methyllycaconitine citrate salt hydrate/methyllycaconitine/methyllycaconitine citrate/methyllycaconitine citrate (mla)
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Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disorder. As the most common form of dementia, it affects more than 35 million people worldwide and is increasing. Excessive extracellular deposition of amyloid-β peptide (Aβ) is a pathologic feature of AD. Accumulating evidence indicates that macroautophagy is involved in the pathogenesis of AD, but its exact role is still unclear. Although major findings on the molecular mechanisms have been reported, there are still no effective treatments to prevent, halt, or reverse Alzheimer’s disease. In this study, we investigated whether Aβ25-35 could trigger an autophagy process and inhibit the growth of SH-SY5Y cells. Furthermore, we examined the effect of methyllycaconitine (MLA) on the cytotoxity of Aβ25-35. MLA had a protective effect against cytotoxity of Aβ, which may be related to its inhibition of Aβ-induced autophagy and the involvement of the mammalian target of rapamycin pathway. Moreover, MLA had a good safety profile. MLA treatment may be a promising therapeutic tool for AD
Methyllycaconitine alleviates amyloid-β peptides-induced cytotoxicity in SH-SY5Y cells.
Zheng X1, Xie Z1, Zhu Z1, Liu Z1, Wang Y1, Wei L1, Yang H1, Yang H1, Liu Y1, Bi J2.
2014 Oct 3
There is a growing body of evidence pointing to the pivotal role of alpha-7 nicotinic acetylcholine receptor (α7 nAchR) dysfunction in cognitive disorders such as Alzheimer’s disease or schizophrenia. This study was undertaken to establish and characterize an in vivo model for cognitive disorder secondary to the blockade of α7 nAChR by its specific antagonist, methyllycaconitine (MLA). The results show that MLA elicited cognitive dysfunction as assessed by reduced spontaneous alternation of mice in the T-maze. The maximal effect of MLA produced 25-30% reduction in the spontaneous alternation of mice, a level comparable with that induced by the muscarinic antagonism of scopolamine. Donepezil and galantamine fully reversed both MLA and scopolamine-induced cognitive dysfunction. However, the ED50 of donepezil and galantamine was significantly shifted to the left in the MLA- compared to scopolamine-treated mice (0.0005 and 0.002 mg/kg for donepezil; 0.0003 and 0.7 mg/kg for galantamine). Moreover, memantine elicited marked reversion of cognitive dysfunction (up to 70%) in MLA-treated mice while only a weak reversal effect at high dose of memantine (less than 20%) was observed in scopolamine-treated mice. The above findings indicate that MLA-induced cognitive dysfunction in the mouse is highly sensitive and more responsive to the current procognitive drugs than the traditional scopolamine-based assay. Thus, it can be of value for the preclinical screening and profiling of cognition-enhancing drugs.
Alzheimer’s disease; cognitive disorders; donepezil; galantamine; memantine; muscarinic receptors; nicotinic
Methyllycaconitine- and scopolamine-induced cognitive dysfunction: differential reversal effect by cognition-enhancing drugs.
Andriambeloson E1, Huyard B1, Poiraud E1, Wagner S1.
The family of nicotinic acetylcholine receptors contains numerous subtypes. Since the subunit compositions of most native neuronal nicotinic receptors are unknown, an important method for distinguishing subtypes of functional neuronal receptors is based on pharmacological criteria, such as affinity for snake toxins. We have now examined the affinities of native chick nicotinic receptors for methyllycaconitine, a toxin purified from Delphinium. We find that methyllycaconitine is a potent antagonist at central nicotinic receptors located on Edinger-Westphal neurons, producing nearly complete functional blockade of nicotinic responses at 10 nM. In marked contrast, methyllycaconitine is 1000-fold less potent at blocking nicotinic responses in the lateral spiriform nucleus. Methyllycaconitine inhibits kappa-bungarotoxin-sensitive nicotinic receptors in ciliary ganglia at 0.5-1.0 microM. Radioligand binding studies also reveal heterogeneity in the affinity of the toxin for nicotinic receptors. Methyllycaconitine binds most avidly to [125I] alpha-bungarotoxin sites in brain (Ki = 5.4 nM), and is 200-fold less potent at muscle nicotinic receptors (IC50 = 1.1 microM). The least potent binding of the toxin is to [3H]nicotine sites in brain (Ki = 3.7 microM). Methyllycaconitine is thus a useful pharmacological tool for distinguishing certain subtypes of native nicotinic receptors. The relatively low affinity of the toxin for nicotinic receptors in the lateral spiriform nucleus is consistent with the known properties of these receptors, which include a high affinity for [3H]nicotine and a lack of sensitivity to alpha- and kappa-bungarotoxin. On the basis of high affinity for methyllycaconitine and insensitivity to alpha-bungarotoxin, the nicotinic receptors in the Edinger-Westphal nucleus are unlike any previously described nicotinic receptor subtype.
Nicotinic acetylcholine receptors in separate brain regions exhibit different affinities for methyllycaconitine.
Yum L1, Wolf KM, Chiappinelli VA.