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

J Alzheimers Dis. 2019;67(1):343-356. doi: 10.3233/JAD-180945.

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: 17– oxo-sparteine; Alzheimer’s disease; Lupanine; neuroprotection; nicotinic receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Calcium Signaling / drug effects
  • Cytisus / chemistry*
  • HEK293 Cells
  • Hippocampus / pathology
  • Humans
  • Mice, Inbred C57BL
  • Nerve Net / drug effects
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology*
  • Oncogene Protein v-akt / metabolism
  • PC12 Cells
  • Rats
  • Receptors, Nicotinic / drug effects*
  • Sparteine / analogs & derivatives*
  • Sparteine / chemistry
  • Sparteine / isolation & purification
  • Sparteine / pharmacology*
  • Synapses / drug effects

Substances

  • Amyloid beta-Peptides
  • Neuroprotective Agents
  • Receptors, Nicotinic
  • lupanine
  • Sparteine
  • Oncogene Protein v-akt