Modulatory effects of α7 nAChRs on the immune system and its relevance for CNS disorders

Kalkman, Hans O.; Feuerbach, Dominik

doi:10.1007/s00018-016-2175-4

Cited by 146 publications

(110 citation statements)

References 252 publications

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“…They are associated closely with neurons, and play important roles in development, maintenance, and homeostasis (Dey et al, 2015; Graeber et al, 2011). Nevertheless, activated microglia and macrophages have many properties in common, including the production and release of inflammatory cytokines that are known to be cytotoxic (Dey et al, 2015; Kalkman and Feuerbach, 2016; Shytle et al, 2004). Accordingly, it should not be surprising that a large body of literature suggests that activated microglia are key players in a wide range of CNS disorders (Graeber et al, 2011; Kalkman and Feuerbach, 2016).…”

Section: Targeting α7nachrs On Microglia and Macrophages In Strokementioning

confidence: 99%

“…Nevertheless, activated microglia and macrophages have many properties in common, including the production and release of inflammatory cytokines that are known to be cytotoxic (Dey et al, 2015; Kalkman and Feuerbach, 2016; Shytle et al, 2004). Accordingly, it should not be surprising that a large body of literature suggests that activated microglia are key players in a wide range of CNS disorders (Graeber et al, 2011; Kalkman and Feuerbach, 2016). While some of these disorders do not involve inflammation in the classical sense (Graeber et al, 2011), there is the common thread that microglial activation to the M1 phenotype contributes to pathology (Graeber et al, 2011; Kalkman and Feuerbach, 2016).…”

Section: Targeting α7nachrs On Microglia and Macrophages In Strokementioning

confidence: 99%

“…Accordingly, it should not be surprising that a large body of literature suggests that activated microglia are key players in a wide range of CNS disorders (Graeber et al, 2011; Kalkman and Feuerbach, 2016). While some of these disorders do not involve inflammation in the classical sense (Graeber et al, 2011), there is the common thread that microglial activation to the M1 phenotype contributes to pathology (Graeber et al, 2011; Kalkman and Feuerbach, 2016). Furthermore, activated microglia are like macrophages in the expression of α7nAChRs that mediate inhibition of LPS-induced TNF-α release (Shytle et al, 2004).…”

Section: Targeting α7nachrs On Microglia and Macrophages In Strokementioning

confidence: 99%

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Cholinergic modulation of the immune system presents new approaches for treating inflammation

Hoover

2017

Pharmacology & Therapeutics

244

169

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The nervous system and immune system have broad and overlapping distributions in the body, and interactions of these ubiquitous systems are central to the field of neuroimmunology. Over the past two decades, there has been explosive growth in our understanding of neuroanatomical, cellular, and molecular mechanisms that mediate central modulation of immune functions through the autonomic nervous system. A major catalyst for growth in this field was the discovery that vagal nerve stimulation (VNS) caused a prominent attenuation of the systemic inflammatory response evoked by endotoxin in experimental animals. This effect was mediated by acetylcholine (ACh) stimulation of nicotinic receptors on splenic macrophages. Hence, the circuit was dubbed the “cholinergic anti-inflammatory pathway”. Subsequent work identified the α7 nicotinic ACh receptor (α7nAChR) as the crucial target for attenuation of pro-inflammatory cytokine release from macrophages and dendritic cells. Further investigation made the important discovery that cholinergic T cells within the spleen and not cholinergic nerve cells were the source of ACh that stimulated α7 receptors on splenic macrophages. Given the important role that inflammation plays in numerous disease processes, cholinergic anti-inflammatory mechanisms are under intensive investigation from a basic science perspective and in translational studies of animal models of diseases such as inflammatory bowel disease and rheumatoid arthritis. This basic work has already fostered several clinical trials examining the efficacy of VNS and cholinergic therapeutics in human inflammatory diseases. This review provides an overview of basic and translational aspects of the cholinergic anti-inflammatory response and relevant pharmacology of drugs acting at the α7nAChR.

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Section: Targeting α7nachrs On Microglia and Macrophages In Strokementioning

confidence: 99%

Section: Targeting α7nachrs On Microglia and Macrophages In Strokementioning

confidence: 99%

Section: Targeting α7nachrs On Microglia and Macrophages In Strokementioning

confidence: 99%

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Cholinergic modulation of the immune system presents new approaches for treating inflammation

Hoover

2017

Pharmacology & Therapeutics

244

169

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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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“…An important connection between the nervous system and the inflammatory response to diseases has been uncovered through the identification of α7 nAChR as an essential regulator of inflammation202122. In this report, we present the evidence that HIV-1 gp120, METH and NT significantly increased Aβ accumulation in HBMECS in an α7 nAChR dependent manner.…”

Section: Disscussionmentioning

confidence: 72%

Alpha7 nicotinic acetylcholine receptor is required for amyloid pathology in brain endothelial cells induced by Glycoprotein 120, methamphetamine and nicotine

Liu

et al. 2017

Sci Rep

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One of the most challenging issues in HIV-associated neurocognitive disorders (HAND) caused by HIV-1 virotoxins and drug abuse is the lack of understanding the underlying mechanisms that are commonly associated with disorders of the blood-brain barrier (BBB), which mainly consists of brain microvascular endothelial cells (BMEC). Here, we hypothesized that Glycoprotein 120 (gp120), methamphetamine (METH) and nicotine (NT) can enhance amyloid-beta (Aβ) accumulation in BMEC through Alpha7 nicotinic acetylcholine receptor (α7 nAChR). Both in vitro (human BMEC) (HBMEC) and in vivo (mice) models of BBB were used to dissect the role of α7 nAChR in up-regulation of Aβ induced by gp120, METH and NT. Aβ release from and transport across HBMEC were significantly increased by these factors. Methyllycaconitine (MLA), an antagonist of α7 nAChR, could efficiently block these pathogenic effects. Furthermore, our animal data showed that these factors could significantly increase the levels of Aβ, Tau and Ubiquitin C-Terminal Hydrolase L1 (UCHL1) in mouse cerebrospinal fluid (CSF) and Aβ in the mouse brains. These pathogenicities were significantly reduced by MLA, suggesting that α7 nAChR may play an important role in neuropathology caused by gp120, METH and NT, which are the major pathogenic factors contributing to the pathogenesis of HAND.

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Modulatory effects of α7 nAChRs on the immune system and its relevance for CNS disorders

Cited by 146 publications

References 252 publications

Cholinergic modulation of the immune system presents new approaches for treating inflammation

Cholinergic modulation of the immune system presents new approaches for treating inflammation

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

Alpha7 nicotinic acetylcholine receptor is required for amyloid pathology in brain endothelial cells induced by Glycoprotein 120, methamphetamine and nicotine

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