Therapeutic Potential of<i>α</i>7 Nicotinic Acetylcholine Receptors

Bertrand, Daniel; Lee, Chih-Hung L.; Flood, Dorothy G.; Marger, Fabrice; Donnelly‐Roberts, Diana L.

doi:10.1124/pr.113.008581

Cited by 130 publications

(115 citation statements)

References 530 publications

(566 reference statements)

Supporting

Mentioning

110

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, examples of sexually dimorphic, ischemic brain injury mediated by both hormonal and non hormonal mechanisms (Liu et al, 2009; Herson and Hurn, 2010; Manwani and McCullough, 2011; Fairbanks et al, 2012; Herson et al, 2013; Zuo et al, 2013; Sanches et al, 2015) include the sensitivity of hippocampal neurons to ischemia in PrP C -null mice (Sakurai-Yamashita et al, 2005), and evidence has been reported of both sexually-dimorphic α-bungarotoxin binding (Arimatsu et al, 1981; Arimatsu and Seto, 1982) as well as changed content of α7nAChR following prenatal stress (Schulz et al, 2013). These data warrant a critical examination of the stoichiometry of hop/STI1:PrPC:α7nAChR complexes in the context of sensitivity to ischemic insults, especially in view of the variegated homo- and/or hetero-multimeric, cholinergic receptors that may assembled around α7nAChR subunits, as indicated by experimental work with various cell types (Bertrand et al, 2015; Wu et al, 2016). …”

Section: The Prion Protein As a Cell Surface Scaffold Proteinmentioning

confidence: 88%

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

Linden

2017

Front. Mol. Neurosci.

115

104

View full text Add to dashboard Cite

The prion glycoprotein (PrPC) is mostly located at the cell surface, tethered to the plasma membrane through a glycosyl-phosphatydil inositol (GPI) anchor. Misfolding of PrPC is associated with the transmissible spongiform encephalopathies (TSEs), whereas its normal conformer serves as a receptor for oligomers of the β-amyloid peptide, which play a major role in the pathogenesis of Alzheimer’s Disease (AD). PrPC is highly expressed in both the nervous and immune systems, as well as in other organs, but its functions are controversial. Extensive experimental work disclosed multiple physiological roles of PrPC at the molecular, cellular and systemic levels, affecting the homeostasis of copper, neuroprotection, stem cell renewal and memory mechanisms, among others. Often each such process has been heralded as the bona fide function of PrPC, despite restricted attention paid to a selected phenotypic trait, associated with either modulation of gene expression or to the engagement of PrPC with a single ligand. In contrast, the GPI-anchored prion protein was shown to bind several extracellular and transmembrane ligands, which are required to endow that protein with the ability to play various roles in transmembrane signal transduction. In addition, differing sets of those ligands are available in cell type- and context-dependent scenarios. To account for such properties, we proposed that PrPC serves as a dynamic platform for the assembly of signaling modules at the cell surface, with widespread consequences for both physiology and behavior. The current review advances the hypothesis that the biological function of the prion protein is that of a cell surface scaffold protein, based on the striking similarities of its functional properties with those of scaffold proteins involved in the organization of intracellular signal transduction pathways. Those properties are: the ability to recruit spatially restricted sets of binding molecules involved in specific signaling; mediation of the crosstalk of signaling pathways; reciprocal allosteric regulation with binding partners; compartmentalized responses; dependence of signaling properties upon posttranslational modification; and stoichiometric requirements and/or oligomerization-dependent impact on signaling. The scaffold concept may contribute to novel approaches to the development of effective treatments to hitherto incurable neurodegenerative diseases, through informed modulation of prion protein-ligand interactions.

show abstract

Section: The Prion Protein As a Cell Surface Scaffold Proteinmentioning

confidence: 88%

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

Linden

2017

Front. Mol. Neurosci.

115

104

View full text Add to dashboard Cite

show abstract

“…Considering that only the higher dose of PNU‐282987 (10 mg/kg) was significantly effective in improving lung inflammation, we cannot rule out the possibility that off‐target effects also contributed to the beneficial effects of PNU‐282987. Because of the high structural similarity between α7nAChR and 5‐HT receptors, most α7nAChR agonists also act as 5‐HT3 antagonists (62). Our results provide the rationale and relevance for development of future therapeutic strategy to treat patients with α7nAChR modulators.…”

Section: Discussionmentioning

confidence: 99%

Acute lung injury is reduced by the α7nAChR agonist PNU‐282987 through changes in the macrophage profile

et al. 2016

View full text Add to dashboard Cite

Nicotinic α-7 acetylcholine receptor (nAChRα7) is a critical regulator of cholinergic anti-inflammatory actions in several diseases, including acute respiratory distress syndrome (ARDS). Given the potential importance of α7nAChR as a therapeutic target, we evaluated whether PNU-282987, an α7nAChR agonist, is effective in protecting the lung against inflammation. We performed intratracheal instillation of LPS to generate acute lung injury (ALI) in C57BL/6 mice. PNU-282987 treatment, either before or after ALI induction, reduced neutrophil recruitment and IL-1β, TNF-α, IL-6, keratinocyte chemoattractant (KC), and IL-10 cytokine levels in the bronchoalveolar lavage fluid (P< 0.05). In addition, lung NF-κB phosphorylation decreased, along with collagen fiber deposition and the number of matrix metalloproteinase-9 and -2 cells, whereas the number of tissue inhibitor of metalloproteinase-1 cells increased (P < 0.05). PNU-282987 treatment also reduced lung mRNA levels and the frequency of M1 macrophages, whereas cells expressing the M2-related markers CD206 and IL-10 increased, suggesting changes in the macrophage profile. Finally, PNU-282987 improved lung function in LPS-treated animals. The collective results suggest that PNU-282987, an agonist of α7nAChR, reduces LPS-induced experimental ALI, thus supporting the notion that drugs that act on α7nAChRs should be explored for ARDS treatment in humans.-Pinheiro, N. M., Santana, F. P. R., Almeida, R. R., Guerreiro, M., Martins, M. A., Caperuto, L. C., Câmara, N. O. S., Wensing, L. A., Prado, V. F., Tibério, I. F. L. C., Prado, M. A. M., Prado, C. M. Acute lung injury is reduced by the α7nAChR agonist PNU-282987 through changes in the macrophage profile.

show abstract

“…In humans but not rodents, CHRNA7 , the gene coding for α7 nAChR protein, is partially duplicated and known as CHRFAM7A (Bertrand et al, 2015). The partially duplicated gene can coassemble with full-length α7 nAChR to potentially regulate its expression and function, which might differentially influence agonist effects between human and rodent.…”

Section: Discussionmentioning

confidence: 99%

“…The partially duplicated gene can coassemble with full-length α7 nAChR to potentially regulate its expression and function, which might differentially influence agonist effects between human and rodent. Additional complexities of the human genetics of CHRNA7 include a highly unstable localization on chromosome 15 that predisposes to inversions, deletions, and duplications, as well as polymorphisms in the promoter region resulting in differential expression levels of the protein (Bertrand et al, 2015). The complexity of genetics of CHRNA7 in humans as compared to the analogous gene in rodents might influence the findings in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Alpha-7 nicotinic agonists for cognitive deficits in neuropsychiatric disorders: A translational meta-analysis of rodent and human studies

Lewis

Schalkwyk²,

Bloch³

2017

Progress in Neuro-Psychopharmacology and Biological Psychiatry

View full text Add to dashboard Cite

Cognitive dysfunction in schizophrenia (SCZ) and Alzheimer’s disease (AD) is a major driver of functional disability but is largely unresponsive to current therapeutics. Animal models of cognitive dysfunction relevant to both disorders suggest the α7 nicotinic acetylcholine receptor (nAChR) may be a promising drug development target, with multiple clinical trials subsequently testing this hypothesis in individuals with SCZ and AD. However, the translational value of rodent cognitive tasks for predicting the overall efficacy of this therapeutic target in clinical trials is unknown. To compare effect sizes between rodent and human studies, we searched PubMed and the Cochrane Library for all randomized, placebo-controlled trials of compounds with pharmacological activity at the α7 nAChR for treatment of cognitive dysfunction in SCZ and AD and identified 18 studies comprising 2670 subjects treated with eight different compounds acting as full or partial agonists. Cognitive outcomes were standardized, and random-effects meta-analyses revealed no statistically significant effects of α7 nAChR agonists on overall cognition or any of eight cognitive subdomains when all doses were included (Range of all cognitive outcomes: Cohen’s d = −0.077 to 0.12, negative favoring drug). In contrast, analysis of 29 rodent studies testing the same α7 agonists revealed large effect sizes in multiple commonly used preclinical behavioral tests of cognition (Range: d = −1.18 to −0.73). Our results suggest that targeting the α7 nAChR with agonists is not a robust treatment for cognitive dysfunction in SCZ or AD and necessitate a better understanding of the translational gap for therapeutics targeting the α7 nAChR.

show abstract

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

Cited by 130 publications

References 530 publications

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

Acute lung injury is reduced by the α7nAChR agonist PNU‐282987 through changes in the macrophage profile

Alpha-7 nicotinic agonists for cognitive deficits in neuropsychiatric disorders: A translational meta-analysis of rodent and human studies

Contact Info

Product

Resources

About