Cotinine Inhibits Amyloid-β Peptide Neurotoxicity and Oligomerization

Burgess, Sarah

doi:10.4172/2161-0495.s6-003

Cited by 9 publications

(9 citation statements)

References 9 publications

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“…In this direction, Echeverria et al [ 30 ] showed through molecular dynamics simulations that important changes in Aβ 1-42 structure might occur due to a possible interaction between COT and H6, Y10 and H14 residues that prevents aggregation. Burgess et al [ 94 ] demonstrated that COT inhibited Aβ neurotoxicity on embryonic cortical neurons only when it was included in pre-aggregation solutions of Aβ 1-42 but not when it was added later in the media, thus suggesting that the COT is neuroprotective against Aβ-induced cortical cell death by preventing its aggregation. This neuroprotective activity of COT was not blocked by mecamylamine, a nAChRs antagonist, suggesting that this beneficial effect of COT is nAChRs-independent [ 94 ].…”

Section: Resultsmentioning

confidence: 99%

“…Burgess et al [ 94 ] demonstrated that COT inhibited Aβ neurotoxicity on embryonic cortical neurons only when it was included in pre-aggregation solutions of Aβ 1-42 but not when it was added later in the media, thus suggesting that the COT is neuroprotective against Aβ-induced cortical cell death by preventing its aggregation. This neuroprotective activity of COT was not blocked by mecamylamine, a nAChRs antagonist, suggesting that this beneficial effect of COT is nAChRs-independent [ 94 ]. In addition, COT diminished Aβ plaque deposition in the cortex and hippocampus of AD mice by reducing the number and size of Aβ plaques and decreasing the insoluble Aβ levels [ 29 , 30 ].…”

Section: Resultsmentioning

confidence: 99%

“…In vitro studies indicated that COT exhibited neuroprotective activity on neuronal cells against Aβ [ 94 , 115 ] and 6-OHDA [ 116 ] neurotoxicity.…”

Section: Resultsmentioning

confidence: 99%

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Cotinine and 6-Hydroxy-L-Nicotine Reverses Memory Deficits and Reduces Oxidative Stress in Aβ25-35-Induced Rat Model of Alzheimer’s Disease

et al. 2020

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Cotinine and 6-Hydroxy-L-Nicotine Reverses Memory Deficits and Reduces Oxidative Stress in Aβ25-35-Induced Rat Model of Alzheimer’s Disease

et al. 2020

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“…Studies to date indicate that cotinine might have properties that would be potentially important for the treatment of AD, schizophrenia, and depression. For example, relevant to AD, cotinine has been shown to be cytoprotective and neuroprotective as demonstrated by its ability to improve the survival of differentiated PC12 cells deprived of nerve growth factor [40], as well as to protect primary cortical neurons from the neurotoxic effects of the amyloid beta (Aβ) peptide or glutamate [41,42]. Cotinine also improved working/short term memory in a delayed match to sample (DMTS) task in monkeys [43], prevented memory loss in an AD mouse model (Tg6799), stimulated the Akt/GSK3β pathway and reduced Aβ aggregation in their brains [44,45].…”

Section: Cotinine As a Prototypic Compound With “Multifunctional” mentioning

confidence: 99%

Nicotinic ligands as multifunctional agents for the treatment of neuropsychiatric disorders

Terry

Callahan

Hernandez

2015

Biochemical Pharmacology

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The challenges associated with developing more effective treatments for neurologic and psychiatric illness such as Alzheimer’s disease and schizophrenia are considerable. Both the symptoms and the pathophysiology of these conditions are complex and poorly understood and the clinical presentations across different patients can be very heterogeneous. Moreover, it has become apparent that the reductionist approach to drug discovery for these illnesses that has dominated the field for decades (i.e., the development of highly selective compounds or other treatment modalities focused on a very specific pathophysiologic target) has not been widely successful. Accordingly, a variety of new strategies have emerged including the development of “multitarget-directed ligands” (MTDLs), the development and/or identification of compounds that exhibit “multifunctional” activity (e.g., pro-cognitive plus neuroprotective, pro-cognitive plus antipsychotic activity), “repurposing” strategies for existing compounds that have other clinical indications, and novel “adjunctive” treatment strategies that might enhance the efficacy of the currently available treatments. Interestingly, a variety of ligands at nicotinic acetylcholine receptors (nAChRs) appear to have the potential to fulfill one or more of these desirable properties (i.e., multifunctional, repurposing, or adjunctive treatment potential). The purpose of this review (while not all-inclusive) is to provide an overview of a variety of nAChR ligands that demonstrate potential in these categories, particularly, “multifunctional” properties. Due to their densities in the mammalian brain and the amount of literature available, the review will focus on ligands of the high affinity α4β2 nAChR and affinity α7 nAChR.

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“…In vitro, cotinine protects against toxic insults in PC12 cells with potency similar to that of nicotine 10 , suppresses the release of oxygen free radicals from neutrophils 11 , augments PI3K-dependent anti-inflammatory pathways in human monocytes 12 , protects against 6-OHDA-toxicity in SH-SY5Y cells 13 , and reduces death induced by Aβ neurotoxicity in primary cortical neurons. 14 In vivo, cotinine has been observed to prevent memory loss in transgenic (Tg) 6799 Alzheimer’s disease mice as well as to stimulate the Akt/GSK3β pathway and reduce Aβ aggregation in their brains. 15 Cotinine has also been evaluated across a variety of additional behavioral assays in rodents and non-human primates for potential effects on information processing and cognition.…”

mentioning

confidence: 99%

Evaluation of nicotine and cotinine analogs as potential neuroprotective agents for Alzheimer’s disease

Gao

Adam

Terry

2014

Bioorganic & Medicinal Chemistry Letters

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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.

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Cotinine Inhibits Amyloid-β Peptide Neurotoxicity and Oligomerization

Cited by 9 publications

References 9 publications

Cotinine and 6-Hydroxy-L-Nicotine Reverses Memory Deficits and Reduces Oxidative Stress in Aβ25-35-Induced Rat Model of Alzheimer’s Disease

Cotinine and 6-Hydroxy-L-Nicotine Reverses Memory Deficits and Reduces Oxidative Stress in Aβ25-35-Induced Rat Model of Alzheimer’s Disease

Nicotinic ligands as multifunctional agents for the treatment of neuropsychiatric disorders

Evaluation of nicotine and cotinine analogs as potential neuroprotective agents for Alzheimer’s disease

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