Lycaconitine

Kamaonensine A-G: Lycaconitine-type C(19)-diterpenoid alkaloids with anti-inflammatory activities from Delphinium kamaonense Huth.[Pubmed:37574118]

Phytochemistry. 2023 Nov;215:113822.

Delphinium kamaonense Huth is a sort of folkloric plant resource which is cultivated and planted with great ornamental and medicinal values. In this work, seven undescribed Lycaconitine-type C(19)-diterpenoid alkaloids, especially a rare skeleton with -CH=N and N-oxide moieties, along with ten known compounds, were isolated from D. kamaonense, of which the structures were determined by various spectroscopic data, combined with calculated electronic circular dichroism (ECD) and single-crystal X-ray diffraction analysis. In vitro nitric oxide inhibitory activities assay of these compounds indicated that Lycaconitine-type C(19)-diterpenoid alkaloids had significant anti-inflammatory inhibitory activities, with kamaonensine E being the most potent (0.9 +/- 0.2 muM) stronger than positive (9.0 +/- 1.3 muM). In the network pharmacology studies, binding three key targets mitogen-activated protein kinase 8 (MAPK8), mitogen-activated protein kinase 14 (MAPK14), and heat shock protein HSP 90-alpha (HSP90alpha), the anti-inflammatory mechanism might be related to MAPK signaling pathways. Furthermore, the molecular docking results revealed that the uncommon amides and methylenedioxy groups might be the most two promising pharmacophores for Lycaconitine-type C(19)-diterpenoid alkaloids.

Grandiflolines A-F, new anti-inflammatory diterpenoid alkaloids isolated from Delphinium grandiflorum.[Pubmed:36199660]

Front Chem. 2022 Sep 19;10:1012874.

Delphinium grandiflorum L. (family Ranunculaceae), one of the most important and widely distributed Delphinium species, has received considerable interest due to its extremely high medicinal value. The discovery of novel metabolites from D. grandiflorum supported and broadened its application as an herbal medicine. In this study, the whole herb of D. grandiflorum was phytochemically investigated to obtain fourteen C(19)-Lycaconitine-type diterpenoid alkaloids (1-14), including six undescribed alkaloids, grandiflolines A-F (1-6). The structural elucidation of them was accomplished by detailed spectroscopic analyses, mainly including HR-MS, 1D and 2D NMR ((1)H-(1)H COSY, NOESY, HMBC and HSQC), and IR spectra. New alkaloids 1-3 and 5 possess a characteristic big up tri, open(2,3) functional group in the A ring, while compounds 5 and 6 feature a rare OH-16 substituent. In addition, known compounds 7-12 were isolated from D. grandiflorum for the first time. Moreover, according to its medicinal use, new alkaloids 1-6 were estimated for their potential in vitro anti-inflammatory effects, and some of them exhibited inhibitory effects on NO production in LPS-activated RAW 264.7 macrophages. Our work enriched the chemical diversity of D. grandiflorum and the genus Delphinium and presented beneficial information for further investigations.

Ras Inhibitor Lonafarnib Rescues Structural and Functional Impairments of Synapses of Abeta(1-42) Mice via alpha7nAChR-Dependent BDNF Upregulation.[Pubmed:35760529]

J Neurosci. 2022 Aug 3;42(31):6090-6107.

Alzheimer's disease (AD) is characterized pathologically by the structural and functional impairments of synapses in the hippocampus, inducing the learning and memory deficiencies. Ras GTPase is closely related to the synaptic function and memory. This study was to investigate the effects of farnesyl transferase inhibitor lonafarnib on the synaptic structure and function in AD male mice and explore the potential mechanism. Our results showed 50 mg/kg lonafarnib (intraperitoneal) rescued the impaired spatial memory and improved the damaged synaptic transmission and plasticity of Abeta(1-42) mice. In addition, lonafarnib ameliorated the morphology of synaptic dendrites and spines in Abeta(1-42) mice. Furthermore, lonafarnib enhanced alpha7nAChR cell surface expression and phosphorylation of downstream Akt and CaMKII in Abeta(1-42) mice, which were inhibited by alpha7nAChR antagonist methyl Lycaconitine (MLA), and increased the phosphorylation of CREB in a CaMKII- but not ERK-dependent way. Lonafarnib enhanced hippocampal brain-derived neurotrophic factor (BDNF) concentration in Abeta(1-42) mice, which was sensitive to MLA and KN93 (an inhibitor of CaMKII), but not related to ERK and Akt pathways. H-Ras, but not Rhes, was related to the lonafarnib induced improvement of alpha7nAChR cell surface expression and BDNF content. Interestingly, lonafarnib induced improvement of synaptic transmission, plasticity and spatial cognition in Abeta(1-42) mice was abolished by BDNF deprivation with TrkB/Fc chimera protein. Our results indicate that lonafarnib can rescue the structural and functional impairments of synapses in the Abeta(1-42) mice, which may be related to the improvement of BDNF content through the H-Ras-alpha7nAChR-dependent CaMKII-CREB pathway, leading to the improvement of spatial cognition.SIGNIFICANCE STATEMENT Alzheimer's disease (AD) is characterized pathologically by the structural and functional impairments of synapses in the hippocampus, inducing the learning and memory deficiencies. However, no effective drugs have not been developed for the treatment of AD synaptic. This study for the first time reported the beneficial effects of Ras inhibitor lonafarnib on the synaptic structure and function in AD mice, providing an alternative way for the treatment of "synaptic disease" in AD patients.

Water-soluble variant of human Lynx1 positively modulates synaptic plasticity and ameliorates cognitive impairment associated with alpha7-nAChR dysfunction.[Pubmed:32222974]

J Neurochem. 2020 Oct;155(1):45-61.

Lynx1 is a GPI-tethered protein colocalized with nicotinic acetylcholine receptors (nAChRs) in the brain areas important for learning and memory. Previously, we demonstrated that at low micromolar concentrations the water-soluble Lynx1 variant lacking GPI-anchor (ws-Lynx1) acts on alpha7-nAChRs as a positive allosteric modulator. We hypothesized that ws-Lynx1 could be used for improvement of cognitive processes dependent on nAChRs. Here we showed that 2 microM ws-Lynx1 increased the acetylcholine-evoked current at alpha7-nAChRs in the rat primary visual cortex L1 interneurons. At higher concentrations ws-Lynx1 inhibits alpha7-nAChRs expressed in Xenopus laevis oocytes with IC(50) ~ 50 microM. In mice, ws-Lynx1 penetrated the blood-brain barrier upon intranasal administration and accumulated in the cortex, hippocampus, and cerebellum. Chronic ws-Lynx1 treatment prevented the olfactory memory and motor learning impairment induced by the alpha7-nAChRs inhibitor methylLycaconitine (MLA). Enhanced long-term potentiation and increased paired-pulse facilitation ratio were observed in the hippocampal slices incubated with ws-Lynx1 and in the slices from ws-Lynx1-treated mice. Long-term potentiation blockade observed in MLA-treated mice was abolished by ws-Lynx1 co-administration. To understand the mechanism of ws-Lynx1 action, we studied the interaction of ws-Lynx1 and MLA at alpha7-nAChRs, measured the basal concentrations of endogenous Lynx1 and the alpha7 nAChR subunit and their association in the mouse brain. Our findings suggest that endogenous Lynx1 limits alpha7-nAChRs activation in the adult brain. Ws-Lynx1 partially displaces Lynx1 causing positive modulation of alpha7-nAChRs and enhancement of synaptic plasticity. Ws-Lynx1 and similar compounds may constitute useful hits for treatment of cognitive deficits associated with the cholinergic system dysfunction.

Simvastatin Enhances Spatial Memory and Long-Term Potentiation in Hippocampal CA1 via Upregulation of alpha7 Nicotinic Acetylcholine Receptor.[Pubmed:26198568]

Mol Neurobiol. 2016 Aug;53(6):4060-4072.

Simvastatin (SV) has been reported to improve cognitive deficits in Alzheimer's disease. Here, we show that chronic administration of SV (20 mg/kg) for 30 days in adult mice (SV mice) enhanced spatial cognitive performance as assessed by Morris water maze and Y-maze. To explore mechanisms underlying SV-enhanced spatial cognition, we further examined synaptic properties and long-term potentiation (LTP) in hippocampal CA1, hippocampal alpha7nAChR expression, and Akt and ERK2 phosphorylation. In comparison with controls, the SV administration caused increase in presynaptic glutamate release and amplitude of NMDAr-dependent LTP (LTP-augmentation), and decrease in threshold of NMDAr-independent LTP induction (LTP-facilitation). The supplement of isoprenoid farnesyl pyrophosphate (FPP) by applying farnesol (FOH) could abolish the spatial cognitive potentiation, increased glutamate release, and LTP-augmentation/facilitation in SV mice. Expression of alpha7nAChR, but not alpha4beta2nAChR, was increased in hippocampal pyramidal cells of SV mice with the reduction of transcription factor AP-2alpha, which were abolished by FOH. Levels of Akt and ERK2 phosphorylation in SV mice were elevated, which were suppressed by FOH or alpha7nAChR antagonist methyl-Lycaconitine (MLA). In hippocampal slices obtained from SV mice, acute perfusion of MLA blocked the increased glutamate release, whereas FOH, PI3K inhibitor LY294002, or MEK inhibitor U0126 could not. In the slices of SV mice, the perfusion of MLA or U0126, but not FOH, abolished the LTP-augmentation and LTP-facilitation. By contrast, LY294002 prevented the LTP-facilitation but failed to affect the LTP-augmentation. The findings indicate that the administration of SV through reducing FPP increases alpha7nAChR expression and alpha7nAChR-related Akt and ERK2 phosphorylation, leading to LTP enhancement and spatial cognitive potentiation.

Characterization of RO5126946, a Novel alpha7 nicotinic acetylcholine receptor-positive allosteric modulator.[Pubmed:24917542]

J Pharmacol Exp Ther. 2014 Aug;350(2):455-68.

Both preclinical evidence and clinical evidence suggest that alpha7 nicotinic acetylcholine receptor activation (alpha7nAChR) improves cognitive function, the decline of which is associated with conditions such as Alzheimer's disease and schizophrenia. Moreover, allosteric modulation of alpha7nAChR is an emerging therapeutic strategy in an attempt to avoid the rapid desensitization properties associated with the alpha7nAChR after orthosteric activation. We used a calcium assay to screen for positive allosteric modulators (PAMs) of alpha7nAChR and report on the pharmacologic characterization of the novel compound RO5126946 (5-chloro-N-[(1S,3R)-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamide), which allosterically modulates alpha7nAChR activity. RO5126946 increased acetylcholine-evoked peak current and delayed current decay but did not affect the recovery of alpha7nAChRs from desensitization. In addition, RO5126946's effects were absent when nicotine-evoked currents were completely blocked by coapplication of the alpha7nAChR-selective antagonist methyl-Lycaconitine. RO5126946 enhanced alpha7nAChR synaptic transmission and positively modulated GABAergic responses. The absence of RO5126946 effects at human alpha4beta2nAChR and 5-hydroxytryptamine 3 receptors, among others, indicated selectivity for alpha7nAChRs. In vivo, RO5126946 is orally bioavailable and brain-penetrant and improves associative learning in a scopolamine-induced deficit model of fear conditioning in rats. In addition, procognitive effects of RO5126946 were investigated in the presence of nicotine to address potential pharmacologic interactions on behavior. RO5126946 potentiated nicotine's effects on fear memory when both compounds were administered at subthreshold doses and did not interfere with procognitive effects observed when both compounds were administered at effective doses. Overall, RO5126946 is a novel alpha7nAChR PAM with cognitive-enhancing properties.

Neuronal stimulation with 5-hydroxytryptamine 4 receptor induces anti-inflammatory actions via alpha7nACh receptors on muscularis macrophages associated with postoperative ileus.[Pubmed:21115544]

Gut. 2011 May;60(5):638-47.

BACKGROUND: The main symptom of postoperative ileus (POI) is an intestinal motility disorder in which monocytes/macrophages and neutrophils play crucial roles. Prokinetic 5-hydroxytryptamine 4 receptor (5-HT(4)R) agonists and dopamine receptor antagonists are potential therapeutic agents for directly ameliorating the motility disorder associated with POI. AIM: To determine the effects of the 5-HT(4)R agonists mosapride citrate (MOS) and CJ-033466 on intestinal smooth muscle contractility relative to immune reactions after POI. METHODS: Intestinal manipulation (IM) was applied to the rat distal ileum. Both MOS (0.3 and 1 mg/kg, s.c.) and CJ-033466 (1 mg/kg, s.c.) were administered to the animals before and after IM. At 24 h after IM, isolated intestinal smooth muscle contractile activity in vitro, gastrointestinal transit in vivo, inflammatory mediator expression and leucocyte infiltration were measured. RESULTS: After IM, ileal circular muscle contractility in vitro and gastrointestinal transit in vivo were reduced and the number of macrophages and neutrophils increased in the inflamed muscle layer, resulting in the induction of inflammatory mediators such as interleukin 1 beta (IL-1beta), IL-6, tumour necrosis factor alpha (TNFalpha), monocyte chemoattractant protein 1 (MCP-1) and inducible nitric oxide synthase (iNOS). Both MOS and CJ-033466 significantly attenuated not only the intestinal motility dysfunction but also the leucocyte infiltration and inflammatory mediator expression after IM. The autonomic ganglionic blocker hexamethonium (1 mg/kg, i.p.) and the alpha7-nicotinic acetylcholine receptor (alpha7nAChR) antagonist methyl Lycaconitine citrate (0.087 mg/kg, i.p.) blocked MOS-mediated ameliorative actions. Immunohistochemically, alpha7nAChR is expressed by monocytes/macrophages but not by neutrophils in the inflamed intestine. CONCLUSION: Stimulating the 5-HT(4)R accelerates acetyl choline (ACh) release from cholinergic myenteric neurons, which subsequently activates alpha7nAChR on activated monocytes/macrophages to inhibit their inflammatory reactions in the muscle layer. In addition to their gastroprokinetic action, 5-HT(4)R agonists might serve as novel therapeutic agents for POI characterised by anti-inflammatory potency.

Kynurenic acid blocks nicotinic synaptic transmission to hippocampal interneurons in young rats.[Pubmed:17459105]

Eur J Neurosci. 2007 May;25(9):2656-65.

The tryptophan metabolite kynurenic acid can block glutamate at ionotropic receptors, but recent evidence suggests a more potent antagonistic action at alpha7 nicotinic receptors for acetylcholine on cultured neurons. The present study examines activity of kynurenic acid at those nicotinic receptors, which mediate cholinergic neurotransmission onto interneurons in the rat hippocampus. Intracellular recordings were made from pyramidal cells and interneurons in the presence of atropine, bicuculline methobromide, (3-aminopropyl)(diethoxymethyl)-phosphinic acid [CGP35348, to block gamma-aminobutyric acid (GABA)(B) receptors] and 3-tropanyl-3,5-dichlorobenzoate (MDL 72222, to block 5-HT3 receptors). In the added presence of glutamate antagonists 2-amino-5-phosphono-pentanoic acid and 6-cyano-7-nitroquinoxaline-2,3-dione, interneurons exhibited a residual excitatory postsynaptic potential (EPSP) that could be blocked by the nicotinic alpha7 receptor blocker methyl-Lycaconitine, but not by dihydro-beta-erythroidine which blocks alpha4beta2 receptors. Kynurenic acid reduced the amplitude of these EPSPs with an EC50 of 136 microM. The amplitudes of nicotinic spontaneous miniature EPSPs were also reduced by methyl-Lycaconitine and kynurenic acid. The results show that kynurenic acid is more potent in blocking nicotinic EPSPs compared with the full, glutamate-mediated EPSPs, but it was substantially less potent than has been reported in cultures, possibly because of differences in the accessibility of synaptic and extrasynaptic receptors. It is suggested that blockade of nicotinic synaptic transmission may be relevant to the actions of kynurenic acid in the hippocampus, but that in the intact brain this activity is likely to be comparable in importance to the blockade of glutamate-mediated transmission.

Nicotinic receptor-mediated enhancement of long-term potentiation involves activation of metabotropic glutamate receptors and ryanodine-sensitive calcium stores in the dentate gyrus.[Pubmed:17156372]

Eur J Neurosci. 2006 Dec;24(11):3109-18.

Little is known about the mechanisms underlying the enhancement of long-term potentiation (LTP) by nicotine. In the present study, the mechanisms of nicotinic enhancement of LTP were investigated in the rat dentate gyrus in vitro. Acute application of nicotine enhanced LTP induction, an action requiring activation of alpha7 nicotinic acetylcholine receptors (nAChRs), as it was blocked by the nAChR antagonist methyl-Lycaconitine, mimicked by the acetylcholine receptor agonist choline and absent in mutant mice null for alpha7 nAChR. Nicotinic enhancement of LTP was both dependent on N-methyl-D-aspartate receptor activation, as no LTP was induced in the presence of nicotine and an N-methyl-D-aspartate receptor antagonist, and expressed post-synaptically, as no change in paired-pulse ratio accompanied nicotinic enhancement of LTP. The nicotinic-enhanced component of LTP, unlike control LTP, was dependent on activation of metabotropic glutamate receptors (mGluRs), being inhibited by the group I/II antagonist LY341495 and the mGluR5 antagonist MPEP, and also dependent on influx of Ca via L-type Ca channels and release from ryanodine (RyR)-sensitive intracellular stores, being prevented by nifedipine and RyR, respectively. It is suggested that nicotinic activation of the Ca-permeable alpha7 nAChRs fills RyR Ca stores and release of Ca from such stores by high-frequency stimulation via Ca-induced Ca release and activation of mGluRs induces an additional component of LTP which summates with control LTP. Chronic application of nicotine in vivo also enhanced LTP induction in slices and was dependent on activation of mGluRs and Ca release from RyR-sensitive intracellular stores, although acutely applied nicotine was not required for such enhanced LTP.

A case of fatal poisoning with the aconite plant: quantitative analysis in biological fluid.[Pubmed:12407981]

Sci Justice. 2002 Apr-Jun;42(2):111-5.

In recent years recorded cases of plant poisoning have become rare, this may in part be due to the possibility of plant ingestion not being indicated at the beginning of an investigation. Aconitum napellus (aconite, Wolfsbane, Monkshood) is one of the most poisonous plants in the UK. It contains various potent alkaloids such as aconitine, isoaconitine, Lycaconitine and napelline. Ingestion of Aconitum plant extracts can result in severe, potentially fatal toxic effects. This paper describes the analytical findings in a recent death in the UK. resulting from deliberate ingestion of Aconitum napellus extract. The concentrations of aconitine measured by HPLC-DAD in the post mortem femoral blood and urine were 10.8 micrograms/L and 264 micrograms/L, respectively. The aconitine concentration in the ante mortem urine was 334 micrograms/L and was estimated to be 6 micrograms/L in the ante mortem serum. Hence, accidental, suicidal or homicidal poisoning due to the ingestion of plant material remains a possibility and should be borne in mind when investigating sudden or unexplained death.

Norditerpenoid alkaloids from the roots of Aconitum leave Royle.[Pubmed:12116884]

Pharmazie. 2002 Jun;57(6):427-9.

From the roots of Aconitum leave Royle growing wild in Northern Pakistan, Swat district, three new alkaloids, 8-methylLycaconitine (1), 14-demethylLycaconitine (2), N-deethylLycaconitine-N-aldehyde (3) have been isolated along with four known compounds, lappaconitine (4), Lycaconitine (5), lapaconidine (6) and lycoctonine (7).

Isolation of a multidrug resistance inhibitor from Aconitum pseudo-laeve var. erectum.[Pubmed:9875455]

Arch Pharm Res. 1998 Jun;21(3):344-7.

To overcome multidrug resistance (MDR) in cancer chemotherapy, we prepared various plant extracts and searched for a component which is effective for inhibition of MDR. MDR inhibition activity was determined by measuring cytotoxicity to MDR cells using multidrug resistant human fibrocarcinoma KB V20C, which is resistant to 20 nM vincristine and expresses high level of mdr1 gene. Of various plant extracts, the MeOH extract of the root of Aconitum pseudo-laeve var. erectum was found to have potent inhibitory activity on MDR. The bioassay-guided fractionation of the MeOH extract of the plant led to the isolation of an alkaloid, Lycaconitine, as an active principle. And the IC50 of Lycaconitine for KB V20C cells was 74 micrograms/ml.

Lycaconitine revisited: partial synthesis and neuronal nicotinic acetylcholine receptor affinities.[Pubmed:8759171]

J Nat Prod. 1996 Jul;59(7):707-9.

The norditerpenoid alkaloid Lycaconitine (2) was synthesized from lycoctonine (3) and its affinity determined for two neuronal nicotinic acetylcholine receptor subtypes. The structure of 2 was confirmed by a combination of spectroscopic methods.

Methyl lycaconitine: A novel nicotinic antagonist.[Pubmed:19912865]

Mol Cell Neurosci. 1992 Jun;3(3):237-43.

MethylLycaconitine (MLA), a natural toxin from Delphinium seeds, was investigated for its ability to antagonize nicotinic responses in several preparations representing different subtypes of neuronal nicotinic acetylcholine receptor. A presynaptic nicotinic receptor mediating dopamine release from rat striatal synaptosomes was blocked by 10 muM MLA, in good agreement with its Ki of 4 muM for inhibition of [(3)H]nicotine binding to striatal membranes. Nicotinic responses in rat superior cervical ganglia were similarly blocked by MLA, and this inhibition was readily reversible. Functional expression of the chick alpha3nalpha1 and alpha4nalpha1 receptor subtypes in Xenopus oocytes confirmed that MLA is a nicotinic antagonist at both receptor subtypes, with IC(50) values of 0.08 and 0.65 muM, respectively. Inhibition by MLA was voltage independent and competitive with agonist concentration. Thus MLA is a useful addition to the nicotinic pharmacopoeia.

Alkaloids of Aconitum barbatum.[Pubmed:17405023]

Planta Med. 1983 Oct;49(10):85-9.

Nine diterpenoid alkaloids were isolated from the roots of ACONITUM BARBATUM VAR. PUBERULUM. Five of them are known: ranaconitine ( 1) [1], lappaconitine ( 2) [2], septentriodine ( 3) [3], septentrionine ( 4) [3], and Lycaconitine ( 5) [4]. The other four are new: puberanine ( 6), puberanidine ( 7), puberaconitine ( 8) and puberaconitidine ( 9).