17 Oxo Sparteine and Lupanine, Obtained from Cytisus scoparius, Exert a Neuroprotection against Soluble Oligomers of Amyloid-β Toxicity by Nicotinic Acetylcholine Receptors

Abstract

Alzheimer's disease (AD) is a neurodegenerative pathology, which is characterized by progressive and irreversible cognitive impairment. Most of the neuronal perturbations described in AD can be associated with soluble amyloid-␤ oligomers (SO-A␤). There is a large amount of evidence demonstrating the neuroprotective effect of Nicotine neurotransmission in AD, mainly through nicotinic acetylcholine receptor (nAChR) activation and antiapoptotic PI3K/Akt/Bcl-2 pathway signaling. Using HPLC and GC/MS, we isolated and characterized two alkaloids obtained from C. scoparius, Lupanine (Lup), and 17-oxo-sparteine (17-ox), and examined their neuroprotective properties in a cellular model of SO-A␤ toxicity. Our results showed that Lup and 17-ox (both at 0.03 M) prevented SO-A␤-induced toxicity in PC12 cells (Lup: 64 ± 7%; 17-ox: 57 ± 6%). Similar results were seen in hippocampal neurons where these alkaloids prevented SO-A␤ neurotoxicity (Lup: 57 ± 2%; 17-ox: 52 ± 3%) and increased the frequency of spontaneous calcium transients (Lup: 60 ± 4%; 17-Ox: 40 ± 3%), suggesting an enhancing effect on neural network activity and synaptic activity potentiation. All of the neuroprotective effects elicited by both alkaloids were completely blocked by ␣-bungarotoxin. Additionally, we observed that the presence of both Lup and 17-ox increased Akt phosphorylation levels (52 ± 4% and 35 ± 7%, respectively) in cells treated with SO-A␤ (3 h). Taken together, our results suggest that the activation of nAChR by Lup and 17-ox induces neuroprotection in different cellular models, and appears to be an interesting target for the development of new pharmacological tools and strategies against AD.

Neuroprotective Properties of Eudesmin on a Cellular Model of Amyloid-β Peptide Toxicity

“…4B). A␤Os treatments reduced the spikes frequency approximately 30% (A␤: 71.8 ± 4.54% of the control), in accordance with our previous work [19,46,47]. Co-incubation with Eu leads to the preservation of calcium transient's frequencies on neurons.…”

Quinolizidine-Type Alkaloids: Chemodiversity, Occurrence, and Bioactivity

“…Regarding sparteine-type alkaloids ( 110 – 130 ), Lupinus plants produce and accumulate this QA type in seeds and leaves 112 and other genera such as Acosmium , Lygos , and Houttuynia (Saururaceae) ( Table 2 ). Additionally, this QA type has also been isolated from seeds, leaves, flowers, and aerial parts of species belonging to the genera Cytisus , 113 Ormosia , 114 Ulex , 115 Genista , 116 Lupinus , 25 and Sophora , 117 which contain structurally related sparteine-type compounds.…”

New Analytical Approach to Quinolizidine Alkaloids and Their Assumed Biosynthesis Pathways in Lupin Seeds

“…Another important motivation for this effort is the desired biological activity that QAs have demonstrated in multiple studies [ 35 ]. Many QAs show beneficial and desired qualities such as antioxidant, antimicrobial, anti-carcinogenic, and anti-inflammatory activities [ 23 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ]. However, several individual alkaloids, especially sparteine, anagyrine, and cysteine, have undesired or even toxic activity, thus their concentrations in edible lupins must be strongly regulated [ 4 , 47 ].…”