Inhibitor Report for: Cotinine

Cotinine (COT) and 6-hydroxy-L-nicotine (6HLN) are two nicotinic derivatives that possess cognitive-improving abilities and antioxidant properties in different rodent models of Alzheimer's disease (AD), eluding the side-effects of nicotine (NIC), the parent molecule. In the current study, we evaluated the impact of COT and 6HLN on memory deterioration, anxiety, and oxidative stress in the scopolamine (SCOP)-induced zebrafish model of AD. For this, COT and 6HLN were acutely administered by immersion to zebrafish that were treated with SCOP before testing. The memory performances were assessed in Y-maze and object discrimination (NOR) tasks, while the anxiety-like behavior was evaluated in the novel tank diving test (NTT). The acetylcholinesterase (AChE) activity and oxidative stress were measured from brain samples. The RT-qPCR analysis was used to evaluate the npy, egr1, bdnf, and nrf2a gene expression. Our data indicated that both COT and 6HLN attenuated the SCOP-induced anxiety-like behavior and memory impairment and reduced the oxidative stress and AChE activity in the brain of zebrafish. Finally, RT-qPCR analysis indicated that COT and 6HLN increased the npy, egr1, bdnf, and nrf2a gene expression. Therefore, COT and 6HLN could be used as tools for improving AD conditions.

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 Abeta(25-35)-induced rat model of Alzheimer's disease (AD). COT and 6HLN were chronically administered to Abeta(25-35)-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 alpha7 and alpha4beta2 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-1beta mRNA levels. Our data revealed that COT and 6HLN could bind to alpha7 and alpha4beta2 nAChRs with similar or even higher affinity than nicotine. Consequently, the treatment exhibited a pro-cognitive, antioxidant, and anti-AChE profile in the Abeta(25-35)-induced rat model of AD. Finally, RT-qPCR analysis revealed that COT and 6HLN positively modulated the bdnf, arc, and il-1beta genes expression. Therefore, these nicotinic derivatives that act on the cholinergic system might represent a promising choice to ameliorate AD conditions.

The trans-isomer of 3'-hydroxycotinine has recently been identified as a major metabolite of nicotine in urine of cigarette smokers. We, therefore, investigated the pharmacokinetics of 3'-hydroxycotinine in six male smokers after intravenous infusion of nicotine, cotinine, and 3'-hydroxycotinine. Serum concentrations of 3'-hydroxycotinine were lower than those of cotinine throughout the observation period of 60 h after infusion of nicotine or cotinine, whereas the amounts excreted in the urine were similar or higher than those of cotinine. The following means and ranges for the pharmacokinetic parameters were derived from the 3'-hydroxycotinine infusion experiment: half-life (t1/2 beta) = 5.9 (4.2-9.5) h; apparent volume of distribution (Vd) = 0.87 (0.51-1.14) l/kg; total clearance (Cl total) = 1.79 (1.08-2.59) ml/min/kg; renal clearance (Clr) = 1.31 (0.85-1.78) ml/min/kg; percentage of renal clearance (Clr/Cl total) = 75.4 +/- 12.8 (60.3-98.2). The high percentage of renal clearance suggests that further metabolization of this compound is limited. No evidence for a mutagenic activity of 3'-hydroxycotinine or of urine extracts from subjects dosed with hydroxycotinine was found with the S. typhimurium (TA 98) microsome assay.

Cotinine (COT) and 6-hydroxy-L-nicotine (6HLN) are two nicotinic derivatives that possess cognitive-improving abilities and antioxidant properties in different rodent models of Alzheimer's disease (AD), eluding the side-effects of nicotine (NIC), the parent molecule. In the current study, we evaluated the impact of COT and 6HLN on memory deterioration, anxiety, and oxidative stress in the scopolamine (SCOP)-induced zebrafish model of AD. For this, COT and 6HLN were acutely administered by immersion to zebrafish that were treated with SCOP before testing. The memory performances were assessed in Y-maze and object discrimination (NOR) tasks, while the anxiety-like behavior was evaluated in the novel tank diving test (NTT). The acetylcholinesterase (AChE) activity and oxidative stress were measured from brain samples. The RT-qPCR analysis was used to evaluate the npy, egr1, bdnf, and nrf2a gene expression. Our data indicated that both COT and 6HLN attenuated the SCOP-induced anxiety-like behavior and memory impairment and reduced the oxidative stress and AChE activity in the brain of zebrafish. Finally, RT-qPCR analysis indicated that COT and 6HLN increased the npy, egr1, bdnf, and nrf2a gene expression. Therefore, COT and 6HLN could be used as tools for improving AD conditions.

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 Abeta(25-35)-induced rat model of Alzheimer's disease (AD). COT and 6HLN were chronically administered to Abeta(25-35)-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 alpha7 and alpha4beta2 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-1beta mRNA levels. Our data revealed that COT and 6HLN could bind to alpha7 and alpha4beta2 nAChRs with similar or even higher affinity than nicotine. Consequently, the treatment exhibited a pro-cognitive, antioxidant, and anti-AChE profile in the Abeta(25-35)-induced rat model of AD. Finally, RT-qPCR analysis revealed that COT and 6HLN positively modulated the bdnf, arc, and il-1beta genes expression. Therefore, these nicotinic derivatives that act on the cholinergic system might represent a promising choice to ameliorate AD conditions.

The currently available therapies for Alzheimer's disease (AD) and related forms of dementia are limited by modest efficacy, adverse side effects, and the fact that they do not prevent the relentless progression of the illness. The purpose of the studies described here was to investigate the neuroprotective effects of the nicotine metabolite cotinine as well as a small series of cotinine and nicotine analogs (including stereoisomers) and to compare their effects to the four clinically prescribed AD therapies.

Alzheimer's disease (AD) affects millions of people world-wide and new effective and safe therapies are needed. Cotinine, the main metabolite of nicotine, has a long half-life and does not have cardiovascular or addictive side effects in humans. We studied the effect of cotinine on amyloid-beta (Abeta) aggregation as well as addressed its impact on working and reference memories. Cotinine reduced Abeta deposition, improved working and reference memories, and inhibited Abeta oligomerization in the brains of transgenic (Tg) 6799 AD mice. In vitro studies confirmed the inhibitory effect of cotinine on Abeta1-42 aggregation. Cotinine stimulated Akt signaling, including the inhibition of glycogen synthase kinase 3beta (GSK3beta), which promotes neuronal survival and the synaptic plasticity processes underlying learning and memory in the hippocampus and cortex of wild type and Tg6799 AD mice. Simulation of the cotinine-Abeta1-42 complex using molecular dynamics showed that cotinine may interact with key histidine residues of Abeta1-42, altering its structure and inhibiting its aggregation. The good safety profile in humans and its beneficial effects suggest that cotinine may be an excellent therapeutic candidate for the treatment of AD.

Cotinine, a major peripheral metabolite of nicotine, has recently been shown to be the most abundant metabolite in rat brain after peripheral nicotine administration. However, little attention has been focused on the contribution of cotinine to the pharmacological effects of nicotine exposure in either animals or humans. The present study determined the concentration-response relationship for (S)-(-)-cotinine-evoked 3H overflow from superfused rat striatal slices preloaded with [3H]dopamine ([3H]DA) and whether this response was mediated by nicotinic receptor stimulation. (S)-(-)-Cotinine (1 microM to 3 mM) evoked 3H overflow from [3H]DA-preloaded rat striatal slices in a concentration-dependent manner with an EC50 value of 30 microM, indicating a lower potency than either (S)-(-)-nicotine or the active nicotine metabolite, (S)-(-)-nornicotine. As reported for (S)-(-)-nicotine and (S)-(-)-nornicotine, desensitization to the effect of (S)-(-)-cotinine was observed. The classic nicotinic receptor antagonists mecamylamine and dihydro-beta-erythroidine inhibited the response to (S)-(-)-cotinine (1-100 microM). Additionally, 3H overflow evoked by (S)-(-)-cotinine (10-1000 microM) was inhibited by superfusion with a low calcium buffer. Interestingly, over the same concentration range, (S)-(-)-cotinine did not inhibit [3H]DA uptake into striatal synaptosomes. These results demonstrate that (S)-(-)-cotinine, a constituent of tobacco products and the major metabolite of nicotine, stimulates nicotinic receptors to evoke the release of DA in a calcium-dependent manner from superfused rat striatal slices. Thus, (S)-(-)-cotinine likely contributes to the neuropharmacological effects of nicotine and tobacco use.

The trans-isomer of 3'-hydroxycotinine has recently been identified as a major metabolite of nicotine in urine of cigarette smokers. We, therefore, investigated the pharmacokinetics of 3'-hydroxycotinine in six male smokers after intravenous infusion of nicotine, cotinine, and 3'-hydroxycotinine. Serum concentrations of 3'-hydroxycotinine were lower than those of cotinine throughout the observation period of 60 h after infusion of nicotine or cotinine, whereas the amounts excreted in the urine were similar or higher than those of cotinine. The following means and ranges for the pharmacokinetic parameters were derived from the 3'-hydroxycotinine infusion experiment: half-life (t1/2 beta) = 5.9 (4.2-9.5) h; apparent volume of distribution (Vd) = 0.87 (0.51-1.14) l/kg; total clearance (Cl total) = 1.79 (1.08-2.59) ml/min/kg; renal clearance (Clr) = 1.31 (0.85-1.78) ml/min/kg; percentage of renal clearance (Clr/Cl total) = 75.4 +/- 12.8 (60.3-98.2). The high percentage of renal clearance suggests that further metabolization of this compound is limited. No evidence for a mutagenic activity of 3'-hydroxycotinine or of urine extracts from subjects dosed with hydroxycotinine was found with the S. typhimurium (TA 98) microsome assay.