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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2017

Open Access 01-12-2017 | Research

Pharmacologic activation of cholinergic alpha7 nicotinic receptors mitigates depressive-like behavior in a mouse model of chronic stress

Authors: Dan Zhao, Xulin Xu, Linna Pan, Wei Zhu, Xiaopei Fu, Lianjun Guo, Qing Lu, Jian Wang

Published in: Journal of Neuroinflammation | Issue 1/2017

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Abstract

Background

It has been shown that chronic stress-induced depression is associated with exaggerated inflammatory response in the brain. Alpha7 nicotinic acetylcholine receptors (α7nAChRs) regulate the cholinergic anti-inflammatory pathway, but the role of cholinergic signaling and α7nAChR in chronic stress has not yet been examined.

Methods

In this study, we used a well-documented model of depression in which mice were exposed to 6 h of restraint stress for 21 consecutive days. Components of cholinergic signaling and TLR4 signaling were analyzed in the hippocampus. The main targets of neuroinflammation and neuronal damage were also evaluated after a series of tests for depression-like behavior.

Results

Chronic restraint stress (CRS) induced alterations in components of central cholinergic signaling in hippocampus, including increases in choline acetyltransferase protein expression and decreases in nuclear STAT3 signaling. CRS also increased TLR4 signaling activity, interleukin-1β, and tumor necrosis factor-α expression, microglial activation, and neuronal morphologic changes. Cholinergic stimulation with the α7nAChR agonist DMXBA significantly alleviated CRS-induced depressive-like behavior, neuroinflammation, and neuronal damage, but these effects were abolished by the selective α7nAChR antagonist α-bungarotoxin. Furthermore, activation of α7nAChRs restored the central cholinergic signaling function, inhibited TLR4-mediated inflammatory signaling and microglial activity, and increased the number of regulatory T cells in the hippocampus.

Conclusions

These findings provide evidence that α7nAChR activation mitigates CRS-induced neuroinflammation and cell death, suggesting that α7nAChRs could be a new therapeutic target for the prevention and treatment of depression.
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Literature
1.
Buynitsky T, Mostofsky DI. Restraint stress in biobehavioral research: recent developments. Neurosci Biobehav Rev. 2009;33:1089–98.CrossRefPubMed
2.
Garate I, Garcia-Bueno B, Madrigal JL, Bravo L, Berrocoso E, Caso JR, Mico JA, Leza JC. Origin and consequences of brain toll-like receptor 4 pathway stimulation in an experimental model of depression. J Neuroinflammation. 2011;8:151.CrossRefPubMedPubMedCentral
3.
Garate I, Garcia-Bueno B, Madrigal JL, Caso JR, Alou L, Gomez-Lus ML, Mico JA, Leza JC. Stress-induced neuroinflammation: role of the toll-like receptor-4 pathway. Biol Psychiatry. 2013;73:32–43.CrossRefPubMed
4.
Zhang Z, Lu H, Yang Q, Wu H, Wang J. Microglial polarization and inflammatory mediators after Intracerebral hemorrhage. Mol Neurobiol. 2017;54:1874–86.CrossRefPubMed
5.
Doyle SL, O'Neill LA. Toll-like receptors: from the discovery of NFkappaB to new insights into transcriptional regulations in innate immunity. Biochem Pharmacol. 2006;72:1102–13.CrossRefPubMed
6.
Trotta T, Porro C, Calvello R, Panaro MA. Biological role of toll-like receptor-4 in the brain. J Neuroimmunol. 2014;268:1–12.CrossRefPubMed
7.
Lucas K, Maes M. Role of the toll like receptor (TLR) radical cycle in chronic inflammation: possible treatments targeting the TLR4 pathway. Mol Neurobiol. 2013;48:190–204.CrossRefPubMed
8.
9.
Czura CJ, Friedman SG, Tracey KJ. Neural inhibition of inflammation: the cholinergic anti-inflammatory pathway. J Endotoxin Res. 2003;9:409–13.CrossRefPubMed
10.
11.
12.
Guan YZ, Jin XD, Guan LX, Yan HC, Wang P, Gong Z, Li SJ, Cao X, Xing YL, Gao TM. Nicotine inhibits microglial proliferation and is neuroprotective in global ischemia rats. Mol Neurobiol. 2015;51:1480–8.CrossRefPubMed
13.
Li H, Zhang ZZ, Zhan J, He XH, Song XM, Wang YL. Protective effect of PNU-120596, a selective alpha7 nicotinic acetylcholine receptor-positive allosteric modulator, on myocardial ischemia-reperfusion injury in rats. J Cardiovasc Pharmacol. 2012;59:507–13.CrossRefPubMed
14.
Lee ST, Chu K, Jung KH, Kang KM, Kim JH, Bahn JJ, Jeon D, Kim M, Lee SK, Roh JK. Cholinergic anti-inflammatory pathway in intracerebral hemorrhage. Brain Res. 2010;1309:164–71.CrossRefPubMed
15.
Norman GJ, Morris JS, Karelina K, Weil ZM, Zhang N, Al-Abed Y, Brothers HM, Wenk GL, Pavlov VA, Tracey KJ, Devries AC. Cardiopulmonary arrest and resuscitation disrupts cholinergic anti-inflammatory processes: a role for cholinergic alpha7 nicotinic receptors. J Neurosci. 2011;31:3446–52.CrossRefPubMedPubMedCentral
16.
Pavlov VA, Ochani M, Yang LH, Gallowitsch-Puerta M, Ochani K, Lin X, Levi J, Parrish WR, Rosas-Ballina M, Czura CJ, et al. Selective alpha7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis. Crit Care Med. 2007;35:1139–44.CrossRefPubMed
17.
Caso JR, Pradillo JM, Hurtado O, Leza JC, Moro MA, Lizasoain I. Toll-like receptor 4 is involved in subacute stress-induced neuroinflammation and in the worsening of experimental stroke. Stroke. 2008;39:1314–20.CrossRefPubMed
18.
Huang P, Li C, Fu T, Zhao D, Yi Z, Lu Q, Guo L, Xu X. Flupirtine attenuates chronic restraint stress-induced cognitive deficits and hippocampal apoptosis in male mice. Behav Brain Res. 2015;288:1–10.CrossRefPubMed
19.
Briggs CA, Anderson DJ, Brioni JD, Buccafusco JJ, Buckley MJ, Campbell JE, Decker MW, Donnelly-Roberts D, Elliott RL, Gopalakrishnan M, et al. Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21 in vitro and in vivo. Pharmacol Biochem Behav. 1997;57:231–41.CrossRefPubMed
20.
Liu Q, Li B, Zhu HY, Wang YQ, Yu J, Wu GC. Clomipramine treatment reversed the glial pathology in a chronic unpredictable stress-induced rat model of depression. Eur Neuropsychopharmacol. 2009;19:796–805.CrossRefPubMed
21.
Jiang B, Wang W, Wang F, ZL H, Xiao JL, Yang S, Zhang J, Peng XZ, Wang JH, Chen JG. The stability of NR2B in the nucleus accumbens controls behavioral and synaptic adaptations to chronic stress. Biol Psychiatry. 2013;74:145–55.CrossRefPubMed
22.
Zhu W, Gao Y, Chang CF, Wan JR, Zhu SS, Wang J. Mouse models of intracerebral hemorrhage in ventricle, cortex, and hippocampus by injections of autologous blood or collagenase. PLoS One. 2014;9:e97423.CrossRefPubMedPubMedCentral
23.
Han A, Yeo H, Park MJ, Kim SH, Choi HJ, Hong CW, Kwon MS. IL-4/10 prevents stress vulnerability following imipramine discontinuation. J Neuroinflammation. 2015;12:197.CrossRefPubMedPubMedCentral
24.
Wang J, Yu L, Jiang C, Fu X, Liu X, Wang M, Ou C, Cui X, Zhou C. Cerebral ischemia increases bone marrow CD4+CD25+FoxP3+ regulatory T cells in mice via signals from sympathetic nervous system. Brain Behav Immun. 2015;43:172–83.CrossRefPubMed
25.
Li C, Lu Q, Huang P, Fu T, Guo L, Xu X. Activity-dependent downregulation of M-type (Kv7) K(+) channels surface expression requires the activation of iGluRs/Ca(2)(+)/PKC signaling pathway in hippocampal neuron. Neuropharmacology. 2015;95:154–67.CrossRefPubMed
26.
Lu Q, Xia N, Xu H, Guo L, Wenzel P, Daiber A, Munzel T, Forstermann U, Li H. Betulinic acid protects against cerebral ischemia-reperfusion injury in mice by reducing oxidative and nitrosative stress. Nitric Oxide. 2011;24:132–8.CrossRefPubMed
27.
Cheng T, Wang W, Li Q, Han X, Xing J, Qi C, Lan X, Wan J, Potts A, Guan F, Wang J. Cerebroprotection of flavanol (-)-epicatechin after traumatic brain injury via Nrf2-dependent and -independent pathways. Free Radic Biol Med. 2016;92:15–28.CrossRefPubMed
28.
Lan X, Han X, Li Q, Gao Y, Cheng T, Wan J, Zhu W, Wang J. Pinocembrin protects hemorrhagic brain primarily by inhibiting toll-like receptor 4 and reducing M1 phenotype microglia. Brain Behav Immun. 2017;61:326–39.CrossRefPubMed
29.
Srikumar BN, Raju TR, Shankaranarayana Rao BS. The involvement of cholinergic and noradrenergic systems in behavioral recovery following oxotremorine treatment to chronically stressed rats. Neuroscience. 2006;143:679–88.CrossRefPubMed
30.
Lykhmus O, Mishra N, Koval L, Kalashnyk O, Gergalova G, Uspenska K, Komisarenko S, Soreq H, Skok M. Molecular mechanisms regulating LPS-induced inflammation in the brain. Front Mol Neurosci. 2016;9:19.CrossRefPubMedPubMedCentral
31.
Li Y, XL X, Zhao D, Pan LN, Huang CW, Guo LJ, Lu Q, Wang J. TLR3 ligand poly IC attenuates reactive astrogliosis and improves recovery of rats after focal cerebral ischemia. CNS Neurosci Ther. 2015;21:905–13.CrossRefPubMedPubMedCentral
32.
Zhao X, Wu T, Chang CF, Wu H, Han X, Li Q, Gao Y, Hou Z, Maruyama T, Zhang J, Wang J. Toxic role of prostaglandin E2 receptor EP1 after intracerebral hemorrhage in mice. Brain Behav Immun. 2015;46:293–310.CrossRefPubMedPubMedCentral
33.
Lu C, Hua F, Liu L, Ha T, Kalbfleisch J, Schweitzer J, Kelley J, Kao R, Williams D, Li C. Scavenger receptor class-A has a central role in cerebral ischemia-reperfusion injury. J Cereb Blood Flow Metab. 2010;30:1972–81.CrossRefPubMedPubMedCentral
34.
Wu H, Wu T, Hua W, Dong X, Gao Y, Zhao X, Chen W, Cao W, Yang Q, Qi J, et al. PGE2 receptor agonist misoprostol protects brain against intracerebral hemorrhage in mice. Neurobiol Aging. 2015;36:1439–50.CrossRefPubMedPubMedCentral
35.
Li CJ, Lu Y, Zhou M, Zong XG, Li C, XL X, Guo LJ, Lu Q. Activation of GABAB receptors ameliorates cognitive impairment via restoring the balance of HCN1/HCN2 surface expression in the hippocampal CA1 area in rats with chronic cerebral hypoperfusion. Mol Neurobiol. 2014;50:704–20.CrossRefPubMed
36.
Pan LN, Zhu W, Li Y, Xu XL, Guo LJ, Lu Q, Wang J. Astrocytic toll-like receptor 3 is associated with ischemic preconditioning-induced protection against brain ischemia in rodents. PLoS One. 2014;9:e99526.CrossRefPubMedPubMedCentral
37.
Voorhees JL, Powell ND, Moldovan L, Mo X, Eubank TD, Marsh CB. Chronic restraint stress upregulates erythropoiesis through glucocorticoid stimulation. PLoS One. 2013;8:e77935.CrossRefPubMedPubMedCentral
38.
Nair A, Bonneau RH. Stress-induced elevation of glucocorticoids increases microglia proliferation through NMDA receptor activation. J Neuroimmunol. 2006;171:72–85.CrossRefPubMed
39.
Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016;16:22–34.CrossRefPubMedPubMedCentral
40.
Yue N, Huang H, Zhu X, Han Q, Wang Y, Li B, Liu Q, Wu G, Zhang Y, Yu J. Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stress-induced depressive-like behaviors. J Neuroinflammation. 2017;14:102.CrossRefPubMedPubMedCentral
41.
Calcia MA, Bonsall DR, Bloomfield PS, Selvaraj S, Barichello T, Howes OD. Stress and neuroinflammation: a systematic review of the effects of stress on microglia and the implications for mental illness. Psychopharmacology. 2016;233:1637–50.CrossRefPubMedPubMedCentral
42.
Lan X, Han X, Li Q, Yang QW, Wang J. Modulators of microglial activation and polarization after intracerebral haemorrhage. Nat Rev Neurol. 2017;13:420–33.CrossRefPubMedPubMedCentral
43.
Zhu W, Cao FS, Feng J, Chen HW, Wan JR, Lu Q, Wang J. NLRP3 inflammasome activation contributes to long-term behavioral alterations in mice injected with lipopolysaccharide. Neuroscience. 2017;343:77–84.CrossRefPubMed
44.
Wu H, Zhang Z, Hu X, Zhao R, Song Y, Ban X, Qi J, Wang J. Dynamic changes of inflammatory markers in brain after hemorrhagic stroke in humans: a postmortem study. Brain Res. 2010;1342:111–7.CrossRefPubMed
45.
MacDowell KS, Caso JR, Martin-Hernandez D, Madrigal JL, Leza JC, Garcia-Bueno B. Paliperidone prevents brain toll-like receptor 4 pathway activation and neuroinflammation in rat models of acute and chronic restraint stress. Int J Neuropsychopharmacol. 2015;18
46.
Woodruff-Pak DS. Mecamylamine reversal by nicotine and by a partial alpha7 nicotinic acetylcholine receptor agonist (GTS-21) in rabbits tested with delay eyeblink classical conditioning. Behav Brain Res. 2003;143:159–67.CrossRefPubMed
47.
Parada E, Egea J, Buendia I, Negredo P, Cunha AC, Cardoso S, Soares MP, Lopez MG. The microglial alpha7-acetylcholine nicotinic receptor is a key element in promoting neuroprotection by inducing heme oxygenase-1 via nuclear factor erythroid-2-related factor 2. Antioxid Redox Signal. 2013;19:1135–48.CrossRefPubMedPubMedCentral
48.
Egea J, Buendia I, Parada E, Navarro E, Leon R, Lopez MG. Anti-inflammatory role of microglial alpha7 nAChRs and its role in neuroprotection. Biochem Pharmacol. 2015;97:463–72.CrossRefPubMed
49.
50.
Hannestad JO, Cosgrove KP, DellaGioia NF, Perkins E, Bois F, Bhagwagar Z, Seibyl JP, McClure-Begley TD, Picciotto MR, Esterlis I. Changes in the cholinergic system between bipolar depression and euthymia as measured with [123I]5IA single photon emission computed tomography. Biol Psychiatry. 2013;74:768–76.CrossRefPubMedPubMedCentral
51.
Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301:386–9.CrossRefPubMed
52.
53.
Brea D, Agulla J, Rodriguez-Yanez M, Barral D, Ramos-Cabrer P, Campos F, Almeida A, Davalos A, Castillo J. Regulatory T cells modulate inflammation and reduce infarct volume in experimental brain ischaemia. J Cell Mol Med. 2014;18:1571–9.CrossRefPubMedPubMedCentral
54.
Li P, Gan Y, Sun BL, Zhang F, Lu B, Gao Y, Liang W, Thomson AW, Chen J, Hu X. Adoptive regulatory T-cell therapy protects against cerebral ischemia. Ann Neurol. 2013;74:458–71.CrossRefPubMedPubMedCentral
55.
Liesz A, Suri-Payer E, Veltkamp C, Doerr H, Sommer C, Rivest S, Giese T, Veltkamp R. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med. 2009;15:192–9.CrossRefPubMed
56.
Kim SJ, Lee H, Lee G, SJ O, Shin MK, Shim I, Bae H. CD4+CD25+ regulatory T cell depletion modulates anxiety and depression-like behaviors in mice. PLoS One. 2012;7:e42054.CrossRefPubMedPubMedCentral
57.
Eyre H, Baune BT. Neuroplastic changes in depression: a role for the immune system. Psychoneuroendocrinology. 2012;37:1397–416.CrossRefPubMed
58.
Li Y, Xiao B, Qiu W, Yang L, Hu B, Tian X, Yang H. Altered expression of CD4(+)CD25(+) regulatory T cells and its 5-HT(1a) receptor in patients with major depression disorder. J Affect Disord. 2010;124:68–75.CrossRefPubMed
59.
Saul AN, Oberyszyn TM, Daugherty C, Kusewitt D, Jones S, Jewell S, Malarkey WB, Lehman A, Lemeshow S, Dhabhar FS. Chronic stress and susceptibility to skin cancer. J Natl Cancer Inst. 2005;97:1760–7.CrossRefPubMedPubMedCentral
60.
Mineur YS, Fote GM, Blakeman S, Cahuzac EL, Newbold SA, Picciotto MR. Multiple nicotinic acetylcholine receptor subtypes in the mouse amygdala regulate affective behaviors and response to social stress. Neuropsychopharmacology. 2016;41:1579–87.CrossRefPubMed
Metadata
Title
Pharmacologic activation of cholinergic alpha7 nicotinic receptors mitigates depressive-like behavior in a mouse model of chronic stress
Authors
Dan Zhao
Xulin Xu
Linna Pan
Wei Zhu
Xiaopei Fu
Lianjun Guo
Qing Lu
Jian Wang
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2017
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-017-1007-2

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