Methyllycaconitine citrate (Synonyms: MLA)

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.