Skip to main content

Advertisement

SpringerLink
Log in

Nicotine Activating α4β2 Nicotinic Acetylcholine Receptors to Suppress Neuroinflammation via JAK2-STAT3 Signaling Pathway in Ischemic Rats and Inflammatory Cells

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Nicotine plays a role in inhibiting inflammatory factors, which contributes to improving cognitive impairment by activating α4β2 nAChRs in ischemic rats, but the underlying mechanism has not been fully elucidated. Janus tyrosine kinase 2-signal transducer and activator of transcription 3 (JAK2-STAT3) signaling pathway is involved in cognitive improvement, and there seems to be a relationship between nAChRs and JAK2-STAT3 as well. The aim of this study is to explore the role of JAK2-STAT3 signaling pathway in nicotine-mediated anti-inflammatory effect. Nicotine, DHβE (the strongest competitive antagonist of α4β2 nAChRs), and AG490 (a specific JAK2-STAT3 blocker) were used to intervene and treat ischemic rats and HEK-293 T-hα4β2 cells. The Morris water maze (MWM) test and 2-[18F]-A-85380 PET imaging were performed to detect the cognitive function and α4β2 nAChRs density in ischemic rats. The results demonstrated that nicotine intervention increased the density of α4β2 nAChRs and improved cognitive impairment, but this effect was blocked by AG490, and the receptors were still upregulated. Essentially, when the JAK2-STAT3 signaling pathway was blocked, nicotine could only upregulate the expression of α4β2 nAChRs, but not improve the cognitive function. PCR and Western blot analysis further confirmed these results. The cell experiments also showed that nicotine could reduce inflammatory factors stimulated by LPS and upregulate the expression of pJAK2 and pSTAT3 in HEK-293 T-hα4β2 cells, while AG490 and DHβE reversed the effect of nicotine. To sum up, our work indicated that JAK2-STAT3 signaling pathway played an important role in nicotine-induced cognitive improvement by upregulating α4β2 nAChRs in ischemic rats.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig.7

Similar content being viewed by others

Data Availability

The authors confirm that the data supporting the findings of this study are available within the article.

References

  1. van der Flier WM, Skoog I, Schneider JA, Pantoni L, Mok V, Chen CLH, Scheltens P (2018) Vascular cognitive impairment. Nat Rev Dis Primers 4:18003. https://doi.org/10.1038/nrdp.2018.3

    Article  PubMed  Google Scholar 

  2. Iadecola C, Duering M, Hachinski V, Joutel A, Pendlebury ST, Schneider JA, Dichgans M (2019) Vascular cognitive impairment and dementia: JACC Scientific Expert Panel. J Am Coll Cardiol 73:3326–3344. https://doi.org/10.1016/j.jacc.2019.04.034

    Article  PubMed  PubMed Central  Google Scholar 

  3. Araya JA, Ramirez AE, Figueroa-Aroca D, Sotes GJ, Perez C, Becerra J, Saez-Orellana F, Guzman L, Aguayo LG, Fuentealba J (2014) Modulation of neuronal nicotinic receptor by quinolizidine alkaloids causes neuroprotection on a cellular Alzheimer model. J Alzheimers Dis 42:143–155. https://doi.org/10.3233/jad-132045

    Article  CAS  PubMed  Google Scholar 

  4. Vieira-Brock PL, McFadden LM, Nielsen SM, Smith MD, Hanson GR, Fleckenstein AE (2015) Nicotine administration attenuates methamphetamine-induced novel object recognition deficits. Int J Neuropsychopharmacol. https://doi.org/10.1093/ijnp/pyv073

    Article  PubMed  PubMed Central  Google Scholar 

  5. Ciobica A, Padurariu M, Hritcu L (2012) The effects of short-term nicotine administration on behavioral and oxidative stress deficiencies induced in a rat model of Parkinson’s disease. Psychiatr Danub 24:194–205

    PubMed  Google Scholar 

  6. Jucaite A, Ohd J, Potter AS, Jaeger J, Karlsson P, Hannesdottir K, Bostrom E, Newhouse PA, Paulsson B (2014) A randomized, double-blind, placebo-controlled crossover study of alpha4beta 2* nicotinic acetylcholine receptor agonist AZD1446 (TC-6683) in adults with attention-deficit/hyperactivity disorder. Psychopharmacology 231:1251–1265. https://doi.org/10.1007/s00213-013-3116-7

    Article  CAS  PubMed  Google Scholar 

  7. Zoli M, Pucci S, Vilella A, Gotti C (2018) Neuronal and extraneuronal nicotinic acetylcholine receptors. Curr Neuropharmacol 16:338–349. https://doi.org/10.2174/1570159X15666170912110450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Paterson D, Nordberg A (2000) Neuronal nicotinic receptors in the human brain. Prog Neurobiol 61:75–111. https://doi.org/10.1016/s0301-0082(99)00045-3

    Article  CAS  PubMed  Google Scholar 

  9. Dani JA (2015) Neuronal nicotinic acetylcholine receptor structure and function and response to nicotine. Int Rev Neurobiol 124:3–19. https://doi.org/10.1016/bs.irn.2015.07.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ding YS, Fowler JS, Logan J, Wang GJ, Telang F, Garza V, Biegon A, Pareto D, Rooney W, Shea C, Alexoff D, Volkow ND, Vocci F (2004) 6-[18F]Fluoro-A-85380, a new PET tracer for the nicotinic acetylcholine receptor: studies in the human brain and in vivo demonstration of specific binding in white matter. Synapse 53:184–189. https://doi.org/10.1002/syn.20051

    Article  CAS  PubMed  Google Scholar 

  11. Lotfipour S, Mandelkern M, Brody AL (2011) Quantitative molecular imaging of neuronal nicotinic acetylcholine receptors in the human brain with A-85380 radiotracers. Curr Med Imaging Rev 7:107–112. https://doi.org/10.2174/157340511795445676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kant R, Constantinescu CC, Parekh P, Pandey SK, Pan ML, Easwaramoorthy B, Mukherjee J (2011) Evaluation of F-nifene binding to alpha4beta2 nicotinic receptors in the rat brain using microPET imaging. EJNMMI Res. https://doi.org/10.1186/2191-219x-1-6

    Article  PubMed  PubMed Central  Google Scholar 

  13. Jiang Y, Yin Y, Li Y (2015) Clinical research progress of fluoride and iodide 3-[2(S) -azacyclobutane methoxy] pyridine. Chin J Nucl Med Molec Imag 35:322–325

    Google Scholar 

  14. Jiang Y, Diao Y, Yin Y, Huang L, Mo Y, Zhang D, Li Y (2017) The quantitative analysis of 2-[18F]-A-85380 nAChRs micro-PET brain imaging in chronic ischemic rats with cognitive dysfunction in vivo. J Isotop 30:110–118

    Google Scholar 

  15. Han T, Wang Q, Lai R, Zhang D, Diao Y, Yin Y (2020) Nicotine induced neurocognitive protection and anti-inflammation effect by activating alpha 4beta 2 nicotinic acetylcholine receptors in ischemic rats. Nicotine Tob Res 22:919–924. https://doi.org/10.1093/ntr/ntz126

    Article  CAS  PubMed  Google Scholar 

  16. Wu Y, Xu J, Xu J, Zheng W, Chen Q, Jiao D (2018) Study on the mechanism of JAK2/STAT3 signaling pathway-mediated inflammatory reaction after cerebral ischemia. Mol Med Rep 17:5007–5012. https://doi.org/10.3892/mmr.2018.8477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chen J, Wang S, Su J, Chu G, You H, Chen Z, Sun H, Chen B, Zhou M (2016) Interleukin-32alpha inactivates JAK2/STAT3 signaling and reverses interleukin-6-induced epithelial-mesenchymal transition, invasion, and metastasis in pancreatic cancer cells. Onco Targets Ther 9:4225–4237. https://doi.org/10.2147/ott.S103581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Qin K, Chen K, Zhao W, Zhao X, Luo J, Wang Q, Gao C, Li X, Wang C (2018) Methotrexate combined with 4-hydroperoxycyclophosphamide downregulates multidrug-resistance P-glycoprotein expression induced by methotrexate in rheumatoid arthritis fibroblast-like synoviocytes via the JAK2/STAT3 pathway. J Immunol Res 2018:3619320. https://doi.org/10.1155/2018/3619320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nicolas CS, Peineau S, Amici M, Csaba Z, Fafouri A, Javalet C, Collett VJ, Hildebrandt L, Seaton G, Choi SL, Sim SE, Bradley C, Lee K, Zhuo M, Kaang BK, Gressens P, Dournaud P, Fitzjohn SM, Bortolotto ZA, Cho K, Collingridge GL (2012) The Jak/STAT pathway is involved in synaptic plasticity. Neuron 73:374–390. https://doi.org/10.1016/j.neuron.2011.11.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cao Y, Wang L, Lin LT, Wang XR, Ma SM, Yang NN, Fan H, Fisher M, Yang JW (2021) Acupuncture attenuates cognitive deficits through α7nAChR mediated anti-inflammatory pathway in chronic cerebral hypoperfusion rats. Life Sci 266:118732. https://doi.org/10.1016/j.lfs.2020.118732

    Article  CAS  PubMed  Google Scholar 

  21. Li X, Sun Y, Jin Q, Song D, Diao Y (2019) Kappa opioid receptor agonists improve postoperative cognitive dysfunction in rats via the JAK2/STAT3 signaling pathway. Int J Mol Med 44:1866–1876. https://doi.org/10.3892/ijmm.2019.4339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Patton MS, Lodge DJ, Morilak DA, Girotti M (2017) Ketamine corrects stress-induced cognitive dysfunction through JAK2/STAT3 signaling in the orbitofrontal cortex. Neuropsychopharmacology 42:1220–1230. https://doi.org/10.1038/npp.2016.236

    Article  CAS  PubMed  Google Scholar 

  23. Zhang Z, Zhou H, Zhou J (2021) Neuritin inhibits astrogliosis to ameliorate diabetic cognitive dysfunction. J Mol Endocrinol 66:259–272. https://doi.org/10.1530/jme-20-0321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bai X, Ju H, Gao L, Xiong Y, Dai R, Huang X, Yang C (2019) Regulation of nicotinic acetylcholine receptor α3 subtype in adipose tissue dysfunction. Prostaglandins Other Lipid Mediat 142:53–58. https://doi.org/10.1016/j.prostaglandins.2019.04.001

    Article  CAS  PubMed  Google Scholar 

  25. Zhang Y, Jia Y, Li P, Li H, Xiao D, Wang Y, Ma X (2017) Reciprocal activation of α5-nAChR and STAT3 in nicotine-induced human lung cancer cell proliferation. J Genet Genom 44:355–362. https://doi.org/10.1016/j.jgg.2017.03.003

    Article  Google Scholar 

  26. Chen X, Jia Y, Zhang Y, Zhou D, Sun H, Ma X (2020) α5-nAChR contributes to epithelial-mesenchymal transition and metastasis by regulating Jab1/Csn5 signalling in lung cancer. J Cell Mol Med 24:2497–2506. https://doi.org/10.1111/jcmm.14941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang Q, Lu Y, Bian H, Guo L, Zhu H (2017) Activation of the α7 nicotinic receptor promotes lipopolysaccharide-induced conversion of M1 microglia to M2. Am J Transl Res 9:971–985

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Gupta D, Lacayo AA, Greene SM, Leahy JL, Jetton TL (2018) β-Cell mass restoration by α7 nicotinic acetylcholine receptor activation. J Biol Chem 293:20295–20306. https://doi.org/10.1074/jbc.RA118.004617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kiguchi N, Saika F, Kobayashi Y, Ko MC, Kishioka S (2015) TC-2559, an α4β2 nicotinic acetylcholine receptor agonist, suppresses the expression of CCL3 and IL-1β through STAT3 inhibition in cultured murine macrophages. J Pharmacol Sci 128:83–86. https://doi.org/10.1016/j.jphs.2015.04.009

    Article  CAS  PubMed  Google Scholar 

  30. Rogers SW, Gahring LC (2015) Upregulation of nicotinic acetylcholine receptor alph4+beta2 through a ligand-independent PI3Kbeta mechanism that is enhanced by TNFalpha and the Jak2/p38Mapk pathways. PLoS ONE 10:e0143319. https://doi.org/10.1371/journal.pone.0143319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kutlu MG, Tumolo JM, Cann C, Gould TJ (2018) Differential effects of alpha4beta2 nicotinic receptor antagonists and partial-agonists on contextual fear extinction in male C57BL/6 mice. Psychopharmacology 235:1211–1219. https://doi.org/10.1007/s00213-018-4837-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lewis AS, Mineur YS, Smith PH, Cahuzac ELM, Picciotto MR (2015) Modulation of aggressive behavior in mice by nicotinic receptor subtypes. Biochem Pharmacol 97:488–497. https://doi.org/10.1016/j.bcp.2015.07.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Seo IA, Lee HK, Shin YK, Lee SH, Seo SY, Park JW, Park HT (2009) Janus kinase 2 inhibitor AG490 inhibits the STAT3 signaling pathway by suppressing protein translation of gp130. Kor J Physiol Pharmacol 13:131–138. https://doi.org/10.4196/kjpp.2009.13.2.131

    Article  CAS  Google Scholar 

  34. Donegan JJ, Girotti M, Weinberg MS, Morilak DA (2014) A novel role for brain interleukin-6: facilitation of cognitive flexibility in rat orbitofrontal cortex. J Neurosci 34:953–962. https://doi.org/10.1523/JNEUROSCI.3968-13.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Mo YX, Yin YF, Li YM (2014) Neural nAChRs PET imaging probes. Nucl Med Commun 35:135–143. https://doi.org/10.1097/MNM.0000000000000032

    Article  PubMed  Google Scholar 

  36. Huang L, Diao Y, Yin Y, Zhang D, Mo Y, Li Y (2013) Radiosynthesis of 2-[18F]-A-85380 and its biodistribution in mice. J Chin Med Univ 42:777–780

    CAS  Google Scholar 

  37. Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates. Academic Press

    Google Scholar 

  38. Ma Y, Wang J, Wang Y, Yang GY (2017) The biphasic function of microglia in ischemic stroke. Prog Neurobiol 157:247–272. https://doi.org/10.1016/j.pneurobio.2016.01.005

    Article  CAS  PubMed  Google Scholar 

  39. Wei P, Liu Q, Li D, Zheng Q, Zhou J, Li J (2015) Acute nicotine treatment attenuates lipopolysaccharide-induced cognitive dysfunction by increasing BDNF expression and inhibiting neuroinflammation in the rat hippocampus. Neurosci Lett 604:161–166. https://doi.org/10.1016/j.neulet.2015.08.008

    Article  CAS  PubMed  Google Scholar 

  40. Osso LA, Chan JR (2015) Astrocytes underlie neuroinflammatory memory impairment. Cell 163:1574–1576. https://doi.org/10.1016/j.cell.2015.12.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Cai M, Lee JH, Yang EJ (2019) Electroacupuncture attenuates cognition impairment via anti-neuroinflammation in an Alzheimer’s disease animal model. J Neuroinflammation 16:264. https://doi.org/10.1186/s12974-019-1665-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Guan YZ, Jin XD, Guan LX, Yan HC, Wang P, Gong Z, Li SJ, Cao X, Xing YL, Gao TM (2015) Nicotine inhibits microglial proliferation and is neuroprotective in global ischemia rats. Mol Neurobiol 51:1480–1488. https://doi.org/10.1007/s12035-014-8825-3

    Article  CAS  PubMed  Google Scholar 

  43. Yu L, Chen C, Wang LF, Kuang X, Liu K, Zhang H, Du JR (2013) Neuroprotective effect of kaempferol glycosides against brain injury and neuroinflammation by inhibiting the activation of NF-kappaB and STAT3 in transient focal stroke. PLoS ONE 8:e55839. https://doi.org/10.1371/journal.pone.0055839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Park JS, Lee J, Lim MA, Kim EK, Kim SM, Ryu JG, Lee JH, Kwok SK, Park KS, Kim HY, Park SH, Cho ML (2014) JAK2-STAT3 blockade by AG490 suppresses autoimmune arthritis in mice via reciprocal regulation of regulatory T Cells and Th17 cells. J Immunol 192:4417–4424. https://doi.org/10.4049/jimmunol.1300514

    Article  CAS  PubMed  Google Scholar 

  45. D’Angelo C, Costantini E, Salvador N, Marchioni M, Di Nicola M, Greig NH, Reale M (2021) nAChRs gene expression and neuroinflammation in APPswe/PS1dE9 transgenic mouse. Sci Rep 11:9711. https://doi.org/10.1038/s41598-021-89139-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Martin A, Szczupak B, Gomez-Vallejo V, Domercq M, Cano A, Padro D, Munoz C, Higuchi M, Matute C, Llop J (2015) In vivo PET imaging of the alpha4beta2 nicotinic acetylcholine receptor as a marker for brain inflammation after cerebral ischemia. J Neurosci 35:5998–6009. https://doi.org/10.1523/JNEUROSCI.3670-14.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by the National Natural Science Foundation of China (Nos. 81671717, 81974270) and Shanghai Pujiang Program (2019PJD032).

Author information

Author notes

  1. Qi Wang, Jinyu Gou, and Shenrui Guo contributed equally to this work and should be considered co-first authors.

Authors and Affiliations

  1. Department of Nuclear Medicine, The First Hospital of China Medical University, Shenyang, 110001, China

    Qi Wang, Dalong Zhang & Yao Diao

  2. Department of Nuclear Medicine, The Fourth Hospital of China Medical University, Shenyang, 110032, China

    Qi Wang

  3. Department of Nuclear Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Kongjiang Road 1665, Yangpu District, Shanghai City, 200092, China

    Jinyu Gou, Shenrui Guo, Feng Wei & Yafu Yin

  4. Department of Nuclear Medicine, Chifeng Municipal Hospital, Inner Mongolia Medical University Chifeng Clinical College Of Medicine, Chifeng City, 024000, China

    Tingting Han

  5. Department of Nuclear Medicine, Nanjing Drum Tower Hospital, Nanjing, 210008, China

    Ruihe Lai

Authors
  1. Qi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jinyu Gou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shenrui Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Feng Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tingting Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ruihe Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dalong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yao Diao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yafu Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Y.Y.: conceived and designed the experiments; W.Q.: performed the animal experiments, the analysis and interpretation of data, and drafted the main manuscript text; G. J.: performed the cell experiments; G.S.: assisted in experiments and data analysis, and drafted the manuscript text; W.F., H.T., and L.R.: assisted in experiments and data analysis; Z.D.: synthesized the tracer of 2-[18F]-A-85380; D.Y.: guided the specific implementation of the experiment.

Corresponding author

Correspondence to Yafu Yin.

Ethics declarations

Ethics Approval and Consent to Participate

Animal care and all experimental procedures were performed in accordance with the Guideline for the Care and Use of Laboratory Animals. All animals received humane care. Study protocols complied with the institution’s guidelines and were approved by the Ethics Committee of The First Hospital of China Medical University.

Consent for Publication

All authors have read and agreed to the published version of the manuscript.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Q., Gou, J., Guo, S. et al. Nicotine Activating α4β2 Nicotinic Acetylcholine Receptors to Suppress Neuroinflammation via JAK2-STAT3 Signaling Pathway in Ischemic Rats and Inflammatory Cells. Mol Neurobiol 59, 3280–3293 (2022). https://doi.org/10.1007/s12035-022-02797-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-022-02797-4

Keywords

Search

Navigation