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author:("Ma, hongze")
1.  l-Isocorypalmine reduces behavioral sensitization and rewarding effects of cocaine in mice by acting on dopamine receptors* 
Drug and alcohol dependence  2013;133(2):693-703.
We previously reported isolation of l-isocorypalmine (l-ICP), a mono-demethylated analog of l-tetrahydropalmatine (l-THP), from the plant Corydalis yanhusuo. Here we characterized its in vitro pharmacological properties and examined its effects on cocaine-induced behaviors in mice.
Receptor binding, cAMP and [35S]GTPγS assays were used to examine pharmacological actions of l-ICP in vitro. Effects of I-ICP on cocaine-induced locomotor hyperactivity and sensitization and conditioned place preference (CPP) in mice were investigated. HPLC was employed to analyze metabolites of I-ICP in mouse serum.
Among more than 40 targets screened, l-ICP and l-THP bound only to dopamine (DA) receptors. l-ICP was a high-affinity partial agonist of D1 and D5 receptors and a moderate-affinity antagonist of D2, D3 and D4 receptors, whereas l-THP bound to only D1 and D5 receptors, with lower affinities than l-ICP. At 10 mg/kg (i.p.), l-ICP inhibited spontaneous locomotor activity for a shorter time than l-THP. Pretreatment with l-ICP reduced cocaine-induced locomotor hyperactivities. Administration of l-ICP before cocaine once a day for 5 days reduced cocaine-induced locomotor sensitization on days 5 and 13 after 7 days of withdrawal. Pretreatment with l-ICP before cocaine daily for 6 days blocked cocaine-induced CPP, while l-ICP itself did not cause preference or aversion. HPLC analysis showed that l-ICP was the main compound in mouse serum following i.p. injection of l-ICP.
l-ICP likely acts as a D1 partial agonist and a D2 antagonist to produce its in vivo effects and may be a promising agent for treatment of cocaine addiction.
PMCID: PMC3954112  PMID: 24080315
tetrahydropalmatine; isocorypalmine; cocaine; conditioned place preference; sensitization; dopamine receptor
2.  A Standardized Kudzu Extract (NPI-031) Reduces Alcohol Consumption in Non Treatment-Seeking Male Heavy Drinkers 
Psychopharmacology  2012;226(1):65-73.
We previously demonstrated that short-term treatment with a standardized kudzu extract (NPI-031) reduced alcohol drinking by men and women in a natural setting. The present study was conducted in non treatment-seeking heavy drinkers to assess the safety and efficacy of four weeks of kudzu extract in an outpatient setting.
This randomized between-subject, double-blind, placebo-controlled study involved two weeks of baseline, four weeks of treatment and two weeks of follow-up. Seventeen men (21–33 years) who reported drinking 27.6 ± 6.5 drinks/week with a diagnosis of alcohol abuse/dependence took either kudzu extract (250 mg isoflavones, t.i.d.) or matched placebo on a daily basis. They reported alcohol consumption and desire to use alcohol using a wrist actigraphy device; twice weekly laboratory visits were scheduled to monitor medication adherence and adverse events.
Medication adherence was excellent and there were no adverse events, changes in vital signs, blood chemistry, renal or liver function. There was no effect on alcohol craving, but kudzu extract significantly reduced the number of drinks consumed each week by 34–57%, reduced the number of heavy drinking days and significantly increased the percent of days abstinent and the number of consecutive days of abstinence.
A standardized formulation of kudzu extract produced minimal side effects, was well-tolerated and resulted in a modest reduction in alcohol consumption in young non treatment-seeking heavy drinkers. Additional studies using treatment-seeking alcohol-dependent persons will be necessary to determine the usefulness of this herbal preparation in reducing alcohol use in other populations.
PMCID: PMC3562758  PMID: 23070022
3.  The Isoflavone Puerarin Reduces Alcohol Intake in Heavy Drinkers: A Pilot Study 
Drug and alcohol dependence  2012;126(1-2):251-256.
Isoflavone compounds naturally occurring in the root of the kudzu plant have been used historically to treat alcohol-related problems. A pilot study was conducted to assess the effects of one primary isoflavone - puerarin- for its ability to modify alcohol intake in humans.
Ten (10) healthy adult volunteers were administered puerarin (1200 mg daily) in a double-blind, placebo-controlled, crossover design experiment for one week prior to an afternoon drinking session lasting 1.5 hours. Participants had access to up to six bottles of their preferred brand of beer in addition to juice and water. A time course of drinking, sip volumes, and total amount consumed were recorded.
Participants consumed on average 3.5 (± 0.55) beers when treated with placebo and 2.4 (± 0.41) beers when treated with puerarin. In contrast to drinking following placebo treatment when 3 participants drank 5 beers and 1 participant drank all 6 beers, none drank 5 or 6 beers when treated with puerarin. Drinking topography also changed. When treated with puerarin, participants decreased sip size, took more sips to finish a beer, and took longer to consume each beer. Additionally, after finishing a beer, latency to opening the next beer was increased.
This study is the first demonstration that a single isoflavone found in the kudzu root can alter alcohol drinking in humans. These results suggest that alcohol consumption patterns are influenced by puerarin administration and this botanical medication may be a useful adjunct in the treatment of excessive alcohol intake.
PMCID: PMC3430804  PMID: 22578529
isoflavone; alcohol consumption; binge drinking; humans
4.  Modified Huo-Luo-Xiao-Ling Dan Suppresses Adjuvant Arthritis by Inhibiting Chemokines and Matrix-Degrading Enzymes 
Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting the joints that can lead to deformities and disability. The prolonged use of conventionally used drugs is associated with severe adverse reactions. Therefore, safer and less expensive therapeutic products are continually being sought. Huo-Luo-Xiao-Ling dan (HLXL), a traditional Chinese herbal mixture, and its modified versions possess anti-arthritic activity. In this paper, we examined the influence of modified HLXL on two of the key mediators of arthritic inflammation and tissue damage, namely, chemokines and matrix-metalloproteinases (MMPs) in the rat adjuvant-induced arthritis (AA) model of RA. We treated arthritic Lewis rats with HLXL (2.3 g/kg) by daily gavage beginning at the onset of AA. The control rats received the vehicle. At the peak phase of AA, rats were sacrificed and their draining lymph node cells (LNC) and spleen adherent cells (SAC) were tested. The HLXL-treated rats showed a significant reduction in the levels of chemokines (RANTES, MCP-1, MIP-1α, and GRO/KC), MMPs (MMP 2 and 9), as well as cytokines (IL-6 and IL-17) that induce them, compared to the control vehicle-treated rats. Thus, HLXL controls arthritis in part by suppressing the mediators of immune pathology, and it might offer a promising alternative/adjunct treatment for RA.
PMCID: PMC3310235  PMID: 22474510
5.  Novel neoclerodane diterpene derivatives from the smoke of salvinorin A 
Tetrahedron letters  2010;51(39):5207-5209.
Salvinorin A is a naturally-occurring potent and selective kappa opioid receptor agonist, and smoking salvinorin A produces the most intense hallucinogenic effects in human. Eight neoclerodane diterpene derivatives were isolated from the smoke of salvinorin A, and their structures were identified by spectroscopic methods. The major structural changes include epimerizations, eliminations, and rearrangements.
PMCID: PMC2950941  PMID: 20936100
Salvinorin A; Neoclerodane diterpenoid; Smoke; Opioid receptor
6.  Suppression of Ongoing Experimental Arthritis by a Chinese Herbal Formula (Huo-Luo-Xiao-Ling Dan) Involves Changes in Antigen-Induced Immunological and Biochemical Mediators of Inflammation 
Rheumatoid arthritis (RA) is one of the major autoimmune diseases of global prevalence. The use of the anti-inflammatory drugs for the treatment of RA is associated with severe adverse reactions and toxicity. This limitation has necessitated the search for novel therapeutic products. We report here a traditional Chinese medicine-based herbal formula, Huo luo xiao ling dan (HLXL), which has potent antiarthritic activity as validated in the rat adjuvant-induced arthritis (AA) model. HLXL (2.3 g/Kg) was fed to Lewis (RT.11) rats daily by gavage beginning at the onset of arthritis and then continued through the observation period. HLXL inhibited the severity of ongoing AA. This suppression of arthritis was associated with significant alterations in the T cell proliferative and cytokine responses as well as the antibody response against the disease-related antigen, mycobacterial heat-shock protein 65 (Bhsp65). There was a reduction in the level of the proinflammatory cytokines IL-17 and IL-1β but enhancement of the anti-inflammatory cytokine IL-10 level. In addition, there was inhibition of both the anti-Bhsp65 antibody response and the serum level of nitric oxide. Thus, HLXL is a promising CAM modality for further testing in RA patients.
PMCID: PMC2958519  PMID: 20981317
7.  Huo-Luo-Xiao-Ling Dan modulates antigen-directed immune response in adjuvant-induced inflammation 
Journal of ethnopharmacology  2009;123(1):40-44.
Ethnopharmacological relevance
HLXL is a traditional Chinese medicine that has long been used in folk medicine for the treatment of chronic inflammatory diseases. However, the precise immunological mechanisms by which HLXL mediates its anti-inflammatory activity are not fully defined.
Aim of the study
To determine the effects of HLXL on antigen-specific immune parameters in adjuvant-induced inflammation model in the Lewis rat.
Materials and Methods
Rats were fed daily with either HLXL (2.3 g/kg) or vehicle (water) beginning 3 d before subcutaneous injection of heat-killed M. tuberculosis H37Ra (Mtb), and then continued for another 6 d. After 9 d of Mtb injection, the draining lymph node cells were tested for T cell proliferative and cytokine responses against mycobacterial heat-shock protein 65 (Bhsp65). Moreover, sera were tested for anti-Bhsp65 antibodies and nitric oxide (NO).
HLXL-treated rats showed reduced T cell proliferative response to Bhsp65 compared to control rats. Furthermore, HLXL suppressed IL-17 response but enhanced IL-10 response without much effect on IFN-γ. HLXL treatment also reduced the levels of anti-Bhsp65 antibodies but not that of NO.
HLXL feeding modulated both the cellular and the humoral immune response to Bhsp65 favoring an anti-inflammatory milieu for suppression of adjuvant-induced inflammation.
PMCID: PMC2925191  PMID: 19429337
Huo-Luo-Xiao-Ling Dan; Immune modulation; Cytokines; Antibodies; T cells; Inflammation
8.  Novel coumarin glycoside and phenethyl vanillate from Notopterygium forbesii and their binding affinities for opioid and dopamine receptors 
Bioorganic & medicinal chemistry  2007;16(6):3218-3223.
Bioactivity-guided fractionation of Notopterygium forbesii has resulted in the isolation of one new coumarin glycoside and one new phenethyl vanillate, together with seventeen known compounds. The structures of these compounds were characterized by spectroscopic methods. These compounds were evaluated for their binding affinities to the opioid and dopamine receptors, and falcarindiol showed weak binding affinities to opioid receptors and moderate affinity for D1 receptor (Ki = 192±6 nM).
PMCID: PMC2366027  PMID: 18166466
Notopterygium forbesii; Coumarin; Falcarindiol; Opioid receptor; Dopamine receptor
9.  Synthesis of deacetyl-1,10-didehydrosalvinorin G 
Tetrahedron letters  2008;49(11):1782-1785.
To unambiguously confirm the actual product in autoxidation of salvinorin A under basic conditions, deacetyl-1,10-didehydrosalvinorin G was synthesized from salvinorin C via intermediate salvinorin H. Furthermore, oxidation of salvinorin D with manganese dioxide gave salvinorin G in good yield.
PMCID: PMC2390901  PMID: 19279674
Salvinorin A; Oxidation; Manganese dioxide; Synthesis
10.  2-Methoxymethyl-Salvinorin B Is a Potent κ Opioid Receptor Agonist with Longer Lasting Action in Vivo Than Salvinorin A 
Salvinorin (Sal) A is a naturally occurring, selective κ opioid receptor (KOPR) agonist with a short duration of action in vivo. Pharmacological properties of a C(2) derivative, 2-methoxy-methyl (MOM)-Sal B, were characterized. MOM-Sal B bound to KOPR with high selectivity and displayed ~3-fold higher affinity than U50,488H [(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methanesulfonate] and Sal A. It acted as a full agonist at KOPR in guanosine 5′-O-(3-[35S]thio)triphosphate binding and was ~5- and ~7-fold more potent than U50,488H and Sal A, respectively. In Chinese hamster ovary cells stably expressing KOPR, all three κ agonists internalized or down-regulated KOPR to similar extents, with MOM-Sal B being the most potent. In mice, MOM-Sal B (0.05–1 mg/kg s.c.) caused immediate and dose-dependent immobility lasting ~3 h, which was blocked by norbinaltorphimine. In contrast, ambulation in a Y-maze was increased when rats received MOM-Sal B (1–5 mg/kg s.c.). In addition, MOM-Sal B (0.5–5 mg/kg i.p.) produced antinociception (hot-plate test) and hypothermia in a dose-dependent manner in rats. MOM-Sal B was more potent than U50,488H in both tests and more efficacious than U50,488H in the hot-plate test. These latter two in vivo effects were blocked by norbinaltorphimine, indicating KOPR-mediated actions. Sal A at 10 mg/kg elicited neither antinociception nor hypothermia 30 min after administration to rats. In summary, MOM-Sal B is a potent and efficacious KOPR agonist with longer lasting in vivo effects than Sal A.
PMCID: PMC2519046  PMID: 18089845
11.  Revised structure of deacetyl-1,10-didehydrosalvinorin G 
Tetrahedron letters  2007;48(31):5461-5464.
In comparison with the NMR data of salvinorin A and its 8-epimer, the published structure of deacetyl-1,10-didehydrosalvinorin G was revised to its 8-epimer. The stereochemistry of 8-epi-deacetyl-1,10-didehydrosalvinorin G was further confirmed by NOESY and chemical synthesis.
PMCID: PMC2390872  PMID: 18665199
Salvinorin A; Epimer; NMR; Revised structure

Results 1-11 (11)