Effect of alpha-7 nicotinic acetylcholine receptor activation on beta-amyloid induced recognition memory impairment. Possible role of neurovascular function

Sadigh-Eteghad, Saeed; Mahmoudi, Javad; Babri, Shirin; Talebi, Mahnaz

doi:10.1590/s0102-865020150110000003

Cited by 31 publications

(12 citation statements)

References 29 publications

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“…CHRFAM7A , a human specific fusion gene in high frequency in the population, has been implicated in a broad array of neuropsychiatric disorders, including schizophrenia, bipolar disorder, dementia with Lewy bodies, Pick disease, and AD; all are human-specific diseases affecting association cortices and higher cognitive function 25 . While CHRN7A has been a promising target for diseases affecting cognition, the effect observed in animal models failed to translate in human clinical trials suggesting a human-specific mechanism 13,14 , we developed a model system to study the modifying effect of CHRFAM7A which (i) has the human biological context, (ii) allows studies in specific cell types, (iii) is a renewable source, and iv) is amenable to scaling. Adapting this iPSC system for high-throughput screening can advance drug discovery in diseases such as AD and schizophrenia and addresses unmet medical needs.…”

Section: Discussionmentioning

confidence: 99%

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iPSC model of CHRFAM7A effect on α7 nicotinic acetylcholine receptor function in the human context

et al. 2019

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The α7 nicotinic acetylcholine receptor (α7nAChR) has been a promising target for diseases affecting cognition and higher cortical functions; however, the effect observed in animal models failed to translate into human clinical trials identifying a translational gap. CHRFAM7A is a human-specific fusion gene with properties that enable incorporation into the α7nAChR and, being human specific, CHRFAM7A effect was not accounted for in preclinical studies. We hypothesized that CHRFAM7A may account for this translational gap and understanding its function may offer novel insights when exploring α7nAChR as a drug target. CHRFAM7A is present in different copy number variations (CNV) in the human genome with high frequency. To study the functional consequences of the presence of the CHRFAM7A, two induced pluripotent stem cell (iPSC) lines (0 copy and 1 copy direct) were developed. The 0 copy line was rescued with CHRFAM7A transfection to control for genetic heterogeneity. As readouts for genotype–phenotype correlation, α7nAChR synaptic transmission and amyloid beta 1–42 (Aβ1–42) uptake were tested. Synaptic transmission in the presence of CHRFAM7A demonstrated that PNU-modulated desensitization of α7nAChR currents increased as a function of CHRFAM7A dosage. CHRFAM7A mitigated the dose response of Aβ1–42 uptake suggesting a protective effect beyond physiological concentrations. Furthermore, in the presence of CHRFAM7A Aβ1–42 uptake activated neuronal interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) without activating the canonical inflammasome pathway. Lead optimization may identify more potent molecules when the screen has a model harboring CHRFAM7A. Incorporating pharmacogenetics into clinical trials may enhance signals in efficacy measures.

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Section: Discussionmentioning

confidence: 99%

“…Agonists and positive allosteric modulators (PAMs) of α7nAChR are being tested in clinical trials for central nervous system indications 11 , and a translational gap emerged 12 . While animal studies consistently demonstrate a cognitive benefit, this effect was not apparent in human trials 13,14 .…”

Section: Introductionmentioning

confidence: 94%

iPSC model of CHRFAM7A effect on α7 nicotinic acetylcholine receptor function in the human context

et al. 2019

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“…It is believed that impaired cerebral vascular perfusion is the one of the first manifestations of most brain disorders [116–119]. NO is a powerful vasodilator which could be released by photodissociation process from its binding sites in the respiratory chain during PBM.…”

Section: Neurobiological Impactsmentioning

confidence: 99%

Brain Photobiomodulation Therapy: a Narrative Review

et al. 2018

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Brain photobiomodulation (PBM) therapy using red to near-infrared (NIR) light is an innovative treatment for a wide range of neurological and psychological conditions. Red/NIR light is able to stimulate complex IV of the mitochondrial respiratory chain (cytochrome c oxidase) and increase ATP synthesis. Moreover, light absorption by ion channels results in release of Ca and leads to activation of transcription factors and gene expression. Brain PBM therapy enhances the metabolic capacity of neurons and stimulates anti-inflammatory, anti-apoptotic, and antioxidant responses, as well as neurogenesis and synaptogenesis. Its therapeutic role in disorders such as dementia and Parkinson's disease, as well as to treat stroke, brain trauma, and depression has gained increasing interest. In the transcranial PBM approach, delivering a sufficient dose to achieve optimal stimulation is challenging due to exponential attenuation of light penetration in tissue. Alternative approaches such as intracranial and intranasal light delivery methods have been suggested to overcome this limitation. This article reviews the state-of-the-art preclinical and clinical evidence regarding the efficacy of brain PBM therapy.

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“…Studies have reported a significant anti-inflammatory effect on primary cultures of neurons and astrocytes (unpublished observations, G. Page). In vivo, it improved recognition memory in an AD mouse model [35]. Moreover, promising effects on cognitive function were also observed in a schizophrenia' disease model [33].…”

Section: Introductionmentioning

confidence: 84%

Neuroprotective effect of the alpha 7 nicotinic receptor agonist PHA 543613 in an in vivo excitotoxic adult rat model

Foucault-Fruchard¹,

Doméné²,

Page³

et al. 2017

Neuroscience

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Neuroinflammation is a key component of the pathophysiology of neurodegenerative diseases. The link between nicotine intake and positive outcome has been established, suggesting a role played by nicotinic receptors (nAChRs), especially α7nAChRs. The objective of this study was to evaluate the potential dose effects of PHA 543613 on neuron survival and striatal microglial activation in a rat model of brain excitotoxicity. A preliminary study was performed in vitro to confirm PHA 543613 agonist properties on α7nAChRs. Rats were lesioned in the right striatum with quinolinic acid (QA) and received either vehicle or PHA 543613 at 6 or 12mg/kg twice a day until sacrifice at Day 4 post-lesion. We first compared the translocator protein quantitative autoradiography in QA-lesioned brains with [H]DPA-714 and [H]PK-11195. The effects of PHA 543613 on microglial activation and neuronal survival were then evaluated through [H]DPA-714 binding and immunofluorescence staining (Ox-42, NeuN) on adjacent brain sections. We demonstrated that [H]DPA-714 provides a better signal-to-noise ratio than [H]PK-11195. Furthermore, we showed that repeated PHA 543613 administration at a dose of 12mg/kg to QA-lesioned rats significantly protected neurons and reduced the intensity of microglial activation. This study reinforces the hypothesis that α7nAChR agonists can provide beneficial effects in the treatment of neurodegenerative diseases through potential modulation of microglial activation.

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Effect of alpha-7 nicotinic acetylcholine receptor activation on beta-amyloid induced recognition memory impairment. Possible role of neurovascular function

Cited by 31 publications

References 29 publications

iPSC model of CHRFAM7A effect on α7 nicotinic acetylcholine receptor function in the human context

iPSC model of CHRFAM7A effect on α7 nicotinic acetylcholine receptor function in the human context

Brain Photobiomodulation Therapy: a Narrative Review

Neuroprotective effect of the alpha 7 nicotinic receptor agonist PHA 543613 in an in vivo excitotoxic adult rat model

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