Suppression of neuroinflammation and immunomodulation by the acetylcholinesterase inhibitor rivastigmine

Nizri, Eran; Irony-Tur-Sinai, Michal; Faranesh, Nabil; Lavon, Iris; Lavi, Ehud; Weinstock, Marta; Brenner, Talma

doi:10.1016/j.jneuroim.2008.06.018

Cited by 108 publications

(86 citation statements)

References 36 publications

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“…In line with this observation, different inhibitors of AChE activity reduce the production of IL-17 and IFN-γ [33,43], and TNF-α [26,43] in T cells. These results further support our suggestion that the suppression of proinflammatory cytokines by TCDD is a component of miR-132-mediated cholinergic anti-inflammatory system.…”

Section: Discussionsupporting

confidence: 67%

MicroRNA‐132 suppresses autoimmune encephalomyelitis by inducing cholinergic anti‐inflammation: A new Ahr‐based exploration

Hanieh

Abdullah

2013

Eur J Immunol

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MicroRNAs (miRNAs) are a small group of RNAs that are emerging as a new avenue by which autoimmune diseases may be modulated. Accumulating evidence shows that miRNAs are involved in the pathogenesis of MS; however, the interaction of miRNAs with environmentally responsive transcription factors that play prominent roles in MS is unexplored. The activation of aryl hydrocarbon receptor by 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) alleviates inflammation in experimental autoimmune encephalomyelitis (EAE), the best available model of MS. Therefore, we predicted that TCDD could attenuate EAE by inducing miRNA(s) targeting inflammatory mediators. Here, we show that TCDD induces cholinergic anti-inflammation in EAE mice by upregulating acetylcholinesterasetargeting miR-132. The expression of miR-132 was downregulated in CD4 + cells and associated with EAE severity, while TCDD treatment attenuated EAE by inducing the miR-132/acetylcholinesterase module. Silencing miR-132 in vivo abolished TCDDinduced cholinergic anti-inflammation and aggravated EAE. Overexpression of miR-132 in encephalitogenic CD4 + cells decreased IL-17 and IFN-γ and suppressed T-cell proliferation. In conclusion, our findings identify a new miRNA-based mechanism through which miR-132 mediates TCDD-induced EAE attenuation, suggesting that miR-132 could be a promising therapeutic target for anti-inflammatory treatment of MS.Keywords: Ahr r Cholinergic anti-inflammation r EAE · MicroRNA r miR-132 r TCDD Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe aryl hydrocarbon receptor (Ahr) is a ligand-dependent transcription factor activated by a long list of exogenous ligands including 2,3,7, [1] and 3-methylcholanthrene [2]. Ahr has been shown to mediate the mechanisms that underlie environmental and immunotoxicity [3]. Therefore, Ahr represents a fascinating link between the environment and the immune system. Previously, we and others have Correspondence: Dr. Hanieh Hamza e-mail: hhanieh@kfu.edu.sa demonstrated that Ahr is implicated in the differentiation of Th17/Treg cells [4][5][6], development of autoimmunity [7], and secretion of proinflammatory cytokines [8,9]. Importantly, activation of Ahr has shown a therapeutic potential for autoimmune inflammation. For example, TCDD mitigates CNS inflammation in experimental autoimmune encephalomyelitis (EAE) [5], an established animal model of MS. However, the toxicity of TCDD prohibits its clinical application, and therefore, mechanistic explanation of TCDD-attenuated inflammation may open intriguing possibilities for applicable treatment of MS in human.The microRNAs (miRNAs) are small endogenous noncoding RNAs of ∼22 nt that post-transcriptionally regulate gene expression. These molecules are implicated in different aspects of C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Hanieh Hamza and Alzahrani AbdullahEur. J. Immunol. 2013Immunol. . 43: 2771Immunol. -2782 inflammation. For instance, miR-155, miR-146a, a...

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Section: Discussionsupporting

confidence: 67%

MicroRNA‐132 suppresses autoimmune encephalomyelitis by inducing cholinergic anti‐inflammation: A new Ahr‐based exploration

Hanieh

Abdullah

2013

Eur J Immunol

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“…We used FITC-conjugated ␣-bungarotoxin (␣-btx; Molecular Probes), a cholinergic nicotinic blocker, for ␣7 detection. Incubation with antisense (AS) to the ␣5 and the ␣7 subunits and the specific sequence of the AS were described previously (9). For leukocyte surface markers, pooled spleen cells were obtained from wild-type (WT) and knockout (KO) mice (as described in the mouse lymphocyte proliferation assay).…”

Section: Flow Cytometry Analysismentioning

confidence: 99%

“…The mice were housed under specific pathogenfree conditions in the animal facility at the Hebrew University Medical School in accordance with National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. All animals were examined daily and evaluated for clinical signs of disease according to a previously described scale (9). Nicotine treatment was delivered by ALZET miniosmotic pumps (DURECT).…”

Section: Eae Induction and Treatmentmentioning

confidence: 99%

“…Signaling downstream to ␣7 nAChR in this system involves the NF-B pathway (7), and vagal innervation was implicated as the source of ACh for the immune cells (8). A previous study done in our laboratory showed that pharmacological activation of ␣7 on T cells has similar anti-inflammatory effects, highlighting the relevance of the cholinergic anti-inflammatory pathway also in adaptive immunity (3,9). However, the specific mechanisms by which ␣7 nAChR activation regulates the immune response are not clearly defined.…”

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confidence: 98%

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Activation of the Cholinergic Anti-Inflammatory System by Nicotine Attenuates Neuroinflammation via Suppression of Th1 and Th17 Responses

Nizri

Irony-Tur-Sinai

Lory

et al. 2009

The Journal of Immunology

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261

230

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The α7 nicotinic acetylcholine receptor (nAChR) was recently described as an anti-inflammatory target in both macrophages and T cells. Its expression by immune cells may explain the epidemiological data claiming a negative link between cigarette smoking and several inflammatory diseases. In this study, we determined the immunological effects of α7 nAChR activation by nicotine. Our results indicate that the α7 nAChR is expressed on the surface of CD4+ T cells and that this expression is up-regulated upon immune activation. Nicotine reduced T cell proliferation in response to an encephalitogenic Ag, as well as the production of Th1 (TNF-α and IFN-γ) and Th17 cytokines (IL-17, IL-17F, IL-21, and IL-22). IL-4 production was increased in the same setting. Attenuation of the Th1 and Th17 lineages was accompanied by reduced T-bet (50%) and increased GATA-3 (350%) expression. Overall, nicotine induced a shift to the Th2 lineage. However, α7−/−-derived T cells were unaffected by nicotine. Furthermore, nicotine reduced NF-κB-mediated transcription as measured by IL-2 and IκB transcription. In vivo, administration of nicotine (2 mg/kg s.c.) suppressed the severity of CD4+ T cell-mediated disease experimental autoimmune encephalomyelitis. α7−/− mice were refractory to nicotine treatment, although disease severity in those animals was reduced, due to impairment in Ag presentation. Accordingly, CD4+ and CD11b+ cells infiltration into the CNS, demyelination, and axonal loss were reduced. Our data implicate a role for the α7 nAChR in immune modulation and suggest that α7 nAChR agonists may be effective in the treatment of inflammatory disorders.

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“…These protective effects could be prevented by the simultaneous injection of mecamylamine, but not by scopolamine [110] , suggesting that the therapeutic effects on cerebrovascular type dementia of rivastigmine may be related to nAChR-mediated cholinergic www.nature.com/aps Wang J et al Acta Pharmacologica Sinica npg enhancement. Moreover, in a mouse model of multiple sclerosis, rivastigmine administration ameliorated neurological dysfunction and memory deficits, and this treatment decreased reactivity of T cells and reduced the production of TNF-α and interferon-γ (INF-γ), which can also be abolished by α7 nACh receptor antagonist [112] . Rivastigmine also lowered lipopolysaccharide-induced over-expression of IL-2 in mice through inhibiting the enhanced activity of AChE [101] .…”

Section: Rivastigminementioning

confidence: 99%

Cholinergic deficiency involved in vascular dementia: possible mechanism and strategy of treatment

2009

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Vascular dementia (VaD) is a progressive neurodegenerative disease with a high prevalence. Several studies have recently reported that VaD patients present cholinergic deficits in the brain and cerebrospinal fluid (CSF) that may be closely related to the pathophysiology of cognitive impairment. Moreover, cholinergic therapies have shown promising effects on cognitive improvement in VaD patients. The precise mechanisms of these cholinergic agents are currently not fully understood; however, accumulating evidence indicates that these drugs may act through the cholinergic anti-inflammatory pathway, in which the efferent vagus nerve signals suppress pro-inflammatory cytokine release and inhibit inflammation, although regulation of oxidative stress and energy metabolism, alleviation of apoptosis may also be involved. In this paper, we provide a brief overview of the cholinergic treatment strategy for VaD and its relevant mechanisms of anti-inflammation.

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Suppression of neuroinflammation and immunomodulation by the acetylcholinesterase inhibitor rivastigmine

Cited by 108 publications

References 36 publications

MicroRNA‐132 suppresses autoimmune encephalomyelitis by inducing cholinergic anti‐inflammation: A new Ahr‐based exploration

MicroRNA‐132 suppresses autoimmune encephalomyelitis by inducing cholinergic anti‐inflammation: A new Ahr‐based exploration

Activation of the Cholinergic Anti-Inflammatory System by Nicotine Attenuates Neuroinflammation via Suppression of Th1 and Th17 Responses

Cholinergic deficiency involved in vascular dementia: possible mechanism and strategy of treatment

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