Modulation of Neuronal Nicotinic Receptor by Quinolizidine Alkaloids Causes Neuroprotection on a Cellular Alzheimer Model

Abstract

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.

Melatonin regulates the autophagic flux via activation of alpha‐7 nicotinic acetylcholine receptors

“…Some reports have suggested that activating α 7nAChR may regulate the brain cholinergic signaling and lead to the enhancement of cognition in Alzheimer's disease models . Nicotine, α 7nAChR agonist, protects neurons from synaptic damage induced by A β oligomers through the upregulation of α 7nAChR/phosphatidylinositol‐3‐kinase (PI3K) signaling pathway . Specific α 7nAChR agonist (A‐582941 and ABT‐107) prevents neurotoxicity induced by A β and 6‐hydroxydopamine (6‐OHDA, Parkinsonism inducer), respectively .…”

Monoacylglycerol lipase inhibitor protects primary cultured neurons against homocysteine-induced impairments in rat caudate nucleus through COX-2 signaling

“…The Bcl-2 protein family is endowed with an anti-apoptotic effect, which is involved in the progression of AD [1]. To verify whether inhibition of MAGL activity could prevent the CN neurons by means of elevating the level of the anti-apoptotic protein p-Bcl-2 reduced by Hcy, we directly add URB602 to the CN neurons.…”

Cannabinoid CB2 Receptor Mediates Nicotine-Induced Anti-Inflammation in N9 Microglial Cells Exposed toβAmyloid via Protein Kinase C

“…Nicotine is a main constituent of tobacco, which induces neuroprotection against A β both in vivo and in vitro [ 9 , 10 ]. In addition, some studies showed that nicotine attenuates A β -induced microglial activation [ 11 , 12 ].…”