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

Gao, Jie; Adam, Bao Ling; Terry, Alvin V.

doi:10.1016/j.bmcl.2014.02.008

Cited by 45 publications

(35 citation statements)

References 33 publications

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“…The cerebral cortices from E17-18 Sprague-Dawley rat embryos were extracted and cultured as described elsewhere (Gao et al, 2014) under aseptic conditions. Timed pregnant rats were purchased from Harlan Sprague-Dawley (Indianapolis, IN) and housed and maintained on a 12-hour light/dark cycle in a temperature-controlled room (25°C) with free access to food and water for at least 3 days before initiating cultures.…”

Section: Embryonic Cortical Culturesmentioning

confidence: 99%

Diisopropylfluorophosphate Impairs the Transport of Membrane-Bound Organelles in Rat Cortical Axons

Gao

Naughton

Wulff

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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The extensive use of organophosphates (OPs) is an ongoing environmental health concern due to multiple reports of OPrelated neurologic abnormalities. The mechanism of the acute toxicity of OPs has been attributed to inhibition of acetylcholinesterase (AChE), but there is growing evidence that this may not account for all the long-term neurotoxic effects of OPs. In previous experiments (using ex vivo and in vitro model systems) we observed that the insecticide OP chlorpyrifos impaired the movements of vesicles and mitochondria in axons. Here, using a time-lapse imaging technique, we evaluated the OP-nerve agent diisopropylfluorophosphate (DFP) across a wide range of concentrations (subnanomolar to micromolar) for effects on fast axonal transport of membrane-bound organelles (MBOs) that contain the amyloid precursor protein (APP) tagged with the fluorescent marker Dendra2 (APPDendra2). Both 1 and 24 hours of exposure to DFP and a positive control compound, colchicine, resulted in a decrease in the velocity of anterograde and retrograde movements of MBOs and an increase in the number of stationary MBOs. These effects occurred at picomolar (100 pM) to low nanomolar (0.1 nM) concentrations that were not associated with compromised cell viability or cytoskeletal damage. Moreover, the effects of DFP on axonal transport occurred at concentrations that did not inhibit AChE activity, and they were not blocked by cholinergic receptor antagonists. Given the fundamental importance of axonal transport to neuronal function, these observations may explain some of the long-term neurologic deficits that have been observed in humans who have been exposed to OPs.

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Section: Embryonic Cortical Culturesmentioning

confidence: 99%

Diisopropylfluorophosphate Impairs the Transport of Membrane-Bound Organelles in Rat Cortical Axons

Gao

Naughton

Wulff

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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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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“…For example, in studies relevant to AD, cotinine has been shown to improve the survival of differentiated PC12 cells deprived of nerve growth factor (Buccafusco and Terry, 2003), as well as primary cortical neurons exposed to toxic concentrations of the amyloid-b peptide or glutamate Gao et al, 2014). Cotinine has also been shown to improve working/short-term memory performance in monkeys (Terry et al, 2005), prevent memory loss in transgenic 6799 Alzheimer's disease mice, and stimulate the Akt/GSK3b pathway and reduce amyloid-b aggregation in mouse brains Patel et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

R-(+) and S-(−) Isomers of Cotinine Augment Cholinergic Responses In Vitro and In Vivo

Terry

Callahan

Bertrand

2014

J Pharmacol Exp Ther

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The nicotine metabolite cotinine (1-methyl-5-[3-pyridynl]-2-pyrrolidinone), like its precursor, has been found to exhibit procognitive and neuroprotective effects in some model systems; however, the mechanism of these effects is unknown. In this study, both the R-(1) and S-(2) isomers of cotinine were initially evaluated in an extensive profiling screen and found to be relatively inactive across a wide range of potential pharmacologic targets. Electrophysiological studies on human a4b2 and a7 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes confirmed the absence of agonistic activity of cotinine at a4b2 or a7 nAChRs. However, a significant increase in the current evoked by a low concentration of acetylcholine was observed at a7 nAChRs exposed to 1.0 mM R-(1)-or S-(2)-cotinine. Based on these results, we used a spontaneous novel object recognition (NOR) procedure for rodents to test the hypothesis that R-(1)-or S-(2)-cotinine might improve recognition memory when administered alone or in combination with the Alzheimer's disease (AD) therapeutic agent donepezil. Although both isomers enhanced NOR performance when they were coadministered with donepezil, neither isomer was active alone. Moreover, the procognitive effects of the drug combinations were blocked by methyllycaconitine and dihydro-b-erythroidine, indicating that both a7 and a4b2 nAChRs contribute to the response. These results indicate that cotinine may sensitize a7 nAChRs to low levels of acetylcholine (a previously uncharacterized mechanism), and that cotinine could be used as an adjunctive agent to improve the effective dose range of cholinergic compounds (e.g., donepezil) in the treatment of AD and other memory disorders.

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

Cited by 45 publications

References 33 publications

Diisopropylfluorophosphate Impairs the Transport of Membrane-Bound Organelles in Rat Cortical Axons

Diisopropylfluorophosphate Impairs the Transport of Membrane-Bound Organelles in Rat Cortical Axons

Nicotinic ligands as multifunctional agents for the treatment of neuropsychiatric disorders

R-(+) and S-(−) Isomers of Cotinine Augment Cholinergic Responses In Vitro and In Vivo

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