Effects of BMS-902483, an α7 nicotinic acetylcholine receptor partial agonist, on cognition and sensory gating in relation to receptor occupancy in rodents

Pieschl, Rick L.; Miller, Regina; Jones, Kelli; Post-Munson, Debra J.; Chen, Ping; Newberry, Kimberly; Benitex, Yulia; Molski, Thaddeus F.; Morgan, Daniel G.; McDonald, Ivar M.; Macor, John E.; Olson, R. E.; Asaka, Yukiko; Digavalli, Siva; Easton, Amy; Herrington, James; Westphal, Ryan S.; Lodge, Nicholas J.; Zaczek, Robert; Bristow, Linda J.; Li, Yuwen

doi:10.1016/j.ejphar.2017.04.024

Cited by 21 publications

(22 citation statements)

References 37 publications

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“…NS6740 was also recently reported to similarly antagonize the effects of BMS-902483 in a novel object recognition test [44]. In the same work, BMS-902483 was shown to enhance hippocampal LTP, an activity presumably related to cogni-tive enhancement.…”

Section: Discussionmentioning

confidence: 82%

“…In any case, the present study challenges the naive assumption that all α7 ligands work by increasing intracellular calcium through ion channel activation. For most therapeutic/in vivo models this mode of action seems hardly even feasible since, in the absence of PAMs, α7 nAChR have extremely low probability of channel opening [61] and are especially ineffective at generating currents when agonist concentrations change slowly, as they would in the brain following a subcutaneous [44] or intraperitoneal injection [8]. It seems likely that the slice experiments NS6740 is down- regulating constitutive α7 ion channel receptor tone reducing tonic pre- synaptic facilitation [18].…”

Section: Discussionmentioning

confidence: 99%

“…NS6740 is, however, able to activate large α7 ion channel currents in the presence of a positive allosteric modulator (PAM), identifying it as a “silent agonist”. The concept that there are two distinct types of α7-mediated signaling is supported by reports that NS6740 is not only ineffective in cognitive tests, it is able to block the effects of cognition-enhancing α7 channel activators, for example, the effects of the α7 agonist BMS-902483 on improving novel object recognition [44]. On its own, BMS-902483 has been also shown to increase hippocampal long-term potentiation (LTP), an effect hypothesized to be related to its positive cognitive effects.…”

Section: Introductionmentioning

confidence: 99%

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NS6740, an α7 nicotinic acetylcholine receptor silent agonist, disrupts hippocampal synaptic plasticity

Papke

Peng

Kumar

et al. 2018

Neuroscience Letters

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Long-term potentiation (LTP) in the dentate gyrus was previously shown to be enhanced by nicotine, an effect dependent on both homomeric α7 and heteromeric α2β2 nicotinic acetylcholine receptors (nAChR). In our experiments, bath-applied nicotine produced no significant enhancement of LTP. The α7 nAChR silent agonist NS6740, a weak activator of α7 nAChR ion channels but an effective modulator of the cholinergic anti-in-flammatory pathway, decreased LTP and, additionally, produced a substantial reduction in the baseline synaptic function prior to the high frequency stimulation used to induce LTP. The effects of NS6740 on the various ligand-gated ion channels associated with the generation and modulation of dentate LTP were evaluated with receptors expressed in Xenopus oocytes. A 60 s pre-application of 5μM NS6740 to α7 receptors blocked the response to subsequent applications of acetylcholine (ACh). In contrast, the responses of α2β2 nAChR to control applications of ACh were not significantly affected by NS6740. Likewise, responses of cells expressing GluRl + GluR2 AMPA- type glutamate receptor subunits or GABAA αl, β2, and γ2L subunits to control agonist applications (100 μM kainic acid or 10 μM GABA, respectively), were unaffected by NS6740. The effects of NS6740 on α7 were in-consistent with simple antagonism since, while unresponsive to ACh, the receptors exposed to NS6740 were effectively activated by the positive allosteric modulator PNU-120596. The results support the hypothesis that NS6740 switches the mode of α7 signaling in a channel-independent manner that can reduce synaptic function.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NS6740, an α7 nicotinic acetylcholine receptor silent agonist, disrupts hippocampal synaptic plasticity

Papke

Peng

Kumar

et al. 2018

Neuroscience Letters

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“…It is a concern that certain compounds may also have undesirable side effects. For example, NS6740 has been shown to antagonize the procognitive effects of other a7 channel activators (Briggs et al, 2009;Pieschl et al, 2017) and may directly reduce synaptic function in the hippocampus (Papke et al, 2018). Like GAT107, the type II PAM PNU-120596 is an extremely effective PAM that has been shown to be an active regulator of the cholinergic anti-inflammatory pathway (Freitas et al, 2013a,b).…”

Section: Discussionmentioning

confidence: 99%

The Antinociceptive and Anti-Inflammatory Properties of the α7 nAChR Weak Partial Agonist p-CF₃N,N-diethyl-N′-phenylpiperazine

Quadri

Bağdaş

Toma

et al. 2018

J Pharmacol Exp Ther

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Chronic pain and inflammatory diseases can be regulated by complex mechanisms involving 7 nicotinic acetylcholine receptors (nAChRs), making this subtype a promising drug target for anti-inflammatory therapies. Recent evidence suggests that suchtreatment of inflammatory pain may rely on metabotropic-like rather than ionotropic activation of the7 receptor subtype in non-neuronal cells. We previously identified para-trifluoromethyl (-CF) ,-diethyl-'-phenylpiperazinium (diEPP) iodide to be among the compounds classified as silent agonists, which are very weak 7 partial agonists that are able to induce positive allosteric modulator (PAM)-sensitive desensitization. Such drugs have been shown to selectively promote7 ionotropic-independent functions. Therefore, we here further investigated the electrophysiological profile of -CF diEPP and its in vivo antinociceptive activity using oocytes expressing7, 42, or 34 nAChRs. The evoked currents confirmed -CF diEPP to be 7-selective with a maximal agonism 5% that of acetylcholine (ACh). Coapplication of-CF diEPP with the type II PAM 4-naphthalene-1-yl-3a,4,5,9b-tetrahydro-3--cyclopenta[c]quinoline-8-sulfonic acid amide (TQS) produced desensitization that could be converted to PAM-potentiated currents, which at a negative holding potential were up to 13-fold greater than ACh controls. Voltage-dependence experiments indicated that channel block may limit both control ACh and TQS-potentiated responses. Although no -CF diEPP agonist activity was detected for the heteromeric nAChRs, it was a noncompetitive antagonist of these receptors. The compound displayed remarkable antihyperalgesic and antiedema effects in in vivo assays. The antinociceptive activity was dose and time dependent. The anti-inflammatory components were sensitive to the 7-selective antagonist methyllycaconitine, which supports the idea that these effects are mediated by the7 nAChR.

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“…On the other hand, the activation of nAChRs is also critical for memory formation and synaptic plasticity [64]. Pieschl et al [65] demonstrated that the α7nAChR agonist BMS-902483 enhances NOR memory in naïve wild-type mice. In addition, α7nAChR knockout mice show cognitive impairments, as demonstrated by decline in sustained attention and olfactory working memory span [66].…”

Section: Discussionmentioning

confidence: 99%

Acute Treatment with T-Type Calcium Channel Enhancer SAK3 Reduces Cognitive Impairments Caused by Methimazole-Induced Hypothyroidism Via Activation of Cholinergic Signaling

Noreen¹,

Yabuki²,

Shinoda³

et al. 2018

Pharmacology

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Hypothyroidism is a common disorder that is associated with psychological disturbances such as dementia, depression, and psychomotor disorders. We recently found that chronic treatment with the T-type calcium channel enhancer SAK3 prevents the cholinergic neurodegeneration induced by a single intraperitoneal (i.p.) injection of methimazole (MMI; 75 mg/kg), thereby improving cognition. Here, we evaluated the acute effect of SAK3 on cognitive impairments and its mechanism of action following the induction of hypothyroidism. Hypothyroidism was induced by 2 injections of MMI (75 mg/kg, i.p.) administered once per week. Four weeks after the final MMI treatment, MMI-treated mice showed reduced serum thyroxine (T4) levels and cognitive impairments without depression-like behaviors. Although acute SAK3 (1.0 mg/kg, p.o.) administration failed to ameliorate the decreased T4 levels and histochemical destruction of the glomerular structure, acute SAK3 (1.0 mg/kg, p.o.) administration significantly reduced cognitive impairments in MMI-treated mice. Importantly, the α7 nicotinic acetylcholine receptor (nAChR)-selective inhibitor methyllycaconitine (MLA; 12 mg/kg, i.p.) and T-type calcium channel-specific blocker NNC 55–0396 (25 mg/kg, i.p.) antagonized the acute effect of SAK3 on memory deficits in MMI-treated mice. We also confirmed that acute SAK3 administration does not rescue reduced olfactory marker protein or choline acetyltransferase immunoreactivity levels in the olfactory bulb or medial septum. Taken together, these results suggest that SAK3 has the ability to improve the cognitive decline caused by hypothyroidism directly through activation of nAChR signaling and T-type calcium channels.

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Effects of BMS-902483, an α7 nicotinic acetylcholine receptor partial agonist, on cognition and sensory gating in relation to receptor occupancy in rodents

Cited by 21 publications

References 37 publications

NS6740, an α7 nicotinic acetylcholine receptor silent agonist, disrupts hippocampal synaptic plasticity

NS6740, an α7 nicotinic acetylcholine receptor silent agonist, disrupts hippocampal synaptic plasticity

The Antinociceptive and Anti-Inflammatory Properties of the α7 nAChR Weak Partial Agonist p-CF₃N,N-diethyl-N′-phenylpiperazine

Acute Treatment with T-Type Calcium Channel Enhancer SAK3 Reduces Cognitive Impairments Caused by Methimazole-Induced Hypothyroidism Via Activation of Cholinergic Signaling

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Effects of BMS-902483, an α7 nicotinic acetylcholine receptor partial agonist, on cognition and sensory gating in relation to receptor occupancy in rodents

Cited by 21 publications

References 37 publications

NS6740, an α7 nicotinic acetylcholine receptor silent agonist, disrupts hippocampal synaptic plasticity

NS6740, an α7 nicotinic acetylcholine receptor silent agonist, disrupts hippocampal synaptic plasticity

The Antinociceptive and Anti-Inflammatory Properties of the α7 nAChR Weak Partial Agonist p-CF3N,N-diethyl-N′-phenylpiperazine

Acute Treatment with T-Type Calcium Channel Enhancer SAK3 Reduces Cognitive Impairments Caused by Methimazole-Induced Hypothyroidism Via Activation of Cholinergic Signaling

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The Antinociceptive and Anti-Inflammatory Properties of the α7 nAChR Weak Partial Agonist p-CF₃N,N-diethyl-N′-phenylpiperazine