Plant Toxins That Affect Nicotinic Acetylcholine Receptors: A Review

Review pubs.acs.org/crt

Plant Toxins That Affect Nicotinic Acetylcholine Receptors: A Review Benedict T. Green,* Kevin D. Welch, Kip E. Panter, and Stephen T. Lee USDA/ARS Poisonous Plant Research Laboratory, 1150 East 1400 North, Logan, Utah 84341, United States ABSTRACT: Plants produce a wide variety of chemical compounds termed secondary metabolites that are not involved in basic metabolism, photosynthesis, or reproduction. These compounds are used as flavors, fragrances, insecticides, dyes, hallucinogens, nutritional supplements, poisons, and pharmaceutical agents. However, in some cases these secondary metabolites found in poisonous plants perturb biological systems. Ingestion of toxins from poisonous plants by grazing livestock often results in large economic losses to the livestock industry. The chemical structures of these compounds are diverse and range from simple, low molecular weight toxins such as oxalate in halogeton to the highly complex norditerpene alkaloids in larkspurs. While the negative effects of plant toxins on people and the impact of plant toxins on livestock producers have been widely publicized, the diversity of these toxins and their potential as new pharmaceutical agents for the treatment of diseases in people and animals has also received widespread interest. Scientists are actively screening plants from all regions of the world for bioactivity and potential pharmaceuticals for the treatment or prevention of many diseases. In this review, we focus the discussion to those plant toxins extensively studied at the USDA Poisonous Plant Research Laboratory that affect the nicotinic acetylcholine receptors including species of Delphinium (Larkspurs), Lupinus (Lupines), Conium (poison hemlock), and Nicotiana (tobaccos).

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CONTENTS

Introduction Nicotinic Acetylcholine Receptors Plant Toxins Delphinium Lupinus Conium Nicotiana Tertogenicity Author Information Corresponding Author Funding Notes Acknowledgments Abbreviations References

pollination or seed dispersal or in some cases, such as alkaloids in seeds, may act as a nitrogen reservoir for germination and early growth. Given the significance of plant compounds to people and animals, the primary function of secondary metabolites in plants remains a topic of extensive discussion and research.1 The chemical structures of these compounds are diverse and range from simple, low molecular weight toxins such as oxalate in halogeton to the highly complex norditerpene alkaloids in larkspurs. While the negative effects of plant toxins on people and the impact of plant toxins on livestock producers have been widely publicized, the diversity of these toxins and their potential as new pharmaceutical agents for the treatment of diseases in people and animals has also received widespread interest. Scientists are actively screening plants from all regions of the world for bioactivity and potential pharmaceuticals for the treatment or prevention of many diseases. In this review, we focus the discussion on those plant toxins extensively studied at the USDA Poisonous Plant Research Laboratory that affect the nicotinic acetylcholine receptors (nAChRs) including species of Delphinium (Larkspurs), Lupinus (Lupines), Conium (poison hemlock), and Nicotiana (tobaccos).

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INTRODUCTION Plants produce a wide variety of chemical compounds termed secondary metabolites. These compounds are considered “secondary” because they are not involved in basic metabolism, photosynthesis, or reproduction and are thought to be an evolutionary adaptation to selective pressures in the environment such as herbivory. For centuries, people have used these compounds for flavors, fragrances, insecticides, dyes, hallucinogens, nutritional supplements, poisons, and pharmaceutical agents. Secondary compounds (toxins) may discourage predation by herbivores, including insects, microorganisms, wildlife, livestock and humans; however, in some cases these toxins (from poisonous plants) result in large economic losses to the livestock industry. Secondary compounds may also be signals to attract insects, birds, or other animals to enhance This article not subject to U.S. Copyright. Published XXXX by the American Chemical Society

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NICOTINIC ACETYLCHOLINE RECEPTORS Nicotinic acetylcholine receptors are ligand-gated cation channels that are members of the Cys-loop family of receptors (for review, see ref 2). For nAChRs in particular, there are 17 identified genetically distinct subunits: α1−10, β1−4, γ, δ, and ε (for review, see ref 3). Functional nAChRs comprise five subunits arranged symmetrically around a central cationchannel pore, and the subunit composition of a nAChR can Received: May 3, 2013

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dx.doi.org/10.1021/tx400166f | Chem. Res. Toxicol. XXXX, XXX, XXX−XXX

Chemical Research in Toxicology

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Figure 1. Image of Delphinium species and the structures of MLA and deltaline, two prototypical norditerpenoid alkaloids found in high concentrations in toxic larkspur populations. The bottom image is reprinted with permission from Photo Al Schneider. Copyright 2006 Al Schneider. The top image is reprinted with permission from USDA/ARS Poisonous Plant Research Laboratory.

vary from a homopentamer like the α7 nAChR to various heteropentamer combinations (each with distinct functional differences) depending on where the receptor is expressed in the body (for review, see ref 4). For example, the fetal muscletype nAChR expressed in the muscle of the developing fetus comprises α1(2)β1γδ nAChR subunits and is sensitive to teratogenic plant alkaloids. These receptors exist in multiple conformation states including a resting closed-channel state, an open-channel state, and a desensitized state, all of which have differing allosterically linked affinities for agonists and antagonists (for review, see ref 5). Depending on their subunit composition, the homo- and heteropentamer combinations also have differing affinities for agonists and antagonists at the ligand binding sites. For example, α4β2 nAChRs have a high affinity for nicotine, a pyridine alkaloid from N. tabacum, and are selectively antagonized by dihydro-β-erythroidine, an alkaloid

from Erythrina spp.6−8 α4β2 nAChRs are responsible for approximately 90% of the nicotine binding in the brain,3 are upregulated in rat fetal brain cells that have been chronically exposed to nicotine,9 and are thought to play a role in the reinforcement of smoking behavior.10 In contrast, the homopentamer α7 nAChR, which may have a role in the etiology of schizophrenia,11 is selectively activated by choline12 or the quinolizidine alkaloid cytisine from Laburnum spp.13,14 and blocked by methyllycaconitine (MLA) a diterpenoid alkaloid from Delphinium spp. In addition to agonists and antagonists like acetylcholine and MLA (both classified as orthosteric ligands of nAChR), there are other compounds which can bind to transmembrane domain locations of the nAChR to affect receptor function. These compounds are known as allosteric modulators.15 Allosteric modulators can be either positive (increase the agonist response) or negative B



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Figure 2. Relationship between serum MLA concentrations and heart rate. There is a significant correlation between MLA serum concentrations and heart rate in cattle (P = 0.0001; Spearman r = 0.75). Data points represent MLA serum concentrations (ng/mL), left axis, and heart rate (beats per minute), right axis, over 96 h in five steers that received an equivalent oral dose of 10.4 mg/kg MLA in the form of dried ground larkspur. Each data point represents the mean ± standard error. (Data are from Green et al.101)

type and the N-(methylsuccinimido) anthranoyllycoctonine (MSAL)-type.28 Although the MSAL-type alkaloids are much more toxic (typically >20x),29−31 the MDL-type alkaloids are generally more abundant in many larkspur populations.32,33 The three MSAL-type alkaloids that are most important due to their toxicity in livestock are MLA, 14-deacetylnudicauline (DAN), and nudicauline (NUD).30 There are two structural features necessary for toxicity: (1) an N-ethyl bicyclo tertiary alkaloid nitrogen atom and (2) a C-18 anthranilic acid ester.34 Structure−function studies have shown that the aromatic ester functional group on MLA is a significant haptophore35 and that the succinimide group imparts significant toxicity to alkaloids.36,37 In addition, substitution of differing functional groups at the C-14 carbon can affect the toxicity of these alkaloids.30 The primary result of larkspur toxicosis in livestock is neuromuscular paralysis from nAChR blockade at the postsynaptic neuromuscular junction.38,39 These effects are species dependent because in mice and rats, MLA elicits central nervous system effects, and in large animals such as cattle, MLA elicits primarily peripheral effects.40,41 Moreover, in Anolis carolinesis lizards, larkspur alkaloids act as postsynaptic competitive inhibitors of acetylcholine at muscle-type nAChR.42 MLA is a potent and selective blocker of α7 nAChRs that block acetylcholine evoked currents in rat fetal hippocampal neurons at picomolar concentrations.3,40,43 MLA strongly competes with the high affinity nAChR ligand αbungarotoxin for binding to nAChRs.34 MLA has been shown to displace 125I α-bungarotoxin binding in rat brain membranes with a Ki of 1.4 nM and displaces 125I α-bungarotoxin binding in human muscle extracts with a Ki of 7.8 μM suggesting it is selective for neuronal nAChR.44 Moreover, the binding of larkspur alkaloids to nAChRs appears to be correlated with toxicity34 and may explain the tolerance of sheep to larkspur if the toxins bind with lower affinity at sheep receptors.41,44 There is also a significant correlation between serum MLA concentration and the physiological effects of MLA such as elevated heart rate (Figure 2). Drugs that increase the persistence of acetylcholine at the neuromuscular junction

(decrease the agonist response) (for review, see ref 16). For example, ivermectin is a positive allosteric modulator of α7 nAChR,17 and progesterone can act as a negative allosteric modulator of α4β2 nAChR. 16,18 Functionally, allosteric modulators are thought to change either the affinity of the receptor for the orthosteric ligand or the intrinsic efficacy of the agonist−receptor interaction.19 In addition to allosteric modulation, nAChR agonists and antagonists at high concentrations (100 μM−1 mM) can directly block the ion channel of the receptor in a noncompetitive manner.20 nAChRs are found throughout the body and serve to mediate diverse physiological functions. Specific locations of nAChRs include the central nervous system, autonomic ganglia, sensory ganglia, and neuromuscular junctions. These receptors can also be located pre- or postsynaptically. Presynaptic nAChRs serve to modulate the release of neurotransmitters including biogenic amines and amino acids.21−24 Postsynaptic nAChRs mediate excitatory neurotransmission. For example, muscle-type nAChRs located in the motor end plate region of the muscle fiber are activated by acetylcholine released from the motor nerve terminal. The opening of muscle-type nAChRs in the postjunctional membrane increases the permeability of the cell membrane to cations, leading to membrane depolarization and ultimately muscle contraction.25

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PLANT TOXINS

The deleterious effects of many poisonous plants are due to toxins produced by the plants that bind to nAChRs. These plant toxins can be either competitive agonists or antagonists of nAChRs. For the remainder of this review, we will focus on plant toxins from the genera Delphinium, Lupinus, Conium, and Nicotiana. Delphinium. There are over 80 wild species of larkspurs (Delphinium) in North America26 (Figure 1). Larkspur species are divided into three general categories based primarily on mature plant height and geographical distribution: low, tall, and plains larkspurs.27 The toxicity of larkspur plants is due to norditerpenoid alkaloids, which occur as one of two chemical structural types, the 7,8-methylenedioxylycoctonine (MDL)C



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such as the acetylcholinesterase inhibitor neostigmine can reverse larkspur toxicosis or reduce susceptibility.45 Lupinus. The genus Lupinus contains more than 500 species of annual, perennial, or soft woody-shrub-like lupines worldwide and are members of the Leguminosae family (Figure 3).46

Figure 4. Concentration−effect relationships with best-fit lines for the actions of anagyrine on membrane potential sensing dye fluorescence in TE-671 cells and SH-SY5Y cells. In each experiment, the membrane depolarization resulting from the addition of epibatidine or anagyrine in log10 molar concentrations was measured and displayed as a percentage of the maximal epibatidine response (10 μM epibatidine for both cell lines). Each datum represents six experiments of duplicate wells. (Data are from Green et al.102)

Figure 3. Images of Lupinus leucophyllus (top panel) and Lupinus sulphureus (bottom panel). The chemical structure of the piperidine alkaloid ammodendrine and the quinolizidine alkaloid anagyrine are included for comparison. Reprinted with permission from USDA/ARS Poisonous Plant Research Laboratory.

The toxicity of Lupinus plants is due to the presence of quinolizidine and piperidine alkaloids. More than 150 quinolizidine alkaloids have been structurally identified from the legume family.47 Eighteen Lupinus species have been shown to contain the quinolizidine alkaloid anagyrine, and 14 of these contain teratogenic amounts of anagyrine.48 Only a small number of the lupine alkaloids have been investigated in detail. For example, 14 alkaloids isolated from Lupinus albus, L. mutabilis, and Anagyris fetida were analyzed for the displacement of 3H-nicotine (a nAChR selective ligand) or 3Hquinuclidinyl benzilate (a muscarinic acetylcholine receptor selective ligand) in a porcine brain membrane preparation.47 Of the 14 lupine alkaloids tested, the α-pyridones (N-methyl cytisine and cytisine) had the highest affinities for nAChR (IC50s of 0.05 and 0.14 μM, respectively), while several quinolizidine alkaloid types including the teratogen anagyrine (IC50 = 132 μM) were also potent displacers of 3H-nicotine. Functionally, the lupine alkaloid anagyrine is a partial agonist at α12β1γδ nAChR expressed by TE-671 cells and α3β4 nAChR expressed by SHSY-5Y cells with percent maximum activations of 39 ± 18 and 27 ± 4% activation for TE-671 and SHSY-5Y cells, respectively (Figure 4). Lupanine, which is widely distributed in legumes and lupine species, has an IC50 of 5 μM at porcine brain nAChRs and is more active than

hydroxylated lupanines or alkaloids of the multiflorine series (IC50 values of >500 μM49). Recent research on the in vivo disposition of lupanine and 13-hydroxylupanine in humans has demonstrated that the urine t1/2 after oral administration was 6.5 and 5.9 h, respectively; and 95% to 100% of the total alkaloid administered was recovered unchanged within 72 h.50 Lupanine, 13- hydroxylupanine, and sparteine have been shown to block ganglionic neurotransmission (predominantly α3β4, nAChR), decrease cardiac contractility, and contract uterine smooth muscle which suggests actions at β-adrenergic receptors.51 Lupanine and sparteine have been shown to block the effects of pneumogastric nerve stimulation in dogs and cats suggesting ganglionic effects due to actions at predominantly α3β4 nAChR,52 and both compounds act as weak antagonists at muscarinic cholinergic receptors. This is inconsistent with information from porcine brain membrane experiments,47 as they reported that sparteine had the second highest affinity for muscarinic acetylcholine receptors of the 14 quinolizidine alkaloids tested, while lupanine had the 12th highest affinity (IC50 = 21 and 190 μM for sparteine and lupanine, respectively, based on the displacement of 3Hquinuclidinyl benzilate (QNB) and micromolar affinity for nAChR (IC50 = 331 and 5 μM for sparteine and lupanine, D



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Figure 5. Images of poison hemlock and chemical structures of predominant alkaloids. Reprinted with permission from USDA/ARS Poisonous Plant Research Laboratory.

respectively based on the displacement of 3H-nicotine)). The toxicity of lupanine administered by intraperitoneal injection to rodents was less than that of sparteine; with LD50 values of 175 vs 36 mg/kg, respectively.52,53 In lupine, alkaloids are produced in the leaves of the plant by chloroplasts and translocated via the phloem to be stored in epidermal cells and seeds of the plant.46 The synthesis of these alkaloids is regulated by light and fluctuates diurnally.54,55 In addition to diurnal alkaloid fluctuations, the piperidine and quinolizidine alkaloid content can vary in plants depending on environmental conditions, season of the year, stage of growth, and species of lupine.56 Alkaloid content is typically highest during early growth stages, decreasing through the flower stage while increasing in the seeds and pods. In addition to the above variables influencing alkaloid concentration, elevation has also been shown to play a role in alkaloid concentrations. For example, in Lupinus argenteus plants collected above 3500 m there was a 6-fold increase in alkaloid concentrations compared to that in those collected at 2700 m.57 Interestingly, in the same study, the researchers saw no difference in herbivory between the lupine populations, and the alkaloid differences persisted even when seedlings from the highest and lowest elevations were grown under identical greenhouse conditions, suggesting genetic differences as plants adapted to elevation. Conium. Poison-hemlock (Conium maculatum) (Figure 5) was introduced into the United States as an ornamental plant

from Europe and has become widespread throughout this country.26 Historically, poison-hemlock has been associated with human poisoning more than livestock poisonings and is believed to be the source of the tea used to execute Socrates.58,59 Because of its popular use as an execution potion and its pharmaceutical properties, coniine was the first alkaloid characterized and the first alkaloid to be prepared synthetically. In addition to the early chemistry, alkaloids of poison hemlock were the first alkaloids to have their biosynthetic pathways in the plant determined.60,61 Eight piperidine alkaloids are known in poison-hemlock (coniine, N-methylconiine, γ-coniceine, conhydrine, conhydrinone, pseudoconhydrine, N-methylpseudoconhydrine, and 2-methyl piperidine), five of which are commonly discussed in the literature.62 Two alkaloids, coniine and γ-coniceine, are most prevalent in the plant and are likely responsible for toxicity and teratogenicity in animals. γConiceine is the predominant alkaloid in the early vegetative stage of plant growth and is a biochemical precursor to the other Conium alkaloids.61,63 Coniine is the predominate alkaloid in the seeds of the late growth stage of the plant. γConiceine (LD50 4.4 mg/kg) is more toxic than coniine (LD50 7.7 mg/kg), which is in turn more toxic than N-methylconiine (LD50 17.8 mg/kg) in mice.64,65 The mechanism of action of the Conium alkaloids is 2-fold. The most clinically significant effect occurs at the neuromuscular junction where they act as nondepolarizing blockers like curare.66 Systemically, the toxins E



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nAChR.70 As a drug, nicotine has pharmacological actions in muscle, the peripheral nervous system, central nervous system, and the cardiovascular system. Nicotine has been shown to have effects on behavior and cognitive function (for review, see refs 71 and 72). Nicotine has been extensively studied as an addictive substance, and its effects are mediated by actions at nAChR (for more information, see refs 25 and 73). Romano and Goldstein74 demonstrated the stereoselectivity of nicotine binding sites in rat brain membranes (stereoselectivity is a property of receptors). Nicotine has binding affinities in the low nanomolar range at α4β2 nAChR, binding affinities of micromolar and above at α7 nAChR, and in the nanomolar range at α3β4 nAChR.3,71,75

cause biphasic nicotinic effects, including salivation, mydriasis, and tachycardia followed by bradycardia due to their actions at autonomic ganglia. The teratogenic effects are undoubtedly related to the neuromuscular effects on the fetus and have been shown to be related to reduction in fetal movement.67 Differences in chemical structure impart significant differences in toxicity/teratogenicity (γ-coniceine > coniine > N-methyl coniine), but the teratogenic potency of the alkaloids is unknown, although we believe it is related to toxicity.68 The clinical signs of poisoning from ingestion of Conium and N. glauca are similar in all animal species tested and appear to be the same as those caused by lupine. They include early signs of nervousness, occlusion of the eyes by the nictitating membrane, progressing quickly through a pattern of nervous system stimulation with peripheral and local effects including frequent urination and defecation, dilated pupils, trembling, incoordination, and excessive salivation. The stimulation soon passes to depression resulting in relaxation, recumbency, and eventually death from respiratory paralysis at high doses. Nicotiana. The Nicotiana genus (Figure 6) consists of about 60 species in North and South America, Australia, and the

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TERTOGENICITY The teratogenic effects of Lupine, Conium, and Nicotiana spp. are discussed together because the malformations associated with these plants are similar, if not the same, and the mechanism of action, the complete inhibition of fetal movement (Figure 7), is believed to be the same for each of the species.76 The syndrome known as “crooked calf disease” associated with lupine ingestion by the pregnant mother was first reported in the late 1950s. Crooked calf disease is associated with various skeletal contracture-type birth defects and occasionally cleft palate.49,70,77 This appears to be similar to an inherited genetic condition where the same type of birth defects are reported in Charolais cattle.78 Through epidemiologic evidence and chemical comparison of teratogenic and nonteratogenic lupines, the quinolizidine alkaloid anagyrine was determined to be the teratogen.79 A second teratogen, the piperidine alkaloid ammodendrine, was found in Lupinus formosus and induces the same type of skeletal birth defects.80,81 Further research determined that the anagyrine-containing lupines only caused birth defects in cattle and did not affect sheep or goats, while the piperidine alkaloid containing lupine, L. formosus, induced similar birth defects experimentally in cattle and goats.76,80 This led to speculation about the possible metabolism or absorption differences between cattle and small ruminants. Keeler and Panter80 hypothesized that the cow might metabolize the quinolizidine alkaloid anagyrine to a complex piperidine, meeting the structural characteristics determined for the simple teratogenic piperidine alkaloids in poison-hemlock.82 This was supported by feeding trials with other piperidine alkaloid-containing plants, extracts, and pure compounds. Even though comparative studies support the hypothesis that the cow may convert the quinolizidine alkaloid anagyrine to a complex piperidine by ruminal metabolism, recent evidence reporting the absorption and elimination patterns of many of the quinolizidine alkaloids, including anagyrine, in cattle, sheep, and goats does not support this theory.83 Keeler and Balls82 fed commercially available structural analogues of coniine to pregnant cows to compare structural relationships to teratogenic effects. Results from Keeler and Balls82 suggested that piperidine alkaloids must meet certain structural criteria to be teratogenic. On the basis of these data, Keeler and Balls82 speculated that the piperidine alkaloids with either a saturated ring or a single double bond with a side chain of at least three carbon atoms in length adjacent to the nitrogen atom might be considered potential teratogens. Additionally, piperidine alkaloids with a double bond adjacent to the N atom of the piperidine ring are more toxic than either the saturated or N-methyl derivatives.68

Figure 6. Images of cultivated tobacco (top left), tree tobacco (bottom two panels), and chemical structures of two common tobacco alkaloids. Reprinted with permission from USDA/ARS Poisonous Plant Research Laboratory.

South Pacific. Many of these species are poisonous to livestock and humans. The annual plant, Nicotiana tabacum, is cultivated as a cash crop, which forms an extensive tobacco industry, while N. glauca is a perennial tree or shrub with no commercial value but is poisonous to livestock. Burley tobacco (N. tabacum) is native to South America. It was introduced and subsequently cultivated in Virginia by European settlers. In 1597, Gerad believed that burley tobacco relieved discomfort from headaches, toothaches, skin problems, burns, wounds, dropsy, piles, colic, and deafness. It was also used as a purgative, emetic, and antihelminitic.69 The major constituent, nicotine, was named after Jean Nicot who helped popularize the use of tobacco in the 16th century as a treatment for headache. Nicotine was first isolated and characterized in 1828, but its pharmacological action was not demonstrated until 1898. Langley, a Cambridge University physiologist, exposed autonomic ganglia from different animal species to nicotine and observed an initial stimulation followed by inhibition of nervous transmission. Langley was the first to propose the idea of the autonomic nervous system with its sympathetic and parasympathetic components. This early research led to the recognition of F



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Figure 7. Effect of nicotine, (−)-coniine mandelic acid, and anabasine on ultrasound monitored fetal movement in the day 40 pregnant goat model. The bars represent the mean ± SEM number of fetal movements detected during a 5 min fetal ultrasound monitoring period of seven fetuses in seven anabasine dosed does (0.8 mg/kg anabasine), six fetuses in six does dosed with (−)-coniine mandelic acid (4.4 mg/kg (−)-coniine mandelic acid), and eight nicotine (0.4 mg/kg) dosed does. Fetal movements were measured at time zero just prior to i.v. injection and 30 and 60 min after i.v. dosing. There were significant differences among the treatments (*P < 0.05). (Data are from Green et al.103,104)

Frequently, minor contractions such as “buck knees” may be attributed to lupine, but the malformations will resolve on their own, and the calf will appear normal. The critical gestational period for exposure in cattle is 40−70 days with susceptible periods extending to 100 days.96,97 The condition has been experimentally induced with dried ground lupine at 1 g/kg body wt and with semipurified preparations of anagyrine at 30 mg anagyrine/kg body wt fed daily from 30 to 70 days gestation.98,99 Crooked calf disease has also been induced by feeding the piperidine alkaloid-containing lupine L. formosus.80 The teratogenic compounds from this plant are believed to be ammodendrine,80 N-acetyl hystrine, and N-methyl ammodendrine.68 These teratogenic alkaloids are absorbed quickly after ingestion and can be detected in blood plasma by 0.5 h with peak levels of N-methyl ammodendrine and N-acetyl hystrine attained by 2 h postgavage and peak levels of ammodendrine attained in about 24 h.83,100 The plasma elimination t1/2 in the cow was about 12 h for ammodendrine and less than 2 h for Nmethyl ammodendrine. N-Acetyl hystrine demonstrated a biphasic elimination pattern with a rapid first phase, t1/2 less than 2 h, and a much slower second phase, t1/2 greater than 12 h.100 Toxicological comparison in a mouse bioassay demonstrated that N-acetyl hystrine is most toxic > N methyl ammodendrine > ammodendrine.68 Plants produce a variety of secondary compounds, and many of them are bioactive in animals. If these compounds possess the correct chemical structure, then they can act as neurotoxins at nAChRs. For example, piperidine alkaloids from Nicotiana spp. can activate and ultimately desensitize nAChR at the neuromuscular junction of developing fetuses.88 The desensitization and resulting inhibition of fetal movement results in arthrogryposis and other fetal defects. The norditerpenoid alkaloids found in larkspurs have a different chemical structure and pharmacological mode of action, but they too act as neurotoxins. Norditerpenoid alkaloids act as antagonists to block the ligand binding sites of nAChR and cause acute toxicosis in adult animals, which can result in death. Even

One piperidine alkaloid, which meets the structural requirements for teratogenesis, is anabasine, the major alkaloid in Nicotiana glauca (tree tobacco). By comparison, in N. tabacum (cultivated tobacco) nicotine is the major alkaloid component of tobacco leaves and anabasine a major component of stalks.84 In a goat model, nicotine does not abolish fetal movement while anabasine does (Figure 7). Research from the late 1960s and early 1970s with N. tabacum stalks that have high concentrations of anabasine identified that the alkaloid to be responsible for the outbreaks of malformed pigs not nicotine from the leaves.85−87 Research has focused on N. glauca, using dried ground plant and solvent extracts from the plant in a goat model, to study the mechanism of teratogenesis with application to other livestock species and humans.88 Recent research demonstrated the relative order of toxicity of three structurally related piperidine alkaloids as anabaseine > anabasine > N-methyl anabasine.68 Moreover, coniine, a simple piperidine from poison hemlock, and anabasine, a simple piperidine from tree tobacco (Nicotiana glauca), have been shown to induce the same fetal defects in cattle, sheep, pigs, and goats.67,89 The related alkaloid anabaseine (a piperidine alkaloid structurally similar to anabasine) has a double (imine) bond between positions 1 and 2 of the piperidine ring and is found in certain marine worms and in ants.90,91 Anabasine and anabaseine are both potent agonists at nAChRs,92 and benzylidene-anabaseine analogues which act as selective partial agonists of α7 nAChR have received much attention for their potential as cognitive enhancers.93−95 Arthrogryposis is the most common malformation caused by potent piperidine alkaloid nAChR agonists like anabasine. The observed terata include one or more of the following: scoliosis, torticollis, kyphosis, or cleft palate. The elbow joints are often immobile because of misalignment of the ulna with the articular surfaces of the distal extremity of the humerus and front limbs rotated laterally. In crooked calf disease, the osseous changes are permanent and become progressively worse as the calf grows and its limbs are subjected to greater load-bearing stress. G



Review

chronic exposure of rats to mainstream cigarette smoke or alpha 4 beta 2 receptors to nicotine. Biochem. Pharmacol. 50, 2001−2008. (10) Dani, J. A., Jenson, D., Broussard, J. I., and De Biasi, M. (2011) Neurophysiology of nicotine addiction. J. Addict. Res. Ther., DOI: 10.4172/2155-6105.S1-001. (11) Lloyd, G. K., and Williams, M. (2000) Neuronal nicotinic acetylcholine receptors as novel drug targets. J. Pharmacol. Exp Ther. 292, 461−467. (12) Papke, R. L., Bencherif, M., and Lippiello, P. (1996) An evaluation of neuronal nicotinic acetylcholine receptor activation by quaternary nitrogen compounds indicates that choline is selective for the alpha 7 subtype. Neurosci. Lett. 213, 201−204. (13) Alkondon, M., Pereira, E. F., Eisenberg, H. M., and Albuquerque, E. X. (1999) Choline and selective antagonists identify two subtypes of nicotinic acetylcholine receptors that modulate GABA release from CA1 interneurons in rat hippocampal slices. J. Neurosci. 19, 2693−2705. (14) Papke, R. L., and Porter Papke, J. K. (2002) Comparative pharmacology of rat and human alpha7 nAChR conducted with net charge analysis. Br. J. Pharmacol. 137, 49−61. (15) Changeux, J. P. (2011) 50th anniversary of the word “allosteric”. Protein Sci. 20, 1119−1124. (16) Bertrand, D., and Gopalakrishnan, M. (2007) Allosteric modulation of nicotinic acetylcholine receptors. Biochem. Pharmacol. 74, 1155−1163. (17) Collins, T., and Millar, N. S. (2010) Nicotinic acetylcholine receptor transmembrane mutations convert ivermectin from a positive to a negative allosteric modulator. Mol. Pharmacol. 78, 198−204. (18) Valera, S., Ballivet, M., and Bertrand, D. (1992) Progesterone modulates a neuronal nicotinic acetylcholine receptor. Proc. Natl. Acad. Sci. U.S.A. 89, 9949−9953. (19) Ehlert, F. J. (2005) Analysis of allosterism in functional assays. J. Pharmacol. Exp. Ther. 315, 740−754. (20) Lape, R., Krashia, P., Colquhoun, D., and Sivilotti, L. G. (2009) Agonist and blocking actions of choline and tetramethylammonium on human muscle acetylcholine receptors. J. Physiol. 587, 5045−5072. (21) Marshall, D. L., Redfern, P. H., and Wonnacott, S. (1997) Presynaptic nicotinic modulation of dopamine release in the three ascending pathways studied by in vivo microdialysis: comparison of naive and chronic nicotine-treated rats. J. Neurochem. 68, 1511−1519. (22) Sershen, H., Balla, A., Lajtha, A., and Vizi, E. S. (1997) Characterization of nicotinic receptors involved in the release of noradrenaline from the hippocampus. Neuroscience 77, 121−130. (23) Rao, T. S., Correa, L. D., Adams, P., Santori, E. M., and Sacaan, A. I. (2003) Pharmacological characterization of dopamine, norepinephrine and serotonin release in the rat prefrontal cortex by neuronal nicotinic acetylcholine receptor agonists. Brain Res. 990, 203−208. (24) Zappettini, S., Grilli, M., Salamone, A., Fedele, E., and Marchi, M. (2010) Pre-synaptic nicotinic receptors evoke endogenous glutamate and aspartate release from hippocampal synaptosomes by way of distinct coupling mechanisms. Br. J. Pharmacol. 161, 1161− 1171. (25) Taylor, P. (2001) Agents Acting at the Neuromuscular Junction and Autonomic Ganglia, in Goodman and Gilman’s The Pharmacological Basis of Therapeutics (Hardman, J. G., Limbird, L. E., and Gilman, A. G., Eds.) pp 193−214, McGraw-Hill, New York. (26) Kingsbury, J. M. (1964) Poisonous Plants of the United States and Canada, Prentice-Hall, Inc., Englewood Cliffs, NJ. (27) Burrows, G. E., and Tyrl, R. J. (2001) Toxic Plants of North America, Iowa State University Press, Ames, IA. (28) Pfister, J. A., Gardner, D. R., Panter, K. E., Manners, G. D., Ralphs, M. H., Stegelmeier, B. L., and Schoch, T. K. (1999) Larkspur (Delphinium spp.) poisoning in livestock. J. Nat. Toxins 8, 81−94. (29) Manners, G. D., Panter, K. E., Ralphs, M. H., Pfister, J. A., Olsen, J. D., and James, L. F. (1993) Toxicity and chemical phenology of norditerpenoid alkaloids in the tall larkspurs (Delphinium species). J. Agric. Food Chem. 41, 96−100.

though the compounds have deleterious effects in mammals, they must provide some advantage to the plants that produce them. The likely purpose of these compounds is to discourage predation, enhance pollination and seed dispersal, or serve as a nitrogen reservoir for germination and early growth. Regardless of the true purpose of plant secondary compounds, the bioactivity of these compounds makes them useful tools in human and veterinary medicine or potentially harmful toxins.

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AUTHOR INFORMATION

Corresponding Author

*Phone: 435-752-2941. Fax: 435-753-5681. E-mail: Ben. [email protected]. Funding

This work was funded by the United States Department of Agriculture, Agricultural Research Service. Notes

The mention of trade names or commercial products in this publication is solely for providing specific information and does not imply recommendation or endorsement by the U.S. Department of Agriculture. The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Isabelle McCollum and Terrie Wierenga for technical assistance.

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ABBREVIATIONS nAChR, nicotinic acetylcholine receptor; MLA, methyllycaconitine; MDL-type alkaloid, 8-methylenedioxylycoctonine alkaloid; MSAL-type alkaloid, N-(methylsuccinimido) anthranoyllycoctonine alkaloid; DAN, 14-deacetylnudicauline; NUD, nudicauline; TE-671, human rhabdomyosarcoma cell line TE671; SHSY-5Y, human neuroblastoma cell line SH-SY5Y; IC50, median inhibitory concentration; LD50, median lethal dose; t1/2, half-life

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REFERENCES

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