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Andrew M. Simons - One of the best experts on this subject based on the ideXlab platform.
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genotype environment interaction and the maintenance of genetic variation an empirical study of Lobelia Inflata campanulaceae
Royal Society Open Science, 2020Co-Authors: Kristen Cote, Andrew M. SimonsAbstract:High levels of genetic variation are often observed in natural populations, suggesting the action of processes such as frequency-dependent selection, heterozygote advantage and variable selection. However, the maintenance of genetic variation in fitness-related traits remains incompletely explained. The extent of genetic variation in obligately self-fertilizing populations of Lobelia Inflata (Campanulaceae L.) strongly implies balancing selection. Lobelia Inflata thus offers an exceptional opportunity for an empirical test of genotype-environment interaction (G × E) as a variance-maintaining mechanism under fluctuating selection: L. Inflata is monocarpic and reproduces only by seed, facilitating assessment of lifetime fitness; genome-wide homozygosity precludes some mechanisms of balancing selection, and microsatellites are, in effect, genotypic lineage markers. Here, we find support for the temporal G × E hypothesis using a manipulated space-for-time approach across four environments: a field environment, an outdoor experimental plot and two differing growth-chamber environments. High genetic variance was confirmed: 83 field-collected individuals consisted of 45 distinct microsatellite lineages with, on average, 4.5 alleles per locus. Rank-order fitness, measured as lifetime fruit production in 16 replicated multilocus genotypes, changed significantly across environments. Phenotypic differences among microsatellite lineages were detected. Results thus support the G × E hypothesis in principle. However, the evaluation of the effect size of this mechanism and fitness effects of life-history traits will require a long-term study of fluctuating selection on labelled genotypes in the field.
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tables s1 and s2 from genotype environment interaction and the maintenance of genetic variation an empirical study of Lobelia Inflata campanulaceae
2020Co-Authors: Kristen Cote, Andrew M. SimonsAbstract:Table S1: The number of replicates of the sixteen, four-locus microsatellite genotypes present in each of the four environments used in the study. Genotypes without sufficient replication in a particular environment (–) were not used in analyses that included that environment. A shared letter within each of the four loci (but not among loci) indicates a shared microsatellite allele. The four loci used correspond with LInflata8, LInflata14, LInflata15 and LInflata21 from [1, 2].; Table S2: Allele frequencies at each of the four microsatellite loci at the time of field collection for the 16 unique genotypes used in the study. The use of the same letter names across the four loci is for convenience and does not imply the same allele.
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microsatellite evidence for obligate autogamy but abundant genetic variation in the herbaceous monocarp Lobelia Inflata campanulaceae
Journal of Evolutionary Biology, 2015Co-Authors: P W Hughes, Andrew M. SimonsAbstract:Although high levels of self-fertilization (>85%) are not uncommon in nature, organisms reproducing entirely through selfing are extremely rare. Predominant selfers are expected to have low genetic diversity because genetic variation is distributed among rather than within lineages and is readily lost through genetic drift. We examined genetic diversity at 22 microsatellite loci in 105 individuals from a population of the semelparous herb Lobelia Inflata L. and found (i) no evidence of heterozygosity through outcrossing, yet (ii) high rates of genetic polymorphism (2-4 alleles per locus). Furthermore, this genetic variation among lineages was associated with phenotypic traits (e.g. flower colour, size at first flower). Coupled with previous work characterizing the fitness consequences of reproductive timing, our results suggest that temporal genotype-by-environment interaction may maintain genetic variation and, because genetic variation occurs only among lineages, this simple system offers a unique opportunity for future tests of this mechanism.
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secondary reproduction in the herbaceous monocarp Lobelia Inflata time constrained primary reproduction does not result in increased deferral of reproductive effort
BMC Ecology, 2014Co-Authors: Patrick William Hughes, Andrew M. SimonsAbstract:Background Although semelparity is a life history characterized by a single reproductive episode within a single reproductive season, some semelparous organisms facultatively express a second bout of reproduction, either in a subsequent season (“facultative iteroparity”) or later within the same season as the primary bout (“secondary reproduction”). Secondary reproduction has been explained as the adaptive deferral of reproductive potential under circumstances in which some fraction of reproductive success would otherwise have been lost (due, for example, to inopportune timing). This deferral hypothesis predicts a positive relationship between constraints on primary reproduction and expression of secondary reproduction. The herbaceous monocarp Lobelia Inflata has been observed occasionally to express a secondary reproductive episode in the field. However, it is unknown whether secondary reproduction is an example of adaptive reproductive deferral, or is more parsimoniously explained as the vestigial expression of iteroparity after a recent transition to semelparity. Here, we experimentally manipulate effective season length in each of three years to test whether secondary reproduction is a form of adaptive plasticity consistent with the deferral hypothesis.
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secondary reproduction in the herbaceous monocarp Lobelia Inflata time constrained primary reproduction does not result in increased deferral of reproductive effort
BMC Ecology, 2014Co-Authors: Patrick William Hughes, Andrew M. SimonsAbstract:Although semelparity is a life history characterized by a single reproductive episode within a single reproductive season, some semelparous organisms facultatively express a second bout of reproduction, either in a subsequent season (“facultative iteroparity”) or later within the same season as the primary bout (“secondary reproduction”). Secondary reproduction has been explained as the adaptive deferral of reproductive potential under circumstances in which some fraction of reproductive success would otherwise have been lost (due, for example, to inopportune timing). This deferral hypothesis predicts a positive relationship between constraints on primary reproduction and expression of secondary reproduction. The herbaceous monocarp Lobelia Inflata has been observed occasionally to express a secondary reproductive episode in the field. However, it is unknown whether secondary reproduction is an example of adaptive reproductive deferral, or is more parsimoniously explained as the vestigial expression of iteroparity after a recent transition to semelparity. Here, we experimentally manipulate effective season length in each of three years to test whether secondary reproduction is a form of adaptive plasticity consistent with the deferral hypothesis. Our results were found to be inconsistent with the adaptive deferral explanation: first, plants whose primary reproduction was time-constrained exhibited decreased (not increased) allocation to subsequent secondary reproduction, a result that was consistent across all three years; second, secondary offspring—although viable in the laboratory—would not have the opportunity for expression under field conditions, and would thus not contribute to reproductive success. Although alternative adaptive explanations for secondary reproduction cannot be precluded, we conclude that the characteristics of secondary reproduction found in L. Inflata are consistent with predictions of incomplete or transitional evolution to annual semelparity.
Yasushi Ohizumi - One of the best experts on this subject based on the ideXlab platform.
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pharmacological properties of β amyrin palmitate a novel centrally acting compound isolated from Lobelia Inflata leaves
Journal of Pharmacy and Pharmacology, 2011Co-Authors: Anas Subarnas, Takeshi Tadano, Yoshiteru Oshima, Kensuke Kisara, Yasushi OhizumiAbstract:Abstract— Effects of β-amyrin palmitate isolated from the leaves of Lobelia Inflata were studied on the central nervous system of mice and were compared with those of antidepressant drugs, mianserin and imipramine. In the forced swimming test, β-amyrin palmitate, like mianserin and imipramine, reduced the duration of immobility of mice significantly in a dose-dependent manner (5, 10 and 20 mg kg−1). β-Amyrin palmitate (5, 10 and 20 mg kg−1) or mianserin (5, 10 and 20 mg kg−1) elicited a dose-related reduction in locomotor activity of mice and antagonized locomotor stimulation induced by methamphetamine. In contrast, imipramine (5, 10 and 20 mg kg−1) increased locomotor activity and potentiated methamphet-amine-induced hyperactivity. β-Amyrin palmitate showed no effect on reserpine-induced hypothermia, whilst mianserin (10 mg kg−1) and imipramine (10 and 20 mg kg−1) antagonized the reserpine-induced effect. Unlike imipramine, β-amyrin palmitate and mianserin did not affect haloperidol-induced catalepsy, tetrabenazine-induced ptosis and apomorphine-induced stereotypy. β-Amyrin palmitate and imipramine had no effects on the head-twitch response induced by 5-hydroxytryptophan, whereas mianserin (5, 10 and 20 mg kg−1) decreased it in a dose-dependent manner. A potentiating effect of β-amyrin palmitate (5, 10 and 20 mg kg−1) on narcosis induced by sodium pentobarbitone was stronger than that of imipramine (10, 20 and 40 mg kg−1) but weaker than that of mianserin (2·5, 5 and 10 mg kg−1). These results suggest that β-amyrin palmitate has similar properties in some respects to mianserin and might possess a sedative action. We suggest that β-amyrin palmitate has antidepressant activity with a mianserin-like profile of action.
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A possible mechanism of antidepressant activity of beta-amyrin palmitate isolated from Lobelia Inflata leaves in the forced swimming test.
Life sciences, 1993Co-Authors: Anas Subarnas, Takeshi Tadano, Norimichi Nakahata, Yuichiro Arai, Hiroyasu Kinemuchi, Yoshiteru Oshima, Kensuke Kisara, Yasushi OhizumiAbstract:A mechanism of antidepressant activity of beta-amyrin palmitate was studied using the forced swimming method in mice. Beta-amyrin palmitate (10 mg/kg) reduced the increase in the duration of immobility induced by tetrabenazine (100 and 200 mg/kg), but showed no effect on that in mice treated with alpha-methyl-para-tyrosine (500 mg/kg). Beta-amyrin palmitate (5 and 10 mg/kg) decreased the duration of immobility in mice treated with desipramine plus 6-hydroxy-dopamine (50 micrograms/mouse), but did not affect that induced by nomifensine plus 6-hydroxydopamine. The decreased immobility produced by desipramine (15 mg/kg) was not affected by beta-amyrin palmitate. A study of norepinephrine release in mouse brain synaptosomes indicated that beta-amyrin palmitate caused a release of [3H]norepinephrine. The results of the present study suggest that beta-amyrin palmitate might release norepinephrine from newly synthesized pools, and thus, it might activate noradrenergic activity.
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An Antidepressant Principle of Lobelia Inflata L. (Campanulaceae)
Journal of pharmaceutical sciences, 1992Co-Authors: Anas Subarnas, Yoshiteru Oshima, Sidik, Yasushi OhizumiAbstract:Abstract A crude methanolic extract of the leaves of Lobelia Inflata exhibited antidepressant activity in mice. The extract was fractionated, monitored by the activity, to give β-amyrin palmitate as an active component.
L Kursinszki - One of the best experts on this subject based on the ideXlab platform.
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Studies on the alkaloid production of genetically transformed and non-transformed cultures of Lobelia Inflata L.
2018Co-Authors: E. Szőke, L Kursinszki, I. Bálványos, A. Krajewska, A. Mészáros, A. NeszmélyiAbstract:The investigations of the growth and alkaloid production of cell suspension-, callus-, organized- and hairy root cultures from Lobelia Inflata L. proved that these cultures are able to synthesize the characteristic piperidine alkaloids of the intact plant. Alkaloid precursor amino acids (Phe, Lys) and plant growth regulators affect not only the growth and differentiation of tissue cultures but also their secondary metabolism. The synthetic regulator Sz/I I combined with Phe increased the total alkaloid content considerably in callus- and organized cultures; regulator Sz/28 especially increased the lobeline content (in organized cultures in response to Lys, in callus tissues as a result of Phe application). With the aim of optimizing growth and alkaloid production of the genetically transformed hairy root cultures of Lobelia Inflata L. we studied the effect of some growth regulators (NAA, IAA, kinetin) and precursor amino acids (Lys, Phe). The kinetin had inhibiting effect on the growth and lobeline production of the hairy roots. The IAA and NAA increased the biomass formation and lobeline production. The highest lobeline level was detected in tissues cultivated on hormone-free medium containing Phe.
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increasing the anti addictive piperidine alkaloid production of in vitromicropropagated indian tobacco by nitrate treatments
Journal of Plant Biochemistry & Physiology, 2017Co-Authors: Viktor Jozsef Vojnich, P Banyai, Ákos Máthé, L Kursinszki, Eniko SzokeAbstract:Background: Lobelia Inflata L. (Indian tobacco) is a traditional medicinal plant native to North America. It contains several piperidine alkaloids. Interest in Lobelia alkaloids, and in particular (-)-lobeline, the most active component, has increased in recent years due to their effect on the central nervous system. Thus, lobeline is currently the subject of renewed interest for its anti-addictive activity in the treatment of drug abuse, and neurological disorders. Our studies were aimed at introducing this species into cultivation in Hungary. Results: For direct characterization of di-substituted and mono-substituted piperidine alkaloids in extracts of L. Inflata, a tandem mass spectrometric method was developed using electrospray ionization. The compounds (-) lobeline, norlobeline, lobelanidine, norlobelanine and other related structures were identified by HPLC-MS/MS. With the aim of increasing the alkaloid production, we have investigated the effect of changing the ammonium and potassium nitrate levels of the basic Murashige-Skoog medium. The highest dry mass, total alkaloid and lobeline content were measured in the herbs and roots cultured at 570 mg L-1 KNO3 content. Conclusions: The highest values for lobeline derivatives norlobeline and lobelidine were also recorded in the herba and roots of Lobelia Inflata cultured on reduced KNO3 containing MS medium. The most sensitive response to media modification was observed in the case of lobelidine. Double-concentration of NH4NO3 had an inhibitory effect on plant growth, total alkaloid and lobeline content.
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hplc esi ms ms of brain neurotransmitter modulator lobeline and related piperidine alkaloids in Lobelia Inflata l
Journal of Mass Spectrometry, 2015Co-Authors: L Kursinszki, Éva SzőkeAbstract:There is a renewed interest in Lobelia alkaloids because of their activity on the central nervous system. Lobeline, the most active of them, a nicotinic receptor ligand and neurotransmitter transporter inhibitor, is a candidate pharmacotherapy for metamphetamine abuse. In the present work, high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry in positive ion mode was used for investigating the alkaloid profile in Lobelia Inflata L. Chromatographic separations were achieved on a Gemini C6-phenyl reversed-phase column providing good peak shape and improved selectivity. Being mostly 2,6-disubstituted piperidines, Lobelia alkaloids presented abundant [M + H]+ ions with typical fragmentation. Identification was possible from a few specific ions, especially those resulting from excision of one of the substituents. Based on fragmentation pattern of lobeline as reference compound, 52 alkaloids were identified in the aqueous methanolic extract of L. Inflata in contrast to the previously known some 20. Structural variability of these alkaloids identified arises basically from their substituents which can be phenyl-2-ketoethyl- or phenyl-2-hydroxyethyl units as well as their methyl-, ethyl- or propyl- homologues attached in different combinations. Several propyl homologue Lobelia alkaloids and five hydroxypiperidine derivatives were found in the plant at the first time. In addition to 8-O-esters of 2-monosubstituted piperidine alkaloids previously reported by us in L. Inflata, a 3-hydroxy-3-phenylpropanoic acid ester of hydroxyallosedamine ring-substituted was also identified as a new natural product. High-performance liquid chromatography-electrospray ionization tandem mass spectrometry can be successfully applied to Lobeliacae plant samples in the routine screening for new and known bioactive constituents, quality control of the crude drug, Lobelia herba, alkaloid production studies, breeding and chemotaxonomy. Copyright © 2015 John Wiley & Sons, Ltd.
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Enhancement of the anti-addictive lobeline and related alkaloid production of in vitro micropropagated Lobelia Inflata L.
In Vitro Cellular & Developmental Biology - Plant, 2014Co-Authors: P Banyai, Viktor Jozsef Vojnich, Ákos Máthé, L Kursinszki, Éva SzőkeAbstract:Lobelia Inflata L. is a medicinally important species that contains numerous piperidine alkaloids. The main alkaloid lobeline is used as a respiratory stimulant. Recently, there have been studies that report on its effect on the central nervous system, drug abuse, and multidrug resistance. We have studied the piperidine alkaloid formation of in vitro cultivated L. Inflata on solid Murashige and Skoog medium. With the aim of increasing the anti-addictive lobeline production, we have investigated the effect of changing MgSO_4 levels of the medium. The compounds (−)-lobeline, norlobelanine, lobelanidine-(−)-8-ethyl-10-phenyl-norlobelionol, (−)-8-ethyl-10-phenyl-lobelionol, norlobeline, lobelidine, and lobelanine were identified by HPLC-tandem mass spectrometry (MS/MS). We studied the effect of changing the MgSO_4 levels on the content of lobeline and its derivatives for in vitro cultivated L. Inflata . The highest lobeline content was measured in roots cultured on 185 mg L^−1 MgSO_4-containing medium; this value was 2.5 times higher (232.4 μg g^−1) than in the control cultures. The greatest (fourfold) increase was observed in lobelidine (71.61 μg g^−1). Addition of MgSO_4 at 740 mg L^−1 resulted in the highest lobeline contents in the herba (aerial tissues; 267.8 μg g^−1), whereas maximum lobeline production was achieved by a further increase in the MgSO_4 level (1,480 mg L^−1), due to an intensive increase in biomass production. A slight increase was observed in the amount of lobeline derivatives in the herba grown in 740 mg L^−1 MgSO_4-containing medium. The most significant increase (25%) was recorded in the level of norlobelanine.
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factors influencing the pharmaceutically important characteristics of Lobelia Inflata l
African Journal of Traditional Complementary and Alternative Medicines, 2009Co-Authors: A Mathe, L Kursinszki, E Szoke, M T HajosAbstract:Lobelia Inflata L. (Lobeliaceae) contains pharmacologically important secondary metabolites, which consist of more than 20 piperidine alkaloids. Lobeline with its stimulatory effect on the respiratory centre is used in anti-smoking preparations. The pharmaceutical importance could be improved by the polyacetylenes (lobetyol, lobetyolin, lobetyolinin). The main goal of the experiments: to introduce the species into field production in Hungary and to identify the factors influencing its pharmaceutically important characteristics. Plantlets were propagated and raised both in vitro and in vivo. After acclimatization in a glass-house they were transplanted to irrigated open field conditions at 4 Hungarian locations. In vitro organized cultures produced intensive growth and considerable secondary metabolites. In contrast to lobetyolin (polyacetylene), the alkaloid (lobeline) content decreased in the open field. The effect of nutrient supply was also considered. Phytochemical analyses revealed differences in the total alkaloid content, both in view of the geographic region of cultures and the propagation technology. The highest alkaloid and polyacetylene contents were detected in the population grown at Mosonmagyarovar. Lobetyolin content exceeded in all samples the content of lobetyolinin. No similar differences were observed with lobeline. Field grown plants contained sufficient amounts of active principles. The nearly 1 t/ha biomass yield and active substance production could be increased by higher plant density and fertilization. N-fertilization increased the above ground phytomass, due to the increased number of side-branches. Dry mass was highest under the influence of MgSO4 (2%) foliar spraying. A similarly positive influence was detected both in the total alkaloid production and the lobeline content. As a contrast, a decrease in the total alkaloid content was observed with the doubling of both polyacetylenes. Acknowledgements: GVOP 3.1.1.-0309/3
Linda P Dwoskin - One of the best experts on this subject based on the ideXlab platform.
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the vesicular monoamine transporter 2 an important pharmacological target for the discovery of novel therapeutics to treat methamphetamine abuse
Advances in pharmacology (San Diego), 2014Co-Authors: Justin R Nickell, Peter A Crooks, Ashish P Vartak, Kiran B Siripurapu, Linda P DwoskinAbstract:Methamphetamine abuse escalates, but no approved therapeutics are available to treat addicted individuals. Methamphetamine increases extracellular dopamine in reward-relevant pathways by interacting at vesicular monoamine transporter-2 (VMAT2) to inhibit dopamine uptake and promote dopamine release from synaptic vesicles, increasing cytosolic dopamine available for reverse transport by the dopamine transporter (DAT). VMAT2 is the target of our iterative drug discovery efforts to identify pharmacotherapeutics for methamphetamine addiction. Lobeline, the major alkaloid in Lobelia Inflata, potently inhibited VMAT2, methamphetamine-evoked striatal dopamine release, and methamphetamine self-administration in rats but exhibited high affinity for nicotinic acetylcholine receptors (nAChRs). Defunctionalized, unsaturated lobeline analog, meso-transdiene (MTD), exhibited lobeline-like in vitro pharmacology, lacked nAChR affinity, but exhibited high affinity for DAT, suggesting potential abuse liability. The 2,4-dicholorophenyl MTD analog, UKMH-106, exhibited selectivity for VMAT2 over DAT, inhibited methamphetamine-evoked dopamine release, but required a difficult synthetic approach. Lobelane, a saturated, defunctionalized lobeline analog, inhibited the neurochemical and behavioral effects of methamphetamine; tolerance developed to the lobelane-induced decrease in methamphetamine self-administration. Improved drug-likeness was afforded by the incorporation of a chiral N-1,2-dihydroxypropyl moiety into lobelane to afford GZ-793A, which inhibited the neurochemical and behavioral effects of methamphetamine, without tolerance. From a series of 2,5-disubstituted pyrrolidine analogs, AV-2-192 emerged as a lead, exhibiting high affinity for VMAT2 and inhibiting methamphetamine-evoked dopamine release. Current results support the hypothesis that potent, selective VMAT2 inhibitors provide the requisite preclinical behavioral profile for evaluation as pharmacotherapeutics for methamphetamine abuse and emphasize selectivity for VMAT2 relative to DAT as a criterion for reducing abuse liability of the therapeutic.
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design synthesis and interaction at the vesicular monoamine transporter 2 of lobeline analogs potential pharmacotherapies for the treatment of psychostimulant abuse
Current Topics in Medicinal Chemistry, 2011Co-Authors: Peter A Crooks, Guangrong Zheng, David B. Horton, Ashish P Vartak, John P Culver, Fang Zheng, Linda P DwoskinAbstract:The vesicular monoamine transporter-2 (VMAT2) is considered as a new target for the development of novel therapeutics to treat psychostimulant abuse. Current information on the structure, function and role of VMAT2 in psychostimulant abuse are presented. Lobeline, the major alkaloidal constituent of Lobelia Inflata, interacts with nicotinic receptors and with VMAT2. Numerous studies have shown that lobeline inhibits both the neurochemical and behavioral effects of amphetamine in rodents, and behavioral studies demonstrate that lobeline has potential as a pharmacotherapy for psychostimulant abuse. Systematic structural modification of the lobeline molecule is described with the aim of improving selectivity and affinity for VMAT2 over neuronal nicotinic acetylcholine receptors and other neurotransmitter transporters. This has led to the discovery of more potent and selective ligands for VMAT2. In addition, a computational neural network analysis of the affinity of these lobeline analogs for VMAT2 has been carried out, which provides computational models that have predictive value in the rational design of VMAT2 ligands and is also useful in identifying drug candidates from virtual libraries for subsequent synthesis and evaluation.
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lobeline displaces 3h dihydrotetrabenazine binding and releases 3h dopamine from rat striatal synaptic vesicles comparison with d amphetamine
Journal of Neurochemistry, 2002Co-Authors: Lihong Teng, Peter A Crooks, Linda P DwoskinAbstract:Lobeline, an alkaloid from Indian tobacco (Lobelia Inflata), is classified as a nicotinic agonist and is currently used as a smoking cessation agent. However, our previous in vitro studies demonstrate that lobeline does not act as a nicotinic agonist but alters presynaptic dopamine (DA) storage by potently inhibiting DA uptake into synaptic vesicles. Recently, d-amphetamine has been reported to act at the level of the synaptic vesicle to alter presynaptic function. The present in vitro studies further elucidate the mechanism of lobeline's action and compare its effects with those of d-amphetamine. [3H]Dihydrotetrabenazine ([3H]DTBZ), used routinely to probe a high-affinity binding site on the vesicular monoamine transporter (VMAT2), bound to vesicle membranes from rat striatum with a KD of 1.67 nM and Bmax of 8.68 pmol/mg of protein. Lobeline inhibited [3H]DTBZ binding with an IC50 of 0.90 microM, consistent with its previously reported IC50 of 0.88 microM for inhibition of [3H]DA uptake into vesicles. These results suggest that lobeline specifically interacts with DTBZ sites on VMAT2 to inhibit DA uptake into synaptic vesicles. Interestingly, d-amphetamine inhibited [3H]DTBZ binding to vesicle membranes with an IC50 of 39.4 microM, a concentration 20 times greater than reported for inhibition of VMAT2 function, suggesting that d-amphetamine interacts with a different site than lobeline on VMAT2 to inhibit monoamine uptake. Kinetic analysis of [3H]DA release from [3H]DA-preloaded synaptic vesicles in the absence of drug revealed a t1/2 of 2.12 min. Lobeline and d-amphetamine evoked [3H]DA release with EC50 values of 25.3 and 2.22 microM, respectively. At a concentration 10 times the EC50, lobeline and d-amphetamine significantly decreased the t1/2 of [3H]DA release to 1.58 and 1.48 min, respectively. Thus, in contrast to d-amphetamine, which is equipotent in inhibiting DA uptake and promoting release from the synaptic vesicles, lobeline more potently (28-fold) inhibits DA uptake (via an interaction with the DTBZ site on VMAT2) than it evokes DA release to redistribute presynaptic DA storage.
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a novel mechanism of action and potential use for lobeline as a treatment for psychostimulant abuse
Biochemical Pharmacology, 2002Co-Authors: Linda P Dwoskin, Peter A CrooksAbstract:Lobeline, an alkaloidal constituent of Lobelia Inflata LINN., has a long history of therapeutic usage ranging from emetic and respiratory stimulant to tobacco smoking cessation agent. Although classified as both an agonist and an antagonist at nicotinic receptors, lobeline has no structural resemblance to nicotine, and structure--function relationships do not suggest a common pharmacophore. Lobeline inhibits nicotine-evoked dopamine release and [3H]nicotine binding, thus acting as a potent antagonist at both alpha3beta2(*) and alpha4beta2(*) neuronal nicotinic receptor subtypes. However, lobeline does not release dopamine from its presynaptic terminal, but appears to induce the metabolism of dopamine intraneuronally. Reevaluation of the mechanism by which lobeline alters dopamine function reveals that its primary mechanism is inhibition of dopamine uptake and promotion of dopamine release from the storage vesicles within the presynaptic terminal, via an interaction with the tetrabenazine-binding site on the vesicular monoamine transporter (VMAT2). Thus, lobeline appears to perturb the fundamental mechanisms of dopamine storage and release. Based on its neurochemical mechanism, the ability of lobeline to functionally antagonize the neurochemical and behavioral effects of the psychostimulants amphetamine and methamphetamine was examined. Lobeline was found to inhibit the amphetamine-induced release of dopamine in vitro, and amphetamine-induced hyperactivity, drug discrimination, and self-administration. However, lobeline does not support self-administration in rats, suggesting a lack of addiction liability. Thus, lobeline may reduce the abuse liability of these psychostimulants. The development of lobeline and lobeline analogs with targeted selectivity at VMAT2 represents a novel class of therapeutic agents having good potential as efficacious treatments for methamphetamine abuse.
Anas Subarnas - One of the best experts on this subject based on the ideXlab platform.
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pharmacological properties of β amyrin palmitate a novel centrally acting compound isolated from Lobelia Inflata leaves
Journal of Pharmacy and Pharmacology, 2011Co-Authors: Anas Subarnas, Takeshi Tadano, Yoshiteru Oshima, Kensuke Kisara, Yasushi OhizumiAbstract:Abstract— Effects of β-amyrin palmitate isolated from the leaves of Lobelia Inflata were studied on the central nervous system of mice and were compared with those of antidepressant drugs, mianserin and imipramine. In the forced swimming test, β-amyrin palmitate, like mianserin and imipramine, reduced the duration of immobility of mice significantly in a dose-dependent manner (5, 10 and 20 mg kg−1). β-Amyrin palmitate (5, 10 and 20 mg kg−1) or mianserin (5, 10 and 20 mg kg−1) elicited a dose-related reduction in locomotor activity of mice and antagonized locomotor stimulation induced by methamphetamine. In contrast, imipramine (5, 10 and 20 mg kg−1) increased locomotor activity and potentiated methamphet-amine-induced hyperactivity. β-Amyrin palmitate showed no effect on reserpine-induced hypothermia, whilst mianserin (10 mg kg−1) and imipramine (10 and 20 mg kg−1) antagonized the reserpine-induced effect. Unlike imipramine, β-amyrin palmitate and mianserin did not affect haloperidol-induced catalepsy, tetrabenazine-induced ptosis and apomorphine-induced stereotypy. β-Amyrin palmitate and imipramine had no effects on the head-twitch response induced by 5-hydroxytryptophan, whereas mianserin (5, 10 and 20 mg kg−1) decreased it in a dose-dependent manner. A potentiating effect of β-amyrin palmitate (5, 10 and 20 mg kg−1) on narcosis induced by sodium pentobarbitone was stronger than that of imipramine (10, 20 and 40 mg kg−1) but weaker than that of mianserin (2·5, 5 and 10 mg kg−1). These results suggest that β-amyrin palmitate has similar properties in some respects to mianserin and might possess a sedative action. We suggest that β-amyrin palmitate has antidepressant activity with a mianserin-like profile of action.
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A possible mechanism of antidepressant activity of beta-amyrin palmitate isolated from Lobelia Inflata leaves in the forced swimming test.
Life sciences, 1993Co-Authors: Anas Subarnas, Takeshi Tadano, Norimichi Nakahata, Yuichiro Arai, Hiroyasu Kinemuchi, Yoshiteru Oshima, Kensuke Kisara, Yasushi OhizumiAbstract:A mechanism of antidepressant activity of beta-amyrin palmitate was studied using the forced swimming method in mice. Beta-amyrin palmitate (10 mg/kg) reduced the increase in the duration of immobility induced by tetrabenazine (100 and 200 mg/kg), but showed no effect on that in mice treated with alpha-methyl-para-tyrosine (500 mg/kg). Beta-amyrin palmitate (5 and 10 mg/kg) decreased the duration of immobility in mice treated with desipramine plus 6-hydroxy-dopamine (50 micrograms/mouse), but did not affect that induced by nomifensine plus 6-hydroxydopamine. The decreased immobility produced by desipramine (15 mg/kg) was not affected by beta-amyrin palmitate. A study of norepinephrine release in mouse brain synaptosomes indicated that beta-amyrin palmitate caused a release of [3H]norepinephrine. The results of the present study suggest that beta-amyrin palmitate might release norepinephrine from newly synthesized pools, and thus, it might activate noradrenergic activity.
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An Antidepressant Principle of Lobelia Inflata L. (Campanulaceae)
Journal of pharmaceutical sciences, 1992Co-Authors: Anas Subarnas, Yoshiteru Oshima, Sidik, Yasushi OhizumiAbstract:Abstract A crude methanolic extract of the leaves of Lobelia Inflata exhibited antidepressant activity in mice. The extract was fractionated, monitored by the activity, to give β-amyrin palmitate as an active component.