Alpha7 nicotinic acetylcholine receptor is required for blood-brain barrier injury-related CNS disorders caused by Cryptococcus neoformans and HIV-1 associated comorbidity factors

Abstract

BackgroundCryptococcal meningitis is the most common fungal infection of the central nervous system (CNS) in HIV/AIDS. HIV-1 virotoxins (e.g., gp41) are able to induce disorders of the blood-brain barrier (BBB), which mainly consists of BMEC. Our recent study suggests that α7 nAChR is an essential regulator of inflammation, which contributes to regulation of NF-κB signaling, neuroinflammation and BBB disorders caused by microbial (e.g., HIV-1 gp120) and non-microbial [e.g., methamphetamine (METH)] factors. However, the underlying mechanisms for multiple comorbidities are unclear.MethodsIn this report, an aggravating role of α7 nAChR in host defense against CNS disorders caused by these comorbidities was demonstrated by chemical [inhibitor: methyllycaconitine (MLA)] and genetic (α7−/− mice) blockages of α7 nAChR.ResultsAs shown in our in vivo studies, BBB injury was significantly reduced in α7−/− mice infected with C. neoformans. Stimulation by the gp41 ectodomain peptide (gp41-I90) and METH was abolished in the α7−/− animals. C. neoformans and gp41-I90 could activate NF-κB. Gp41-I90- and METH-induced monocyte transmigration and senescence were significantly inhibited by MLA and CAPE (caffeic acid phenethyl ester, an NF-κB inhibitor).ConclusionsCollectively, our data suggest that α7 nAChR plays a detrimental role in the host defense against C. neoformans- and HIV-1 associated comorbidity factors-induced BBB injury and CNS disorders.

Melatonin promotes blood-brain barrier integrity in methamphetamine-induced inflammation in primary rat brain microvascular endothelial cells

“…Thus, these results suggest that melatonin protects from METH-induced inflammation by directly inhibiting the NF-κB pathway and partly inhibiting the NOX2 mechanism. As previous studies have reviewed, the inflammation which triggers the NF-κB signaling was mediated via several mechanisms including NOX2, toll-like receptors (TLRs)-4, and α7-nicotinic acetylcholine receptors (α7-nAChR) (Gloire et al, 2006;Maloney et al, 2009;Gray and Jandeleit-Dahm, 2015;Zhang et al, 2015). From the result, the partial inhibition of NOX2 on NF-κB signaling might be co-activated with other mechanisms, especially the α7-nAChR which has been previously reported to have a role in inflammation due to BBB impairment that is caused by METH administration (Zhang et al, 2015).…”

“…As previous studies have reviewed, the inflammation which triggers the NF-κB signaling was mediated via several mechanisms including NOX2, toll-like receptors (TLRs)-4, and α7-nicotinic acetylcholine receptors (α7-nAChR) (Gloire et al, 2006;Maloney et al, 2009;Gray and Jandeleit-Dahm, 2015;Zhang et al, 2015). From the result, the partial inhibition of NOX2 on NF-κB signaling might be co-activated with other mechanisms, especially the α7-nAChR which has been previously reported to have a role in inflammation due to BBB impairment that is caused by METH administration (Zhang et al, 2015). Inhibition of the NF-κB activity, METH failed to induce BBB impairment by a decrease in the oxidative damage and the apoptosis, thereby increasing the BBB integrity, as observed in the increasing of the TEER value and the decreasing of the paracellular permeability.…”

“…BBB impairment by METH has been reviewed in several mechanisms, including the hyperactivity of NADPH oxidase (NOX)-2 which generates excessive amounts of free radicals, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) (Ramirez et al, 2009;Park et al, 2012); the dysfunction of cytoskeleton and the trans-membrane protein of tight junction, which is the controlling of paracellular permeability (Park et al, 2013;Fernandes et al, 2015); the dysfunction of the uptake and the efflux activities (ElAli et al, 2012); and the activation of caspase cascade in cell death response or apoptosis (Abdul-Muneer et al, 2011;Ma et al, 2014;Fisehr et al, 2015). Moreover, overexpression of inflammatory mediators such as inducible nitric oxide synthase (iNOS), nitric oxide (NO), interleukin (IL)-1, and tumor necrosis factor (TNF), which is an important factor in inflammatory response, has also been reported (Fernandes et al, 2014;CoelhoSantos et al, 2015;Parikh et al, 2015;Zhang et al, 2015;Skaper et al, 2014;Husain et al, 2015;Kothur et al, 2015). Previous studies have demonstrated that the release of cytokines causes progressive BBB impairment by the upregulation of leukocyte-endothelial cell adhesion molecules such as intercellular adhesion molecules (ICAM)-1, vascular cell adhesion molecules (VCAM)-1, and matrix metallopeptidase (MMP)-9 leads to tight junction impairment (Urrutia et al, 2013;Fernandes et al, 2014;Wang et al, 2014aWang et al, , 2014bParikh et al, 2015).…”

WITHDRAWN: Melatonin improves methamphetamine-induced blood brain barrier impairment through NADPH oxidase-2 in primary rat brain microvascular endothelium cells

“…As previous studies have reviewed, the inflammation which triggers the NF-κB signaling was mediated via several mechanisms including NOX2, toll-like receptors (TLRs)-4, and α7-nicotinic acetylcholine receptors (α7-nAChR) (Gloireet al, 2006;Maloney et al, 2009;Gray and Jandeleit-Dahm, 2015;Zhanget al, 2015). From the result, the partial inhibition of NOX2 on NF-κB signaling might be co-activated with other mechanisms, especially the α7-nAChR which has been previously reported to have a role in inflammation due to BBB impairment that is caused by METH administration (Zhang et al, 2015). Inhibition of the NF-κB activity, METH failed to induce BBB impairment by a decrease in the oxidative damage and the apoptosis, thereby increasing the BBB integrity, as observed in the increasing of the TEER value and the decreasing of the paracellular permeability.…”

“…BBB impairment by METH has been reviewed in several mechanisms, including the hyperactivity of NADPH oxidase (NOX)-2 which generates excessive amounts of free radicals, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) (Ramirez et al, 2009;Park et al, 2012); the dysfunction of cytoskeleton and the transmembrane protein of tight junction, which is the controlling of paracellular permeability (Park et al, 2013;Fernandes et al, 2015); the dysfunction of the uptake and the efflux activities (Elali et al, 2012); and the activation of caspase cascade in cell death response or apoptosis (Abdul et al, 2011;Ma et al, 2014;Fisher et al, 2015). Moreover, overexpression of inflammatory mediators such as inducible nitric oxide synthase (iNOS), nitric oxide (NO), interleukin (IL)-1, and tumor necrosis factor (TNF) α, which is an important factor in inflammatory response, has also been reported (Fernandes et al, 2014;Coelho-Santos et al, 2015;Parikh et al, 2015;Zhang et al, 2015;Skaper et al, 2014;Hussain et al, 2015;Kothur et al, 2015).…”