1. 17 Oxo Sparteine and Lupanine, Obtained from Cytisus scoparius, Exert a Neuroprotection against Soluble Oligomers of Amyloid-β Toxicity by Nicotinic Acetylcholine Receptors
- Author
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Daniela Mennickent, Sergio Triviño, Gustavo Moraga-Cid, Claudia Pérez, Jorge Fuentealba, Luis G. Aguayo, Victoria P San Martín, José Becerra, Pamela A. Godoy, Gonzalo E. Yévenes, Patricio A. Castro, Oscar Ramirez-Molina, Javiera Gavilán, Tiare Silva-Grecchi, and Leonardo Guzmán
- Subjects
0301 basic medicine ,Sparteine ,Receptors, Nicotinic ,Pharmacology ,Hippocampus ,PC12 Cells ,Neuroprotection ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Calcium Signaling ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cytisus ,Acetylcholine receptor ,Neurons ,Amyloid beta-Peptides ,Chemistry ,General Neuroscience ,Neurotoxicity ,Long-term potentiation ,General Medicine ,medicine.disease ,Rats ,Mice, Inbred C57BL ,Oncogene Protein v-akt ,Psychiatry and Mental health ,Clinical Psychology ,Nicotinic acetylcholine receptor ,HEK293 Cells ,Neuroprotective Agents ,030104 developmental biology ,Nicotinic agonist ,Synapses ,Nerve Net ,Geriatrics and Gerontology ,030217 neurology & neurosurgery - 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- β oligomers (SO-Aβ). 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-Aβ toxicity. Our results showed that Lup and 17- ox (both at 0.03μM) prevented SO-Aβ-induced toxicity in PC12 cells (Lup: 64±7%; 17- ox: 57±6%). Similar results were seen in hippocampal neurons where these alkaloids prevented SO-Aβ 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 α-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-Aβ (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.
- Published
- 2019