHER]