α7 Nicotinic Receptor Agonists: Potential Therapeutic Drugs for Treatment of Cognitive Impairments in Schizophrenia and Alzheimer’s Disease

Toyohara, Jun; Hashimoto, Kenji

doi:10.2174/1874104501004010037

Cited by 64 publications

(71 citation statements)

References 147 publications

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“…Selective α7nAChR agonists are currently evaluated as potential therapeutic drugs for the treatment of cognitive impairments in schizophrenia and Alzheimer's disease. [110][111][112][113][114] To date, however, only a very limited number of studies have been performed to evaluate their anti-inflammatory potential in humans. Based on the observation that the selective α7nAChR agonist GTS-21 attenuated cytokine production by stimulated whole blood and human monocytes more potently than nicotine, 115 116 its effect was tested in a human endotoxin model.…”

Section: Human Evidencementioning

confidence: 99%

The vagal innervation of the gut and immune homeostasis

Matteoli

Gomez‐Pinilla

Giovangiulio

et al. 2015

Autonomic Neuroscience

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The central nervous system interacts dynamically with the immune system to modulate inflammation through humoral and neural pathways. Recently, in animal models of sepsis, the vagus nerve (VN) has been proposed to play a crucial role in the regulation of the immune response, also referred to as the cholinergic anti-inflammatory pathway. The VN, through release of acetylcholine, dampens immune cell activation by interacting with α-7 nicotinic acetylcholine receptors. Recent evidence suggests that the vagal innervation of the gastrointestinal tract also plays a major role controlling intestinal immune activation. Indeed, VN electrical stimulation potently reduces intestinal inflammation restoring intestinal homeostasis, whereas vagotomy has the reverse effect. In this review, we will discuss the current understanding concerning the mechanisms and effects involved in the cholinergic anti-inflammatory pathway in the gastrointestinal tract. Deeper investigation on this counter-regulatory neuroimmune mechanism will provide new insights in the cross-talk between the nervous and immune system leading to the identification of new therapeutic targets to treat intestinal immune disease.

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Section: Human Evidencementioning

confidence: 99%

The vagal innervation of the gut and immune homeostasis

Matteoli

Gomez‐Pinilla

Giovangiulio

et al. 2015

Autonomic Neuroscience

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“…Both subtypes have been shown to be reduced in post-mortem studies of schizophrenia patients (Breese et al, 2000;Freedman et al, 1995). Post-mortem studies of Alzheimer's disease patients have revealed a reduction in the α4β2 subtype (Warpman and Nordberg, 1995) while studies showing changes in α7 receptor levels in this illness are conflicting (see Toyohara and Hashimoto, 2010 for review).…”

Section: Introductionmentioning

confidence: 99%

Nicotinic α7 and α4β2 agonists enhance the formation and retrieval of recognition memory: Potential mechanisms for cognitive performance enhancement in neurological and psychiatric disorders

McLean

Grayson

Marsh

et al. 2016

Behavioural Brain Research

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In the current study we investigated the efficacy of donepezil, risperidone and selective nicotinic α7 and α4β2 receptor agonists to reverse a delay-induced deficit in recognition memory. Adult female hooded-Lister rats received drug treatments and were tested in the novel object recognition (NOR) task following a 6 hour inter-trial interval (ITI). In all treatment groups there was no preference for the left or right identical objects in the acquisition trial. In the retention trial vehicle, risperidone (0.16mg/kg), PNU-282987, an α7 agonist (5mg/kg) and RJR-2403, an α4β2 agonist (1mg/kg) treated rats were unable to discriminate between the novel and familiar objects following a 6 hour ITI. In contrast, donepezil (1.0mg/kg), PNU-282987 (10mg/kg) and RJR-2403 (0.1mg/kg) treated rats spent significantly more time exploring the novel compared to the familiar object following the 6 hour ITI, indicative of enhanced cognitive performance (P<0.05-P<0.01). Interestingly, these compounds were efficacious when administered either before the acquisition or the retention trial of the task, suggesting an important role for nicotinic receptor subtypes in the formation and retrieval of recognition memory.

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“…Therefore, agonists and positive allosteric modulators (PAMs) of α7-nAChR are broadly investigated as potential drug leads against these CNS diseases. 20,21 The methodology developed encompasses LC separation of mixtures with parallel MS detection and nanofractionation onto 96-well plates. The 96-well plates are subsequently freeze-dried and then subjected to a functional α7-nAChR activity bioassay.…”

Section: Introductionmentioning

confidence: 99%

At-Line Cellular Screening Methodology for Bioactives in Mixtures Targeting the α7-Nicotinic Acetylcholine Receptor

et al. 2016

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The α7-nicotinic acetylcholine receptor (α7-nAChR) is a ligand-gated ion channel expressed in different regions of the central nervous system (CNS). The α7-nAChR has been associated with Alzheimer's disease, epilepsy, and schizophrenia, and therefore is extensively studied as a drug target for the treatment of these diseases. Important sources for new compounds in drug discovery are natural extracts. Since natural extracts are complex mixtures, identification of the bioactives demands the use of analytical techniques to separate a bioactive from inactive compounds. This study describes screening methodology for identifying bioactive compounds in mixtures acting on the α7-nAChR. The methodology developed combines liquid chromatography (LC) coupled via a split with both an at-line calcium (Ca 2+ )-flux assay and highresolution mass spectrometry (MS). This allows evaluation of α7-nAChR responses after LC separation, while parallel MS enables compound identification. The methodology was optimized for analysis of agonists and positive allosteric modulators, and was successfully applied to screening of the hallucinogen mushroom Psilocybe Mckennaii. The crude mushroom extract was analyzed using both reversed-phase and hydrophilic interaction liquid chromatography. Matching retention times and peak shapes of bioactives found with data from the parallel MS measurements allowed rapid pinpointing of accurate masses corresponding to the bioactives.

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α7 Nicotinic Receptor Agonists: Potential Therapeutic Drugs for Treatment of Cognitive Impairments in Schizophrenia and Alzheimer’s Disease

Cited by 64 publications

References 147 publications

The vagal innervation of the gut and immune homeostasis

The vagal innervation of the gut and immune homeostasis

Nicotinic α7 and α4β2 agonists enhance the formation and retrieval of recognition memory: Potential mechanisms for cognitive performance enhancement in neurological and psychiatric disorders

At-Line Cellular Screening Methodology for Bioactives in Mixtures Targeting the α7-Nicotinic Acetylcholine Receptor

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