The Therapeutic Potential of α7 Nicotinic Acetylcholine Receptor (α7 nAChR) Agonists for the Treatment of the Cognitive Deficits Associated with Schizophrenia

Beinat, Corinne; Banister, Samuel D.; Herrera, Marco; Law, Vivian; Kassiou, Michael

doi:10.1007/s40263-015-0260-0

Cited by 66 publications

(57 citation statements)

References 97 publications

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“…In this regard, galantamine, a cholinesterase inhibitor that is also a α7 nAChR-PAM has shown neurocognitive improvement in subjects with schizophrenia (Buchanan et al, 2008; Schubert et al, 2006). A number of type I and type II PAMs have shown beneficial effects on sensory gating, working memory and executive functions in animal models (reviewed in (Beinat et al, 2015; Terry Jr et al, 2015). However, a recent phase I clinical trial with JNJ-39393406, an α7 nAChR PAM, did not reveal any beneficial effects on P50 sensory gating and other electrophysiological markers of early information processing in regularly smoking patients with schizophrenia (Winterer et al, 2013).…”

Section: Resultsmentioning

confidence: 99%

nAChR dysfunction as a common substrate for schizophrenia and comorbid nicotine addiction: Current trends and perspectives

Parikh

Kutlu

Gould

2016

Schizophrenia Research

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Introduction The prevalence of tobacco use in the population with schizophrenia is enormously high. Moreover, nicotine dependence is found to be associated with symptom severity and poor outcome in patients with schizophrenia. The neurobiological mechanisms that explain schizophrenia-nicotine dependence comorbidity are not known. This study systematically reviews the evidence highlighting the contribution of nicotinic acetylcholine receptors (nAChRs) to nicotine abuse in schizophrenia. Methods Electronic data bases (Medline, Google Scholar, and Web of Science) were searched using the selected key words that match the aims set forth for this review. A total of 275 articles were used for the qualitative synthesis of this review. Results Substantial evidence from preclinical and clinical studies indicated that dysregulation of α7 and β2-subunit containing nAChRs account for the cognitive and affective symptoms of schizophrenia and nicotine use may represent a strategy to remediate these symptoms. Additionally, recent meta-analyses proposed that early tobacco use may itself increase the risk of developing schizophrenia. Genetic studies demonstrating that nAChR dysfunction that may act as a shared vulnerability factor for comorbid tobacco dependence and schizophrenia were found to support this view. The development of nAChR modulators was considered an effective therapeutic strategy to ameliorate psychiatric symptoms and to promote smoking cessation in schizophrenia patients. Conclusions The relationship between schizophrenia and smoking is complex. While the debate for the self-medication versus addiction vulnerability hypothesis continues, it is widely accepted that a dysfunction in the central nAChRs represent a common substrate for various symptoms of schizophrenia and comorbid nicotine dependence.

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Section: Resultsmentioning

confidence: 99%

nAChR dysfunction as a common substrate for schizophrenia and comorbid nicotine addiction: Current trends and perspectives

Parikh

Kutlu

Gould

2016

Schizophrenia Research

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“…Abnormalities of α 7 nAChRs are implicated in inflammatory processes 2 , schizophrenia 3 , Alzheimer’s disease 4 , depression 5 , and substance abuse disorders 6 . In vivo imaging of α 7 nAChRs with positron emission tomography (PET) enables noninvasive measurements of receptor availability 7 , and thus provides a critical tool for investigating the role of these receptors in the basic biology underlying neuropsychiatric disorders.…”

Section: Introductionmentioning

confidence: 99%

PET imaging of α7 nicotinic acetylcholine receptors: a comparative study of [18F]ASEM and [18F]DBT-10 in nonhuman primates, and further evaluation of [18F]ASEM in humans

Hillmer

Zheng

et al. 2017

Eur J Nucl Med Mol Imaging

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Purpose The α7 nicotinic acetylcholine receptor (nAChR) is implicated in many neuropsychiatric disorders, making it an important target for positron emission tomography (PET) imaging. The first aim of this work was to compare two α7 nAChRs PET radioligands, [18F]ASEM (3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-([18F]fluorodibenzo[b,d]thiophene 5,5-dioxide) and [18F]DBT-10 (7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-([18F]fluorodibenzo[b,d]thiophene 5,5-dioxide), in nonhuman primates. The second aim was to further assess the quantification and test-retest variability of [18F]ASEM in humans. Methods PET scans with high specific activity [18F]ASEM or [18F]DBT-10 were acquired in three rhesus monkeys (1 M, 2 F), and the kinetic properties of these radiotracers were compared. Additional [18F]ASEM PET scans with blocking doses of nicotine, varenicline, and cold ASEM were acquired separately in two animals. Next, six human subjects (5 M, 1 F) were imaged with [18F]ASEM PET for 180 min, and arterial sampling was used to measure the parent input function. Different modeling approaches were compared to identify the optimal analysis method and scan duration for quantification of [18F]ASEM distribution volume (VT). In addition, retest scans were acquired in four subjects (3 M, 1F), and the test-retest variability of VT was assessed. Results In the rhesus monkey brain [18F]ASEM and [18F]DBT-10 exhibited highly similar kinetic profiles. Dose-dependent blockade of [18F]ASEM binding was observed, while administration of either nicotine or varenicline did not change [18F]ASEM VT [18F]ASEM was selected for further validation because it has been used in humans. Accurate quantification of [18F]ASEM VT in humans was achieved using multilinear analysis with at least 90 min of data acqusition, resulting in VT values ranging from 19.6±2.5 mL/cm3 in cerebellum to 25.9±2.9 mL/cm3 in thalamus. Test-retest variability of VT was 11.7±9.8%. Conclusions These results confirm [18F]ASEM as a suitable radiotracer for the imaging and quantification of α7 nAChRs in humans.

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“…Among them, the neuronal α7 receptor subtype (α7 nAChRs) has attracted considerable interest as a potential target for therapeutic intervention in schizophrenia, Alzheimer's disease and different pain conditions [4,5]. Most of the compounds described as modulators of these channels are competitive agonists or antagonists that interact at the orthosteric binding site of the endogenous ligand, acetylcholine [2,6]. However, recent efforts have been focused on exploring the pharmacological diversity of compounds able to interact with the receptor at allosteric binding sites [7,8].…”

mentioning

confidence: 99%

1,3-Diphenylpropan-1-Ones as Allosteric Modulators of α7 Nach Receptors with Analgesic and Antioxidant Properties

Criado¹,

Balsera

Mulet³

et al. 2016

Future Med. Chem.

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The Therapeutic Potential of α7 Nicotinic Acetylcholine Receptor (α7 nAChR) Agonists for the Treatment of the Cognitive Deficits Associated with Schizophrenia

Cited by 66 publications

References 97 publications

nAChR dysfunction as a common substrate for schizophrenia and comorbid nicotine addiction: Current trends and perspectives

nAChR dysfunction as a common substrate for schizophrenia and comorbid nicotine addiction: Current trends and perspectives

PET imaging of α7 nicotinic acetylcholine receptors: a comparative study of [18F]ASEM and [18F]DBT-10 in nonhuman primates, and further evaluation of [18F]ASEM in humans

1,3-Diphenylpropan-1-Ones as Allosteric Modulators of α7 Nach Receptors with Analgesic and Antioxidant Properties

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