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Methyllycaconitine citrate Sale

(Synonyms: 甲基牛扁亭柠檬酸盐; MLA) 目录号 : GC13678

An antagonist of α7-containing nAChRs

Methyllycaconitine citrate Chemical Structure

Cas No.:112825-05-5; 351344-10-0

规格 价格 库存 购买数量
10mM (in 1mL DMSO)
¥1,386.00
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5mg
¥819.00
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10mg
¥1,440.00
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25mg
¥2,970.00
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50mg
¥5,310.00
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Sample solution is provided at 25 µL, 10mM.

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实验参考方法

Cell experiment [1]:

Cell lines

The human neuroblastoma cell line SH-SY5Y

Preparation Method

Cells were cultured in RPMI-1640 supplemented with 10% FBS at 37 °C. Cells at 60-70% confluence were treated with concentrations of Aβ25-35, Methyllycaconitine citrate, rapamycin or Aβ25 35 with or without Methyllycaconitine citrate.

Reaction Conditions

2.5-20uM Methyllycaconitine citratefor 24h

Applications

Pretreatment with 5 and 10 uM Methyllycaconitine citrate inhibited the decreased cell viability induced by Aβ25-35, which suggested that MLA had a protective effect against Aβ-induced cytotoxicity. Furthermore, cell viability did not decrease after exposure to Methyllycaconitine citrate (2.5, 5, 10, 20 uM), which suggests a good safety profile

Animal experiment [2]:

Animal models

White Swiss-Webster male mice

Preparation Method

Mice were initially injected with primary injection solution (0.2 mL) for a dose of 50 µg of hapten fetuin conjugate( Methyllycaconitine citrate and MLA-BSA). Booster injections (0.2 mL) with the same dose of hapten fetuin conjugate in incomplete Freund's adjuvant were given at 3-wk intervals. Control mice were initially injected s.c. with control primary injection solution. At the same time, the treated mice received booster injections the control mice were given control booster injections (0.2 mL).

Dosage form

1 mg/mL Methyllycaconitine citrate 0.2ML

Applications

Vaccination altered Methyllycaconitine citrate toxicity in mice and that vaccination may be useful in decreasing the effects of larkspur toxins in animals.

References:

[1]. Zheng X, Xie Z, et,al. Methyllycaconitine alleviates amyloid-β peptides-induced cytotoxicity in SH-SY5Y cells. PLoS One. 2014 Oct 31;9(10):e111536. doi: 10.1371/journal.pone.0111536. PMID: 25360664; PMCID: PMC4216102.
[2]. Lee ST, Stegelmeier BL, et,al. Evaluation of vaccination against methyllycaconitine toxicity in mice. J Anim Sci. 2003 Jan;81(1):232-8. doi: 10.2527/2003.811232x. PMID: 12597394.

产品描述

Methyllycaconitine citrate (MLA), a norditerpenoid alkaloid isolated from the seeds of Delphinium brownie. Methyllycaconitine citrate (MLA) is an antagonist of α7-containing neuronal nicotinic acetylcholine receptors (α7nAChR)[2].

Pretreatment with 5 and 10 uM MLA inhibited the decreased cell viability induced by Aβ25-35, which suggested that MLA had a protective effect against Aβ-induced cytotoxicity. Furthermore, cell viability did not decrease after exposure to MLA (2.5, 5, 10, 20 uM), which suggests a good safety profile[1].Because of Methyllycaconitine citrate (MLA) is specific, concentration-dependent, reversible, and voltage-independent antagonism, it could inhibit acetylcholine- and anatoxin-induced whole-cell currents in cultured fetal rat hippocampal neurons[3].

When test the influence of Methyllycaconitine citrate on acute METH effects and neurotoxicity in mice, using both in vivo and in vitro models. MLA inhibited METH-induced climbing behavior by 50%. Acute effects after 30-min preincubation with 1μM METH also included a decrease in striatal synaptosome dopamine (DA) uptake, which was prevented by MLA. METH-induced neurotoxicity was assessed in vivo in terms of loss of striatal dopaminergic terminals (73%) and of tyrosine hydroxylase levels (by 90%) at 72 h post-treatment, which was significantly attenuated by MLA[4]. 50 nM Methyllycaconitine citrate partially inhibited (by 16%) [(3)H]dopamine release from rat striatal synaptosomes stimulated with 10 microM nicotine. Other alpha7-selective antagonists had no effect. Similarly, Methyllycaconitine citrate (50 nM) inhibited [(3)H]dopamine release evoked by the partial agonist (2-chloro-5-pyridyl)-9-azabicyclo[4.2.1]non-2-ene (UB-165) (0.2 microM) by 37%[5]. Methyllycaconitine citrate was administered to animals allowed to self-administer nicotine intravenously, and also to animals that had been prepared with nicotine-containing osmotic mini-pumps and trained on a brain stimulation reward procedure. The results indicated that pretreatment with the highest doses of MLA used (3.9 and 7.8 mg/kg) significantly reduced nicotine self-administration at two doses of self-administered nicotine (0.03 and 0.06 mg/kg/infusion) [6]. Vaccination altered methyllycaconitine toxicity in mice and that vaccination may be useful in decreasing the effects of larkspur toxins in animals[7].

References:
[1]. Zheng X, Xie Z, et,al. Methyllycaconitine alleviates amyloid-β peptides-induced cytotoxicity in SH-SY5Y cells. PLoS One. 2014 Oct 31;9(10):e111536. doi: 10.1371/journal.pone.0111536. PMID: 25360664; PMCID: PMC4216102.
[2]. Kalappa BI, Sun F, et,al. A positive allosteric modulator of α7 nAChRs augments neuroprotective effects of endogenous nicotinic agonists in cerebral ischaemia. Br J Pharmacol. 2013 Aug;169(8):1862-78. doi: 10.1111/bph.12247. PMID: 23713819; PMCID: PMC3753841.
[3]. Alkondon M, Pereira EF, et,al. Blockade of nicotinic currents in hippocampal neurons defines methyllycaconitine as a potent and specific receptor antagonist. Mol Pharmacol. 1992 Apr;41(4):802-8. PMID: 1569927.
[4]. Escubedo E, Chipana C, et,al. Methyllycaconitine prevents methamphetamine-induced effects in mouse striatum: involvement of alpha7 nicotinic receptors. J Pharmacol Exp Ther. 2005 Nov;315(2):658-67. doi: 10.1124/jpet.105.089748. Epub 2005 Aug 2. PMID: 16076935.
[5]. Mogg AJ, Whiteaker P, et,al.Methyllycaconitine is a potent antagonist of alpha-conotoxin-MII-sensitive presynaptic nicotinic acetylcholine receptors in rat striatum. J Pharmacol Exp Ther. 2002 Jul;302(1):197-204. doi: 10.1124/jpet.302.1.197. PMID: 12065717.
[6]. Markou A, Paterson NE. The nicotinic antagonist methyllycaconitine has differential effects on nicotine self-administration and nicotine withdrawal in the rat. Nicotine Tob Res. 2001 Nov;3(4):361-73. doi: 10.1080/14622200110073380. PMID: 11694204.
[7]. Lee ST, Stegelmeier BL,et,al. Evaluation of vaccination against methyllycaconitine toxicity in mice. J Anim Sci. 2003 Jan;81(1):232-8. doi: 10.2527/2003.811232x. PMID: 12597394.

Methyllycaconitine citrate (MLA),一种从飞燕草种子中分离出来的降二萜类生物碱。 Methyllycaconitine citrate (MLA) 是含 α7 的神经元烟碱乙酰胆碱受体 (α7nAChR) 的拮抗剂[2]

用 5 和 10 uM MLA 预处理可抑制 Aβ25-35 诱导的细胞活力降低,这表明 MLA 对 Aβ 诱导的细胞毒性具有保护作用。此外,细胞活力在接触 MLA(2.5、5、10、20 uM)后并未降低,这表明具有良好的安全性[1]。由于柠檬酸甲基乌头碱 (MLA) 具有特异性,因此浓度-依赖性、可逆性和电压非依赖性拮抗作用,可抑制培养的胎鼠海马神经元中乙酰胆碱和类毒素诱导的全细胞电流[3]

当使用体内和体外模型测试柠檬酸甲基乌头碱对小鼠急性 METH 效应和神经毒性的影响时。 MLA 将 METH 诱导的攀爬行为抑制了 50%。与 1μM METH 预孵育 30 分钟后的急性效应还包括纹状体突触体多巴胺 (DA) 摄取减少,这被 MLA 阻止了。在治疗后 72 小时,根据纹状体多巴胺能末端 (73%) 和酪氨酸羟化酶水平 (90%) 的损失在体内评估了 METH 诱导的神经毒性,这被 MLA 显着减弱[4]< /sup>。 50 nM Methyllycaconitine 柠檬酸盐部分抑制(16%)[(3)H] 多巴胺从用 10 microM 尼古丁刺激的大鼠纹状体突触体释放。其他 alpha7 选择性拮抗剂没有效果。同样,Methyllycaconitine citrate (50 nM) 可抑制部分激动剂 (2-chloro-5-pyridyl)-9-azabicyclo[4.2.1]non-2-ene (UB-165) 引起的 [(3)H] 多巴胺释放(0.2 microM) 37%[5]。将柠檬酸甲基乌头碱施用于允许自己静脉内施用尼古丁的动物,以及已经用含尼古丁渗透微型泵制备并接受脑刺激奖励程序训练的动物。结果表明,使用最高剂量的 MLA(3.9 和 7.8 mg/kg)进行预处理显着减少了两种自我给药尼古丁剂量(0.03 和 0.06 mg/kg/输注)的尼古丁自我给药[6] 。疫苗接种改变了甲基乌头碱对小鼠的毒性,疫苗接种可能有助于降低飞燕草毒素对动物的影响[7]

Chemical Properties

Cas No. 112825-05-5; 351344-10-0 SDF
别名 甲基牛扁亭柠檬酸盐; MLA
化学名 20-ethyl-1α,6β,14α,16β-tetramethoxy-4-[[[2-[(3S)-3-methyl-2,5-dioxo-1-pyrrolidinyl]benzoyl]oxy]methyl]-aconitane-7,8-diol, 2-hydroxy-1,2,3-propanetricarboxylate
Canonical SMILES CCN1C[C@]2(COC(C3=C(N4C(C[C@H](C)C4=O)=O)C=CC=C3)=O)CC[C@H](OC)[C@]56[C@]2([H])[C@H](OC)[C@]([C@@H]16)(O)[C@](C[C@H](OC)[C@@]([H])(C7)[C@@H]8OC)(O)[C@]8([H])[C@]57[H].OC(CC(O)=O)(C(O)=O)CC(O)=O
分子式 C37H50N2O10.C6H8O7 分子量 874.93
溶解度 Soluble in water to 100 mM 储存条件 Desiccate at -20°C
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Research Update

Dexmedetomidine suppresses serum syndecan-1 elevation and improves survival in a rat hemorrhagic shock model

Hemorrhagic shock causes vascular endothelial glycocalyx (EGCX) damage and systemic inflammation. Dexmedetomidine (DEX) has anti-inflammatory and EGCX-protective effects, but its effect on hemorrhagic shock has not been investigated. Therefore, we investigated whether DEX reduces inflammation and protects EGCX during hemorrhagic shock. Anesthetized Sprague-Dawley rats were randomly assigned to five groups (n=7 per group): no shock (SHAM), hemorrhagic shock (HS), hemorrhagic shock with DEX (HS+DEX), hemorrhagic shock with DEX and the α7 nicotinic type acetylcholine receptor antagonist methyllycaconitine citrate (HS+DEX/MLA), and hemorrhagic shock with MLA (HS+MLA). HS was induced by shedding blood to a mean blood pressure of 25-30 mmHg, which was maintained for 30 min, after which rats were resuscitated with Ringer's lactate solution at three times the bleeding volume. The survival rate was assessed up to 3 h after the start of fluid resuscitation. Serum tumor necrosis factor-alpha (TNF-α) and syndecan-1 concentrations, and wet-to-dry ratio of the heart were measured 90 min after the start of fluid resuscitation. The survival rate after 3 h was significantly higher in the HS+DEX group than in the HS group. Serum TNF-α and syndecan-1 concentrations, and the wet-to-dry ratio of heart were elevated by HS, but significantly decreased by DEX. These effects were antagonized by MLA. DEX suppressed the inflammatory response and serum syndecan-1 elevation, and prolonged survival in rats with HS.

Studies on the role of alpha 7 nicotinic acetylcholine receptors in K562 cell proliferation and signaling

The results we obtained from this study gave information about the determination of alpha 7 nicotinic acetylcholine receptor (α7-nACh) expression in human erythroleukemia cells, as well as whether it has a role in calcium release and cell proliferation in the presence of nicotinic agonist, antagonists. Determining the roles of α7 nicotinic receptors in erythroleukemia cells will also contribute to leukemia-related signal transduction studies. This study is primarily to determine the role of nicotinic agonists and antagonists in cell proliferation, α7 nicotinic acetylcholine receptor expression, and calcium release. The aim of this study, which is a continuation and an important part of our previous studies on the cholinergic system, has contributed to the literature on the human erythroleukemia cell signaling mechanism. Cell viability was evaluated by the trypan blue exclusion test and Bromodeoxyuridine/5-Bromo-2'-deoxyuridine (BrdU) labeling. Acetylcholine, nicotinic alpha 7 receptor antagonist methyllycaconitine citrate, and cholinergic antagonist atropine were used to determine the role of α7-nACh in K562 cell proliferation. In our experiments, the fluorescence spectrophotometer was used in Ca2+ measurements. The expression of nicotinic alpha 7 receptor was evaluated by western blot. The stimulating effect of acetylcholine in K562 cell proliferation was reversed by both the α7 nicotinic antagonist methyllycaconitine citrate and the cholinergic antagonist, atropine. Methyllycaconitine citrate inhibited K562 cell proliferation partially explained the roles of nicotinic receptors in signal transduction. While ACh caused an increase in intracellular Ca2+, methyllycaconitine citrate decreased intracellular Ca2+ level in K562 cell. The effects of nicotinic agonists and/or antagonists on erythroleukemic cells on proliferation, calcium level contributed to the interaction of nicotinic receptors with different signaling pathways. Proliferation mechanisms in erythroleukemic cells are under the control of the α7 nicotinic acetylcholine receptor via calcium influx and different signalling pathway.

Tropisetron attenuates cisplatin-induced nephrotoxicity in mice

Nephrotoxicity is one of the most important complications of cisplatin, a potent chemotherapeutic agent used in the treatment of various malignancies. 5-HT3 antagonists are widely used to counteract chemotherapy-induced emesis and new studies reveal that they poses notable anti-inflammatory properties. In current study, we investigated the effects of 5-HT3 antagonists on cisplatin induced nephrotoxicity in mice. To identify the underlying mechanism of renal protection by tropisetron, we investigated the probable involvement of alpha7 nicotinic acetylcholine receptor (α7nAChR). A single injection of cisplatin (20mg/kg; i.p) induced nephrotoxicity, 5-HT3 antagonists (tropisetron, granisetron and ondansetron,) were given twice daily for 3 day (3mg/kg; i.p). Finally animals were euthanized and blood sample was collected to measure urea and creatinin level. Also kidneys were removed for histopathological examination and biochemical measurements including glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD) activity, inducible nitric oxide synthase (iNOS) expression and inflammatory cytokines. Tropisetron decreased the expression of inflammatory molecules including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and iNOS and improved histopathological damage and renal dysfunction. However other 5-HT3 antagonists, granisetron or ondansetron do not have any elicit effects on biochemical markers and histological damages. Since methyllycaconitine, antagonist of α7nAChR, was unable to reverse the beneficial effect of tropisetron, we concluded that this effect of tropisetron is not mediated by α7nAChR.Our results showed that tropisetron treatment markedly ameliorated the experimental cisplatin induced-nephrotoxicity and this effect might be 5-HT3 receptor and α7nAChR independent.

Low-dose nicotine promotes autophagy of cardiomyocytes by upregulating HO-1 expression

Nicotine as a major component of addiction in cigarettes has been reported to play protective roles in some pathological processes. It is reported that activation of the nicotinic acetylcholine receptor also has a cardioprotective effect. Thus, in our study, we investigated the effect and mechanism of nicotine on the autophagy of cardiomyocytes, and whether nicotine protects cardiomyocytes against palmitic acid (PA) injury. The results indicated that low-dose nicotine promoted neonatal mouse cardiac myocytes (NMCMs) autophagy and accelerated autophagic flux while inhibiting NMCMs apoptosis, but high-dose nicotine inhibited autophagy and promoted apoptosis. Moreover, low-dose nicotine upregulated heme oxygenase-1 (HO-1) expression and knocking down HO-1 abolished the effects of nicotine on the autophagy and apoptosis of NMCMs. Methyllycaconitine citrate (α7-nAChR blocker, MLA) inhibited HO-1 expression and the effects of nicotine on autophagy and apoptosis of NMCMs. Furthermore, low-dose nicotine improved the inhibited autophagy and increased apoptosis induced by palmitic acid (PA) in NMCMs and these effects were reversed by knocking down HO-1. In conclusion, our data suggested that low-dose nicotine promoted autophagy and inhibited apoptosis of cardiomyocytes by upregulating HO-1.

Alpha7 Nicotinic Acetylcholine Receptor Antagonists Prevent Meningitic Escherichia coli-Induced Blood-Brain Barrier Disruptions by Targeting the CISH/JAK2/STAT5b Axis

Despite the availability of antibiotics over the last several decades, excessive antibiotic treatments for bacterial sepsis and meningitis (BSM) in children may result in several adverse outcomes. Hematogenous pathogens may directly induce permeability increases in human brain microvascular endothelial cells (HBMECs) and blood-brain barrier (BBB) dysfunctions. Our preliminary studies demonstrated that the alpha7 nicotinic acetylcholine receptor (α7nAChR) played an important role in the pathogenesis of BSM, accompanied by increasing cytokine-inducible SH2-containing protein (CISH) at the transcriptome level, but it has remained unclear how α7nAChR-CISH works mechanistically. The study aims to explore the underlying mechanism of α7nAChR and CISH during E. coli-induced BSM in vitro (HBMECs) and in vivo (α7nAChR-KO mouse). We found that in the stage of E. coli K1-induced BBB disruptions, α7nAChR functioned as the key regulator that affects the integrity of HBMECs by activating the JAK2-STAT5 signaling pathway, while CISH inhibited JAK2-STAT5 activation and exhibited protective effects against E. coli infection. Notably, we first validated that the expression of CISH could be regulated by α7nAChR in HBMECs. In addition, we determined the protective effects of MLA (methyllycaconitine citrate) and MEM (memantine hydrochloride) (functioning as α7nAChR antagonists) on infected HBMECs and suggested that the α7nAChR-CISH axis could explain the protective effects of the two small-molecule compounds on E. coli-induced HBMECs injuries and BBB disruptions. In conclusion, we dissected the α7nAChR/CISH/JAK2/STAT5 axis as critical for the pathogenesis of E. coli-induced brain microvascular leakage and BBB disruptions and provided novel evidence for the development of α7nAChR antagonists in the prevention of pediatric E. coli BSM.