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Effects of huperzine A on secretion of nerve growth factor in cultured rat cortical astrocytes and neurite outgrowth in rat PC12 cells

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Acta Pharmacologica Sinica 2005年第6期26卷 673-678页

作者： Li-li TANG, Rui WANG, Xi-can TANG~2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai China

Aim: To study the effects of huperzine A (HupA) on neuritogenic activity and the expression of nerve growth factor (NGF). Methods: After being treated with 10 μmol/L HupA, neurite outgrowth of PC 12 cells was observed and counted under phase-contrast microscopy. Mitogenic activity was assayed by [~3H]thymidine incorporation. Cell cytotoxicity was evaluated by lactate dehydrogenase (LDH) release. AChE activity, mRNA and protein expression were measured by the Ellman’s method, RT-PCR, and Western blot, respectively. NGF mRNA and protein levels were determined by RT-PCR and ELISA assays. Results: Treatment of PC 12 cells with 10 渭mol/L HupA for 48 h markedly increased the number of neurite-bearing cells, but caused no significant alteration in cell viability or other signs of cytotoxicity. In addition to inhibiting AChE activity, 10 渭mol/L HupA also increased the mRNA and protein levels of this enzyme. In addition, following 2 h exposure of the astrocytes to 10 渭mol/L HupA, there was a significant up-regula-tion of mRNA for NGF and P75 low-affinity NGF receptor. The protein level of NGF was also increased after 24 h treatment with HupA. Conclusion: Our findings demonstrate for the first time that HupA has a direct or indirect neurotrophic activity, which might be beneficial in treatment of neurodegenerative disorders such as Alzheimer disease.

关键词： huperzine A nerve growth factor neurite outgrowth: acetylcholinesterase inhibitors

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Self-microemulsifying drug delivery system for improving the bioavailability of huperzine A by lymphatic uptake

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Acta Pharmaceutica Sinica B 2017年第3期7卷 353-360页

作者： Fang Li Rongfeng Hu Bin Wang Yun Gui Gang Cheng Song Gao Lei Ye Jihui Tang Anhui University of Chinese Medicine Hefei 230038China National Chinese Medicinal Materials Products Quality Supervision and Inspection Center(Anhui) Bozhou 236800China Key Laboratory of Xin'an Medicine Ministry of Education Hefei 230038China Anhui“115”Xin'an Traditional Chinese Medical Research&Development Innovation Team Hefei 230038China Anhui Province Key Laboratory of R&D of Chinese Medicine Hefei 230038China School of Pharmacy Anhui Medical UniversityHefei 230022China

huperzine A(Hup-A) is a poorly water-soluble drug with low oral bioavailability. A selfmicroemulsifying drug delivery system(SMEDDS) was used to enhance the oral bioavailability and lymphatic uptake and transport of Hup-A. A single-pass intestinal perfusion(SPIP) technique and a chylomicron flow-blocking approach were used to study its intestinal absorption, mesenteric lymph node distribution and intestinal lymphatic uptake. The value of the area under the plasma concentration–time curve(AUC) of Hup-A SMEDDS was significantly higher than that of a Hup-A suspension(P <0.01).The absorption rate constant(K_a) and the apparent permeability coefficient(P_(app)) for Hup-A in different parts of the intestine suggested a passive transport mechanism, and the values of K_a and P_(app) of Hup-A SMEDDS in the ileum were much higher than those in other intestinal segments. The determination of Hup-A concentration in mesenteric lymph nodes can be used to explain the intestinal lymphatic absorption of Hup-A SMEDDS. For Hup-A SMEDDS, the values of AUC and maximum plasma concentration(C_(max)) of the blocking model were significantly lower than those of the control model(P<0.05). The proportion of lymphatic transport of Hup-A SMEDDS and Hup-A suspension were about 40% and 5%,respectively, suggesting that SMEDDS can significantly improve the intestinal lymphatic uptake and transport of Hup-A.

关键词： huperzine A Self-microemulsion Drug delivery systems SMEDDS Bioavailability Single-pass intestinal perfusion Lymphatic transport

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Comparative studies of huperzine A,donepezil,and rivastigmine on brain acetylcholine,dopamine,norepinephrine,and 5-hydroxytryptamine lev-els in freely-moving rats

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Acta Pharmacologica Sinica 2006年第9期27卷 1127-1136页

作者： Yan-qi LIANG Xi-can TANG~2 State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Shanghai Instituties for Biological Sciences,Graduate School of the Chinese Academy of Sciences,Chinese Academy of Sciences,Shanghai 201203.China State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Shanghai Instituties for Biological Sciences Graduate School of the Chinese Academy of Sciences Chinese Academy of Sciences Shanghai China

Aim:To assess the effects of cholinesterase inhibitors huperzine A,donepeziland rivastigmine on cerebral neurotransmitters in the cortex and hippocampus infreely-moving rats.Methods:Double-probe cerebral microdialysis and HPLC withelectrochemical detection were used to detect neurotransmitters.Results:Ourresults showed that huperzine A(0.***.0.5,and 0.75μmol/kg,po)dose-depen-dently elevated extracellular acetylcholine(ACh)levels in the medial prefrontalcortex(mPFC)and hippocampus.Oral administration of donepezil(5.4μmol/kg)orrivastigmine(1μmol/kg)also elicited significant increases in ACh in the mPFC andhippocampus.The time course of cortical acetylcholinesterase(ACHE)inhibitionwith the 3 inhibitors minored the increases of ACh at the same dose.The markedelevation of ACh after oral administration of huperzine A(0.5μmol/kg)anddonepezil(5.4μmol/kg)was associated with a significantly increased release ofdopamine(DA)in the mPFC or hippocampus.None of the 3 inhibitors affectednorepinephrine(NE)and 5-hydroxytryptamine(5-HT)levels in the mPFC andhippocampus.The effects of huperzine A and rivastigmine did not depend on theroute of administration,but donepezil was less efficacious by the oral route thanby ip injection.The ability of huperzine A to increase ACh levels was unchangedwhen tests were performed after multiple oral administration of the drug at 0.5μmol/kg,once per day for 30 d.Conclusion:The present findings showed that,inmolar terms,huperzine A had similar potency on increasing mPFC ACh and DAlevels as compared to the 11-and 2-fold dosages of donepezil and rivastigmine,respectively,and had longer lasting effects after oral dosing.

关键词： huperzine A donepezil rivastigmine acetylcholine dopamine norepinephrine 5-hydroxy tryptamine Alzheimer’s disease rats

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Drug brain distribution following intranasal administration of huperzine A in situ gel in rats

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Acta Pharmacologica Sinica 2007年第2期28卷 273-278页

作者： Yan ZHAO Peng YUE Tao TAO~2 Qing-hua CHEN Shanghai Institute of Pharmaceutical Industry,Shanghai 200040,China Shanghai Institute of Pharmaceutical Industry Shanghai China

Aim:To determine the uptake extent of huperzine A(Hup A)into the brain afterintranasal administration of Hup A in situ gel to rats,and to compare the pharma-cokinetic parameters between intranasal administration and iv and po.Methods:Hup A was administered to male Sprague-Dawley rats via nasal,iv and oral routesat the dose of 166.7,166.7,and 500 μg/kg,respectively.Blood and brain tissuesamples including the cerebrum,hippocampus,cerebellum and olfactory bulbwere collected,and the concentrations of Hup A in the samples were assayed byHPLC.The area under the concentration-time curve(AUC0→6 h)and the ratio ofthe AUCbrain to the AUCplasma(drug targeting efficiency,DTE)were calculated toevaluate the brain targeting efficiency of the drug via 3 administration routes.Results:The AUC0→6 h of the drug in the cerebrum,hippocampus,cerebellum,left olfactory bulb and right olfactory bulb after intranasal administration of theHup A in situ gel were 1.5,1.3,1.0,1.2,and 1.0 times of those after iv administrationof the injection,and 2.7,2.2,1.9,3.1,and 2.6 times of those after administration ofthe oral formulation.The AUCbrain0→6 h/AUCplasma0→6 h of HupAin the cerebrum,hippocampus and left olfactory bulb following the intranasal administration dosewere significantly higher(P<0.05)than the iv dose.Conclusion:Intranasal deliv-ery showed a viable,non-invasive strategy for delivering the drug into brain.

关键词： huperzine A in situ gel brain distribution intranasal administration

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Progress in studies of huperzine A,a natural cholinesterase inhibitor from Chinese herbal medicine

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Acta Pharmacologica Sinica 2006年第1期27卷 1-26页

作者： Rui WANG Hart YAN Xi-can TANG State Key Lahoratory of Drug Research.Shanghai Institute of Materia Medica.Shanghai Institutes for Biological Sciences Chinese Academy of Sciences.Shanghai 201203,China State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai China

huperzine A (HupA),a novel alkaloid isolated flom the Chinese herb Huperziaserrata,is a potent,highly specific and reversible inhibitor of acetylcholinesterase(ACHE).Compared with tacrine,donepezil,and rivastigmine,HupA has betterpenetration through the blood-brain barrier,higher oral bioavailability,and longerduration of AChE inhibitory action.HupA has been found to improve cognitivedeficits in a broad range of animal models.HupA possesses the ability to protectcells against hydrogen peroxide,β-amyloid protein (or peptide),glutamate,ischemia and staurosporine-induced cytotoxicity and apoptosis.These protec-tive effects are related to its ability to attenuate oxidative stress,regulate theexpression of apoptotic proteins Bcl-2.Bax,P53,and caspase-3,protectmitochondria,upregulate nerve growth factor and its receptors,and interfere withamyloid precursor protein metabolism.Antagonizing effects of HupA on N-me-thyl-D-aspartate receptors and potassium currents may also contribute to itsneuroprotection as well.Pharmacokinetic studies in rodents,canines,and healthyhuman volunteers indicated that HupA was absorbed rapidly,distributed widelyin the body,and eliminated at a moderate rate with the property of slow andprolonged release after oral administration.Animal and clinical safety tests showedthat HupA had no unexpected toxicity,particularly the dose-limiting hepalotoxic-ity induced by tacrine.The phase Ⅳ clinical trials in China have demonstratedthat HupA significantly improved memory deficits in elderly people with benignsenescent forgetfulness,and patients with Alzheimer disease and vasculardementia,with minimal peripheral cholinergic side effects and no unexpectedtoxicity.HupA can also be used as a protective agent against organophosphateintoxication.

关键词： huperzine A Alzheimer disease acetylcholinesterase cholinesterase inhibitors cognitive enhancer neuroprotect agents oxidative stress apoptosis

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Pharmacokinetics and Tolerability of Oral Dosage Forms of huperzine A in Healthy Chinese Male Volunteers: a Randomized,Single Dose, Three-period, Six-sequence Crossover Study

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2017年第5期37卷 795-802页

作者：伍三兰甘珺饶静贺思洁朱雯雯赵瑛吕永宁黄建耿刘亚妮 Department of Pharmacy Union Hospital Tongji Medical College Huazhong University of Science and Technology Clinical Research Organization for Pharmaceutical Products Union Hospital Tongji Medical College Huazhong University of Science and Technology Department of Pharmaceutics School of Pharmacy Tongji Medical College Huangzhong University of Science and Technology

huperzine A is a potent, reversible, and blood-brain barrier permeable acetylcholinesterase inhibitor. The aim of this study was to compare the pharmacokinetics, tolerability, and bioavailability of two formulations with the established reference formulation of huperzine A in a fasting, healthy Chinese male population. This was a randomized, single-dose, 3-period, 6-sequence crossover study. The plasma concentrations of huperzine A were determined by liquid chromatography tandem mass spectrometry. Tolerability was assessed based on subject interview, vital sign monitoring, physical examination, and routine blood and urine tests. The mean（SD） pharmacokinetic parameters of the reference drug were Cmax, 1.550（0.528） ng/m L; t1/2, 12.092（1.898） h; AUC0-72 h, 17.550（3.794） ng·h/m L. Those of the test formulation A and test formulation B were Cmax, 1.412（0.467）, 1.521（0.608） ng/m L; t1/2, 12.073（2.068）, 12.271（1.678） h; AUC0-72 h, 15.286（3.434） ng·h/mL, 15.673（3.586） ng·h/m L. The 90% confidence intervals for the AUC0-72 h and Cmax were between 0.80 and 1.25. No adverse events were reported by the subjects or found with results of clinical laboratory test. The test and reference products met the regulatory criteria for bioequivalence in these fasting, healthy Chinese male volunteers. All three formulations appeared to be well tolerated.

关键词： huperzine A pharrnacokinetics bioequivalence tolerability liquid chromatography tandem mass spectrometry

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Eleutheroside B or E enhances learning and memory in experimentally aged rats

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Neural Regeneration Research 2013年第12期8卷 1103-1112页

作者： Debin Huang Zehua Hu Zhaofen Yu Department of Pharmacology Hubei Institute for Nationalities

Eleutheroside B or E, the main component of Acanthopanax, can relieve fatigue, enhance memory, and improve human cognition. Numerous studies have confirmed that high doses of acetylcholine significantly attenuate clinical symptoms and delay the progression of Alzheimer＇s disease. The present study replicated a rat model of aging induced by injecting quinolinic acid into the hippocampal CA1 region. These rats were intraperitoneally injected with low, medium and high doses of eleutheroside B or E （50, 100, 200 mg/kg）, and rats injected with huperzine A or PBS were used as controls. At 4 weeks after administration, behavioral tests showed that the escape latencies and errors in searching for the platform in a Morris water maze were dose-dependently reduced in rats treated with medium and high-dose eleutheroside B or E. Hematoxylin-eosin staining showed that the number of surviving hippocampal neurons was greater and pathological injury was milder in three eleutheroside B or E groups compared with model group. Hippocampal homogenates showed enhanced cholinesterase activity, and dose-dependent increases in acetylcholine content and decreases in choline content following eleutheroside B or E treatment, similar to those seen in the huperzine A group. These findings indicate that eleutheroside B or E improves learning and memory in aged rats. These effects of eleutheroside B or E may be mediated by activation of cholinesterase or enhanced reuse of choline to accelerate the synthesis of acetylcholine in hippocampal neurons.

关键词： neural regeneration traditional Chinese medicine eleutheroside B or E quinolinic acid aged rats huperzine A learning and memory hippocampus acetylcholine cholinesterase choline mechanism grants-supported paper neuroregeneration

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huperzine A, acting on polyamine site, inhibited NMDA- induced current in acutely dissociated hippocampal neurons

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Acta Pharmacologica Sinica 1999年第5期 86-86页

HU Guo-Yttan, ZHANG Jing-Ming(State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China ) (-)-huperzine A (Hup A), an alkaloid isolated from Chinese herb Huperzia serrata (Thunb) Trey, was reported to possess protective effects against glutamate-induced neuronal cell

关键词： NMDA acting on polyamine site huperzine A inhibited NMDA

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Multiple oral administrations of huperzine A tablet as a treatment for Alzheimer's disease

Multiple oral administrations of huperzine A tablet as a tre...

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山东省药学会第一届学术年会

作者： Dafeng Chu Wanhui Liu, Yunli Xue, Shandong Luye Pharmaceutical Co., Ltd, Yantai 264005, China Correspondence No 9, Baoyuan Road, Laishan District, Yantai, Shandong, 264005, P. R. China

THE PHARMACOKINETICS OF huperzine A WAS INVESTIGATED IN DOGS AFTER SINGLE INTRAVENOUS, ORAL AND TWO MULTIPLE ORAL ADMINISTRATIONS AT DOSES OF 10μG/KG/DAY. CONCENTRATIONS OF huperzine A WERE DETERMINED BY A VALIDATED LC/MS/MS METHOD. AFTER SINGLE INTRAVENOUS AND ORAL ADMINISTRATIONS, huperzine A WAS MODESTLY ELIMINATED WITH THE SIMILAR MEAN T1/2 OF 5.61 AND 5. 71 H, RESPECTIVELY. huperzine A WAS WELL DISTRIBUTED INTO TISSUES WITH THE MEAN VD AND Vss OF 5. 36 AND 3. 96 L/KG, RESPECTIVELY. AFTER A SINGLE ORAL ADMINISTRATION, huperzine A WAS RAPIDLY AND NEARLY COMPLETELY ABSORBED WITH THE MEAN TWAX OF 1. 25 H AND THE MEAN ORAL BIOAVAILABILITY OF 93. 7 %. AFTER FIRSTLY ORALLY ADMINISTRATED IN THE MORNING AND THEN AT 6 H AFTER IT DAILY OVER 6 CONSECUTIVE DAYS, huperzine A ATTAINED STEADY STATE LEVELS IN PLASMA BY 4 DAYS WITH THE PTF OF 1.97, THE PTS OF 4. 51, CAV OF 0. 78 NG/ML AND THE RVC OF 1.27. AFTER ORALLY ADMINISTERED EVERY 12 H DAILY OVER 6 CONSECUTIVE DAYS, huperzine A ATTAINED STEADY STATE LEVELS IN PLASMA BY 3 DAYS WITH THE PTF OF 2. 23, THE PTS OF 7. 70, THE GAV OF 0. 59 NG/ML AND THE RAC OF 2. 15. AFTER TWO MULTIPLE ORAL ADMINISTRATIONS OF huperzine A, CAX WERE OBSERVED WITHIN 1.15 H AND T1/2 WAS PROLONGED TO 7.70 AND 10.09 H, RESPECTIVELY. IN CONCLUSION, huperzine A HAVE A RAPID AND NEARLY COMPLETE ORAL ABSORPTION AND IS EXTENSIVELY DISTRIBUTED INTO TISSUES AFTER DRUG ADMINISTRATION IN DOGS. MULTIPLE DOSES ADMINISTRATIONS OF huperzine A, FIRSTLY ADMINISTRATED IN THE MORNING AND THEN AT 6 H AFTER IT DAILY WERE SUPPORTED TO BE BENEFICIAL FOR TREATING PATIENTS WITH AD.

关键词： huperzine A PHARMACOKINETICS BIOAVAILABILITY

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huperzine A protects neural stem cells against Aβ induced apoptosis in a neural stem cells and microglia co-culture system

Huperzine A protects neural stem cells against Aβ induced a...

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2016年广东省药师周大会

作者： Ning Zhu Jizong Lin Kewan Wang Meidan Wei Qingzhuang Chen Yong Wang Department of Pharmacy Zhujiang HospitalSouthern Medical University Department of Hepatobiliary Surgery the Third Affiliated HospitalSun Yat-Sen University Department of Neurosurgery Nanfang HospitalSouthern Medical University

Objectives This study aims to explore whether huperzine A(Hup A) could protect neural stem cells against Amyloid beta-peptide Aβ induced apoptosis in a neural stem cells(NSCs) and microglia co-culture system Methods Rat NSCs and microglial cells were isolated,cultured and identified with immunofluorescence Assays(IFA).Co-culture systems of NSCs and microglial cells were employed using Transwell Permeable Supports.The effects of Aβ1-42 on NSCs were studied in 4 groups using co-culture systems:NSCs,Aβ+NSCs,co-culture and Aβ+co-culture groups.Bromodeoxyuridine(Brd U) incorporation and flow cytometry were utilized to assess the differences of proliferation,differentiation and apoptosis of NSCs between the groups.LQ test was performed to assess the amounts of IL-6,TNF-α and MIP-α secreted,and flow cytometry and Western blotting were used to assess apoptosis of NSCs and the expressions of Bcl-2 and Bax in each group.Results IFA results showed that isolated rat NSCs were nestin-positive and microglial cells were CD11 b/c-positive.Among all the groups,the Aβ+co-culture group has the lowest Brd U expression level,the lowest MAP2-positive,Ch AT-positive cell counts and the highest NSC apoptosis rate.Smaller amounts of IL-6,TNF-α and MIP-α were being secreted by microglial cells in the Hup A+Aβ+co-culture group compared with those in the Aβ+co-culture group.Also the Bcl-2:Bax ratio was much higher in the Hup A+Aβ+co-culture group than in the Aβ+co-culture group.Conclusions Hup A inhibits cell apoptosis through restraining microglia’s inflammatory response induced by Aβ.

关键词： huperzine A Alzheimer’s disease Amyloid beta-peptide neural stem cells microglial cells

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