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

Article type: Research Article

Authors: Gavilan, Javiera^a | Mennickent, Daniela^a | Ramirez-Molina, Oscar^a | Triviño, Sergio^d | Perez, Claudia^d | Silva-Grecchi, Tiare^a | Godoy, Pamela A.^a | Becerra, Jose^d | Aguayo, Luis G.^b | Moraga-Cid, Gustavo^b | Martin, Victoria San^b | Yevenes, Gonzalo E.^b | Castro, Patricio A.^b | Guzman, Leonardo^b | Fuentealba, Jorge^{a; c; *}

Affiliations: [a] Laboratorio de Screening de Compuestos Neuroactivos, Universidad de Concepción, Chile | [b] Departamento de Fisiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Chile | [c] Centro de Investigaciones Avanzadas en Biomedicina-U. de Concepcion (CIAB UdeC), Chile | [d] Departamento de Botánica, Laboratorio de Química de Productos Naturales, Universidad de Concepción, Chile

Correspondence: [*] Correspondence to: Jorge Fuentealba, PhD, Laboratory of Neuroactive Compound Screening, Faculty of Biological Sciences, Physiology Department, PO Box 160-C, University of Concepción, Barrio Universitario s/n, Concepción, Chile. Tel.: +56 41 2661082; Fax: +56 41 2204557; E-mail: [email protected].

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.

Keywords: Alzheimer’s disease, 17– oxo-sparteine, Lupanine, neuroprotection, nicotinic receptor

DOI: 10.3233/JAD-180945

Journal: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 343-356, 2019