An electrophysiological characterization of naturally occurring tobacco alkaloids and their action on human α4β2 and α7 nicotinic acetylcholine receptors
“…Electrophysiological studies showed weak or no agonistic effect of COT on α4β2 nAChRs [ 68 , 74 ]. However, a previous study performed on monkeys showed that COT interacted with α4β2 subtype of nAChRs and stimulated the dopamine release from caudate synaptosomes [ 75 ].…”
The nicotinic derivatives, cotinine (COT), and 6-hydroxy-L-nicotine (6HLN), showed promising cognitive-improving effects without exhibiting the nicotine’s side-effects. Here, we investigated the impact of COT and 6HLN on memory impairment and the oxidative stress in the Aβ25-35-induced rat model of Alzheimer’s disease (AD). COT and 6HLN were chronically administered to Aβ25-35-treated rats, and their memory performances were assessed using in vivo tasks (Y-maze, novel object recognition, and radial arm maze). By using in silico tools, we attempted to associate the behavioral outcomes with the calculated binding potential of these nicotinic compounds in the allosteric sites of α7 and α4β2 subtypes of the nicotinic acetylcholine receptors (nAChRs). The oxidative status and acetylcholinesterase (AChE) activity were determined from the hippocampal tissues. RT-qPCR assessed bdnf, arc, and il-1β mRNA levels. Our data revealed that COT and 6HLN could bind to α7 and α4β2 nAChRs with similar or even higher affinity than nicotine. Consequently, the treatment exhibited a pro-cognitive, antioxidant, and anti-AChE profile in the Aβ25-35-induced rat model of AD. Finally, RT-qPCR analysis revealed that COT and 6HLN positively modulated the bdnf, arc, and il-1β genes expression. Therefore, these nicotinic derivatives that act on the cholinergic system might represent a promising choice to ameliorate AD conditions.
“…Electrophysiological studies showed weak or no agonistic effect of COT on α4β2 nAChRs [ 68 , 74 ]. However, a previous study performed on monkeys showed that COT interacted with α4β2 subtype of nAChRs and stimulated the dopamine release from caudate synaptosomes [ 75 ].…”
The nicotinic derivatives, cotinine (COT), and 6-hydroxy-L-nicotine (6HLN), showed promising cognitive-improving effects without exhibiting the nicotine’s side-effects. Here, we investigated the impact of COT and 6HLN on memory impairment and the oxidative stress in the Aβ25-35-induced rat model of Alzheimer’s disease (AD). COT and 6HLN were chronically administered to Aβ25-35-treated rats, and their memory performances were assessed using in vivo tasks (Y-maze, novel object recognition, and radial arm maze). By using in silico tools, we attempted to associate the behavioral outcomes with the calculated binding potential of these nicotinic compounds in the allosteric sites of α7 and α4β2 subtypes of the nicotinic acetylcholine receptors (nAChRs). The oxidative status and acetylcholinesterase (AChE) activity were determined from the hippocampal tissues. RT-qPCR assessed bdnf, arc, and il-1β mRNA levels. Our data revealed that COT and 6HLN could bind to α7 and α4β2 nAChRs with similar or even higher affinity than nicotine. Consequently, the treatment exhibited a pro-cognitive, antioxidant, and anti-AChE profile in the Aβ25-35-induced rat model of AD. Finally, RT-qPCR analysis revealed that COT and 6HLN positively modulated the bdnf, arc, and il-1β genes expression. Therefore, these nicotinic derivatives that act on the cholinergic system might represent a promising choice to ameliorate AD conditions.
“…On the other hand, the administration route of nicotine in vivo models (i.e., oral administration, subcutaneous injection) plays a crucial role in the potential antiinflammatory effects of nicotine in intestinal inflammation (AlSharari et al, 2013) therefore we might have not been able to capture the full potential of nicotine with our model as nicotine dissemination through the blood stream, intestinal absorption, or gastrointestinal metabolism might play a crucial role in nicotine bioavailability and anti-inflammatory effects in the gut. Of note, other minor tobacco alkaloids, nAChR agonists as well, were also suggested as having potential antiinflammatory effects (Olsson et al, 1993;Bai et al, 2007;Alijevic et al, 2020;Ruiz Castro et al, 2020). Among these, the alkaloids anatabine and cotinine have displayed protective effects in animal models of inflammatory conditions, including Alzheimer's disease (Paris et al, 2011), Parkinson's disease (Barreto et al, 2014), sepsis (Zabrodskii et al, 2015), and IBD (Bai et al, 2007;Ruiz Castro et al, 2020).…”
Intestinal inflammation is the collective term for immune system-mediated diseases of unknown, multifactorial etiology, with often complex interactions between genetic and environmental factors. To mechanistically investigate the effect of treatment with compounds possessing immunomodulating properties in the context of intestinal inflammation, we developed an immunocompetent in vitro triculture intestinal model consisting of a differentiated intestinal epithelial layer (Caco-2/HT29-MTX) and immunocompetent cells (differentiated THP-1). The triculture mimicked a healthy intestine with stable barrier integrity. Lipopolysaccharide treatment triggered a controlled and reversible inflammatory state, resulting in significant impairment of barrier integrity and release of pro-inflammatory cytokines and chemokines, which are known hallmarks of intestinal inflammation. Treatment with known anti-inflammatory reference compounds (TPCA-1 and budenoside) prevented the induction of an inflammatory state; the decreasing triculture responses to this treatment measured by cytokine release, transepithelial electric resistance (TEER), and epithelial layer permeability proved the suitability of the intestinal model for anti-inflammatory drug screening. Finally, selected tobacco alkaloids (nicotine and anatabine (R/S and S forms)) were tested in the in vitro triculture for their potential anti-inflammatory properties. Indeed, naturally occurring alkaloids, such as tobacco-derived alkaloids, have shown substantial anti-inflammatory effects in several in vitro and in vivo models of inflammation, gaining increasing interest. Similar to the anti-inflammatory reference compounds, one of the tobacco alkaloids under investigation partially prevented the decrease in the TEER and increase in permeability and reduced the release of pro-inflammatory cytokines and chemokines. Taken together, these data confirm that our in vitro model is suitable for screening potential anti-inflammatory compounds in the context of intestinal inflammation.
“… 54 In 2020, McHugh and co-workers re-examined the therapeutic potential of N -methylanatabine through an electrophysiological characterization test using Xenopus oocytes expressing the human α4β2-nAChRs. 55 The agonist potency (EC 50 ) and the maximal receptor response (I max ) of N -methylanatabine (EC 50 = 6.2 µM; I max = 26%) at the human α4β2-receptor were ~8- and 6-fold less active than nicotine (EC 50 = 0.8 µM; I max = 159%) respectively. 55 Fig.…”
Section: Plant-derivedmentioning
confidence: 99%
“… 55 The agonist potency (EC 50 ) and the maximal receptor response (I max ) of N -methylanatabine (EC 50 = 6.2 µM; I max = 26%) at the human α4β2-receptor were ~8- and 6-fold less active than nicotine (EC 50 = 0.8 µM; I max = 159%) respectively. 55 Fig. 5 N -methylanatabine.…”
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