Methyllycaconitine citrate

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]。}