Modulation of neuronal nicotinic receptor by quinolizidine alkaloids causes neuroprotection on a cellular Alzheimer model.
Alzheimer's disease (AD) is a progressive and neurodegenerative disorder and one of the current therapies involves strengthening the cholinergic tone in central synapses. Neuroprotective properties for nicotine have been described in AD, through its actions on nicotinic receptors and the further activation of the PI3K/Akt/Bcl-2 survival pathway. We have tested a quinolizidine alkaloid extract (TM0112) obtained from Teline monspessulanna (L.) K. Koch seeds to evaluate its action on nicotinic acetylcholine receptor (nAChR) in a neuronal AD model. Our data show that PC-12 cells pretreated with amyloid-β (Aβ) peptide for 24 h in presence of TM0112 modified Aβ-reduction on cellular viability (Aβ = 80 ± 3%; +TM0112 = 113 ± 4%, n = 15). In addition, this effect was blocked with atropine, MLA, and α-BTX (+TM0112+atropine = 87 ± 4%; +TM0112+MLA = 86 ± 4%; +TM0112+α-BTX = 92 ± 3%). Furthermore, similar protective effects were observed in rat cortical neurons (Aβ = 63 ± 6%; +TM0112 = 114 ± 8%), but not in HEK293T cells (Aβ = 61.4 ± 6.1%; +TM0112 = 62.8 ± 5.2) that do not express α7 nAChR. Moreover, the frequency of synaptic activity in the neuronal network (Aβ = 51.6 ± 16.9%; +TM0112 = 210.8 ± 47.9%, n > 10), as well as the intracellular Ca2+ transients were recovered by TM0112 (Aβ = 61.4 ± 6.9%; +TM0112 = 112.0 ± 5.7%; n = 3) in rat hippocampal neurons. TM0112 increased P-Akt, up to 250% with respect to control, and elevated Bcl-2/Bax percentage (Aβ = 61.0 ± 8.2%; +TM0112 = 105.4 ± 19.5%, n = 4), suggesting a coupling between nAChR activation and an intracellular neuroprotective pathway. Our results suggest that TM0112 could be a new potential source for anti-AD drugs.
Laboratorio de Screening de Compuestos Neuroactivos, Departamento de Fisiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile.
Juan A
JA
Araya
Laboratorio de Screening de Compuestos Neuroactivos, Departamento de Fisiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile.
Alejandra E
AE
Ramírez
Laboratorio de Screening de Compuestos Neuroactivos, Departamento de Fisiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile.
Daniela
D
Figueroa-Aroca
Laboratorio de Química de Productos Naturales, Departamento de Botánica, Facultad de Ciencias Naturales y Oceanográficas, Universidad de Concepción, Concepción, Chile.
Gastón J
GJ
Sotes
Laboratorio de Química de Productos Naturales, Departamento de Botánica, Facultad de Ciencias Naturales y Oceanográficas, Universidad de Concepción, Concepción, Chile.
Claudia
C
Pérez
Laboratorio de Química de Productos Naturales, Departamento de Botánica, Facultad de Ciencias Naturales y Oceanográficas, Universidad de Concepción, Concepción, Chile.
Jose
J
Becerra
Laboratorio de Screening de Compuestos Neuroactivos, Departamento de Fisiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile.
Francisco
F
Saez-Orellana
Laboratorio de Neurobiología Molecular, Departamento de Fisiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile.
Leonardo
L
Guzmán
Laboratorio de Neurofisiología, Departamento de Fisiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile.
Luis G
LG
Aguayo
Laboratorio de Screening de Compuestos Neuroactivos, Departamento de Fisiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile.
Jorge
J
Fuentealba
D000470:Alkaloids / Q000494:pharmacology*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D007887:Fabaceae; D057809:HEK293 Cells; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000633:toxicity; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology; D054837:Quinolizidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012639:Seeds; D009435:Synaptic Transmission / Q000187:drug effects
D000470:Alkaloids; D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010936:Plant Extracts; D054837:Quinolizidines; D011978:Receptors, Nicotinic; C078592:amyloid beta-protein (1-40)
Alkaloids; Alzheimer's disease; Teline monspessulana; neuroprotection; nicotinic receptor