The α7 nicotinic receptor agonist 4OH-GTS-21 protects axotomized septohippocampal cholinergic neurons in wild type but not amyloid-overexpressing transgenic mice

Ren, Ke; King, Michael A.; Liu, J.; Siemann, Justin K.; Altman, Molly K.; Meyers, Craig; Hughes, Jeffrey A.; Meyer, Edwin M.

doi:10.1016/j.neuroscience.2007.05.013

Cited by 29 publications

(25 citation statements)

References 46 publications

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“…One such issue involves whether or not EVP-6124 will be effective in patients with more moderate-to-severe forms of AD. For example, some a7 nAChR agonists are unable to activate their targeted receptors as disease progresses [73][74][75]. While the selective a7 nAChR partial agonist 4-OH-GTS-21 was protective against the atrophy of axotomized septal cholinergic neurons, this effect was lost in mice overexpressing Ab1-42 [74].…”

Section: Expert Commentarymentioning

confidence: 99%

Safety and clinical effects of EVP-6124 in subjects with Alzheimer's disease currently or previously receiving an acetylcholinesterase inhibitor medication

Deardorff¹,

Shobassy

Grossberg

2014

Expert Review of Neurotherapeutics

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Alzheimer's disease (AD) is a prevalent and currently incurable brain disease whose impact will continue to rise as the population ages. With limited treatment options, a variety of experimental therapies are currently in clinical trials. EVP-6124 (encenicline) is an α7 nicotinic acetylcholine receptor partial agonist under investigation for the symptomatic treatment of AD. EVP-6124 activates the α7 nicotinic acetylcholine receptor at low nanomolar brain concentrations and improves memory performance in rats. Treatment with EVP-6124 in Phase I and II trials involving patients with mild-to-moderate AD was well tolerated and showed statistically significant improvements compared with placebo on cognitive and functional measures. Two Phase III trials under the title COGNITIV AD will assess the efficacy and tolerability of EVP-6124 in patients with mild-to-moderate AD. Based on the completed clinical trials and proposed mechanism of action, EVP-6124 would appear to be a good candidate for therapy in combination with cholinesterase inhibitors.

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Section: Expert Commentarymentioning

confidence: 99%

Safety and clinical effects of EVP-6124 in subjects with Alzheimer's disease currently or previously receiving an acetylcholinesterase inhibitor medication

Deardorff¹,

Shobassy

Grossberg

2014

Expert Review of Neurotherapeutics

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“…The ␣7nAChR has also been implicated in AD (51)(52)(53)(54), as expression of these receptors is either decreased or increased in AD brains (55,56) and animal models of AD (57). Furthermore, there is evidence that ␣7nAChR interacts with A␤ 1-42 oligomers (58,59).…”

Section: Journal Of Biological Chemistry 36547mentioning

confidence: 99%

Role of α7 Nicotinic Acetylcholine Receptor in Calcium Signaling Induced by Prion Protein Interaction with Stress-inducible Protein 1

Beraldo

Arantes

Santos

et al. 2010

Journal of Biological Chemistry

106

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The prion protein (PrP C ) is a conserved glycosylphosphatidylinositol-anchored cell surface protein expressed by neurons and other cells. Stress-inducible protein 1 (STI1) binds PrP C extracellularly, and this activated signaling complex promotes neuronal differentiation and neuroprotection via the extracellular signal-regulated kinase 1 and 2 (ERK1/2) and cAMP-dependent protein kinase 1 (PKA) pathways. However, the mechanism by which the PrP C -STI1 interaction transduces extracellular signals to the intracellular environment is unknown. We found that in hippocampal neurons, STI1-PrP C engagement induces an increase in intracellular Ca 2؉ levels. This effect was not detected in PrP C -null neurons or wild-type neurons treated with an STI1 mutant unable to bind PrP C . Using a best candidate approach to test for potential channels involved in Ca 2؉ influx evoked by STI1-PrP C , we found that ␣-bungarotoxin, a specific inhibitor for ␣7 nicotinic acetylcholine receptor (␣7nAChR), was able to block PrP C -STI1-mediated signaling, neuroprotection, and neuritogenesis. Importantly, when ␣7nAChR was transfected into HEK 293 cells, it formed a functional complex with PrP C and allowed reconstitution of signaling by PrP C -STI1 interaction. These results indicate that STI1 can interact with the PrP C ⅐␣7nAChR complex to promote signaling and provide a novel potential target for modulation of the effects of prion protein in neurodegenerative diseases.Prions are the infectious components of transmissible spongiform encephalopathies that can self-perpetuate by imprinting an anomalous conformation onto a glycosylphosphatidylinositol-anchored host protein known as the prion protein (PrP C ). 3Conversion of PrP C to the protease-resistant prion is thought to be a major event in prion diseases (1). However, despite the wealth of knowledge on prions, the roles of PrP C on synaptic function and neuronal health are still not completely understood. Studies in yeast, mammalian cells, and mouse models support the hypothesis that PrP C plays a major role in neuroprotection and neuronal differentiation (for review, see Refs. 1-3).In humans, the initial cognitive dysfunction observed in transmissible spongiform encephalopathies is remarkably similar to those observed in Alzheimer disease (AD). Therefore, synaptic failure is likely to play a major role in the cognitive alterations seen in these neurological disorders (4). For instance, in AD, the role for A␤ ligands in synaptic dysfunction has received considerable attention (5, 6). Interestingly, recent work provided evidence that PrP C functions as a receptor for A␤ and that this interaction mediates some of the effects of A␤ oligomers in synaptic plasticity (7) although these results are controversial at the moment (8, 9). Moreover, PrP C seems to regulate the ␤-secretase cleavage of amyloid precursor protein, thereby regulating the production of A␤ (10). In addition, ␣-secretase regulates the cleavage of PrP C , generating an N-terminal fragment with neuroprotective activity (11,12)...

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“…Consequently, 4OH-GTS-21 may cause more receptor activation over extended intervals than other agonists which may induce greater inhibition. Also, like GTS-21, 4OH-GTS-21 produces positive cognitive and cytoprotective effects in rats (Ren et al, 2007a) and 4OH-GTS-21 has been shown to be able to increase spontaneous firing rates in α7-expressing neurons (Uteshev et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Modulation of spontaneous hippocampal synaptic events with 5-hydroxyindole, 4OH-GTS-21, and rAAV-mediated α7 nicotinic receptor gene transfer

et al. 2008

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One approach to treatment of negative cognitive effects associated with Alzheimer's disease and schizophrenia may involve activation of neuronal α7 nicotinic acetylcholine receptors (nAChRs). We used the α7-selective partial agonist 3-(4-hydroxy, 2-methoxy-benzylidene)anabaseine (4OH-GTS-21), the α7 modulator 5-hydroxyindole (5-HI), and recombinant adeno-associated virus (rAAV)-mediated α7 gene transfer in order to test the hypothesis whether combining these strategies would significantly increase indirect measures of α7 nAChR function, including measures of spontaneous synaptic events in CA1 pyramidal cells. 5-HI (1mM), and 5-HI (1 mM) + 4OH-GTS-21 (5 μM) increased the frequency of APV-and NBQX-sensitive currents, while 5-HI + 4OH-GTS-21 increased the frequency and amplitude of bicuculline-sensitive currents. Effects on EPSCs were blocked with tetrodotoxin (TTX) (1 μM), but not by methyllycaconitine (MLA) (50 nM). Neither TTX nor MLA reduced the potentiation of IPSC frequencies. However, TTX blocked, and in some cases MLA reduced, the potentiation of IPSC amplitudes. These data suggest that effects of 5-HI + 4OH-GTS-21 on EPSC frequency were associated with action potential-dependent transmitter release produced by 5HI, and that potentiation of IPSC amplitudes resulted at least in part, from activation of α7 nAChRs. Finally, rAAV-mediated α7 gene transfer did not alter the magnitude of effects produced by 5-HI or 5-HI + 4OH-GTS-21. Thus, although we previously showed direct measures of α7 nAChR function were enhanced by α7 gene transfer, indirect measures of α7 nAChRs function were not significantly enhanced by combining α7 gene transfer with either agonist activation or positive allosteric modulation of α7 nAChRs.

show abstract

The α7 nicotinic receptor agonist 4OH-GTS-21 protects axotomized septohippocampal cholinergic neurons in wild type but not amyloid-overexpressing transgenic mice

Cited by 29 publications

References 46 publications

Safety and clinical effects of EVP-6124 in subjects with Alzheimer's disease currently or previously receiving an acetylcholinesterase inhibitor medication

Safety and clinical effects of EVP-6124 in subjects with Alzheimer's disease currently or previously receiving an acetylcholinesterase inhibitor medication

Role of α7 Nicotinic Acetylcholine Receptor in Calcium Signaling Induced by Prion Protein Interaction with Stress-inducible Protein 1

Modulation of spontaneous hippocampal synaptic events with 5-hydroxyindole, 4OH-GTS-21, and rAAV-mediated α7 nicotinic receptor gene transfer

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