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

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-beta oligomers (SO-A beta). 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 beta toxicity. Our results showed that Lup and 17-ox (both at 0.03 mu M) prevented SO-A beta-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 beta 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 a-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 beta (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.