Skip to main content
SpringerLink
Log in

Nicotine Inhibits Microglial Proliferation and Is Neuroprotective in Global Ischemia Rats

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Ischemic injury in rodent models reliably leads to the activation of microglia, which might play a detrimental role in neuronal survival. Our preliminary studies suggest that nicotine plays a potential role in decreasing the numbers of cultured microglia in vitro. In the present study, we found treatment with nicotine 2, 6, and 12 h after ischemia for 7 days significantly increased the survival of CA1 pyramidal neurons in ischemia/reperfusion rats. This effect was accompanied by a significant reduction in the increase of microglia rather than astrocytes, as well as a significant reduction of enhanced expression of tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) in CA1 induced by ischemia/reperfusion. Nicotine inhibits microglial proliferation in primary cultures with and without the stimulation of granulocyte–macrophage colony-stimulating factor (GM-CSF). Pre-treatment with α-bungarotoxin, a selective α7 nicotinic acetylcholine receptor (α7 nAChR) antagonist, could prevent the inhibitory effects of nicotine on cultured microglial proliferation suggesting that nicotine inhibits the microglial proliferation in an α7 nAChR-dependent fashion. Our results suggest that nicotine inhibits the inflammation mediated by microglia via α7 nAChR and is neuroprotective against ischemic stroke, even when administered 12 h after the insult. α7 nAChR agonists may have uses as anti-ischemic compounds in humans.

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

Similar content being viewed by others

Reference

  1. Wang CX, Shuaib A (2002) Involvement of inflammatory cytokines in central nervous system injury. Prog Neurobiol 67(2):161–172

    Article  CAS  PubMed  Google Scholar 

  2. Wang Q, Tang XN, Yenari MA (2007) The inflammatory response in stroke. J Neuroimmunol 184(1–2):53–68

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405(6785):458–462

    Article  CAS  PubMed  Google Scholar 

  4. Tracey KJ (2002) The inflammatory reflex. Nature 420(6917):853–859

    Article  CAS  PubMed  Google Scholar 

  5. Ay I, Lu J, Ay H, Gregory Sorensen A (2009) Vagus nerve stimulation reduces infarct size in rat focal cerebral ischemia. Neurosci Lett 459(3):147–151

    Article  CAS  PubMed  Google Scholar 

  6. Mravec B (2010) The role of the vagus nerve in stroke. Auton Neurosci 158(1–2):8–12

    Article  PubMed  Google Scholar 

  7. Guan YZ , Gao TM (2007) Effects of nicotine on proliferation of microglia related to cerebral inflammations. J Harbin Med Univ 41(6):566–568

  8. Guan YZ, Jin XD , Liu GL , Gao TM (2007) Effects of cholinergic agonists on microglial activation induced by glutamate. J Fourth Mil Med Univ 28(22):2041–2043

  9. Li XM, Yang JM, Hu DH, Hou FQ, Zhao M, Zhu XH, Wang Y, Li JG, Hu P, Chen L, Qin LN, Gao TM (2007) Contribution of downregulation of L-type calcium currents to delayed neuronal death in rat hippocampus after global cerebral ischemia and reperfusion. J Neurosci 27(19):5249–5259

    Article  CAS  PubMed  Google Scholar 

  10. Pulsinelli WA, Brierley JB (1979) A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke 10(3):267–272

    Article  CAS  PubMed  Google Scholar 

  11. Kirino T, Tamura A, Sano K (1984) Delayed neuronal death in the rat hippocampus following transient forebrain ischemia. Acta Neuropathol 64(2):139–147

    Article  CAS  PubMed  Google Scholar 

  12. Giulian D, Baker TJ (1986) Characterization of ameboid microglia isolated from developing mammalian brain. J Neurosci 6(8):2163–2178

    CAS  PubMed  Google Scholar 

  13. Giulian D, Vaca K (1993) Inflammatory glia mediate delayed neuronal damage after ischemia in the central nervous system. Stroke 24(12 Suppl):I84–I90

    CAS  PubMed  Google Scholar 

  14. Rogove AD, Tsirka SE (1998) Neurotoxic responses by microglia elicited by excitotoxic injury in the mouse hippocampus. Curr Biol 8(1):19–25

    Article  CAS  PubMed  Google Scholar 

  15. Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J (1998) Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci U S A 95(26):15769–15774

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J (1999) A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci U S A 96(23):13496–13500

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Lee JM, Zipfel GJ, Choi DW (1999) The changing landscape of ischaemic brain injury mechanisms. Nature 399(6738 Suppl):A7–A14

    Article  CAS  PubMed  Google Scholar 

  18. Smith T, Groom A, Zhu B, Turski L (2000) Autoimmune encephalomyelitis ameliorated by AMPA antagonists. Nat Med 6(1):62–66

    Article  CAS  PubMed  Google Scholar 

  19. Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19(8):312–318

    Article  CAS  PubMed  Google Scholar 

  20. Morioka T, Kalehua AN, Streit WJ (1991) The microglial reaction in the rat dorsal hippocampus following transient forebrain ischemia. J Cereb Blood Flow Metab 11(6):966–973

    Article  CAS  PubMed  Google Scholar 

  21. Bhat NR, Zhang P, Lee JC, Hogan EL (1998) Extracellular signal-regulated kinase and p38 subgroups of mitogen-activated protein kinases regulate inducible nitric oxide synthase and tumor necrosis factor-alpha gene expression in endotoxin-stimulated primary glial cultures. J Neurosci 18(5):1633–1641

    CAS  PubMed  Google Scholar 

  22. Fiebich BL, Butcher RD, Gebicke-Haerter PJ (1998) Protein kinase C-mediated regulation of inducible nitric oxide synthase expression in cultured microglial cells. J Neuroimmunol 92(1–2):170–178

    Article  CAS  PubMed  Google Scholar 

  23. Zhou R, Yang Z, Tang X, Tan Y, Wu X, Liu F (2013) Propofol protects against focal cerebral ischemia via inhibition of microglia-mediated proinflammatory cytokines in a rat model of experimental stroke. PLoS One 8(12):e82729

    Article  PubMed Central  PubMed  Google Scholar 

  24. De Simone R, Ajmone-Cat MA, Carnevale D, Minghetti L (2005) Activation of alpha7 nicotinic acetylcholine receptor by nicotine selectively up-regulates cyclooxygenase-2 and prostaglandin E2 in rat microglial cultures. J Neuroinflammation 2(1):4

    Article  PubMed Central  PubMed  Google Scholar 

  25. Dong Y, Benveniste EN (2001) Immune function of astrocytes. Glia 36(2):180–190

    Article  CAS  PubMed  Google Scholar 

  26. Ridet JL, Malhotra SK, Privat A, Gage FH (1997) Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci 20(12):570–577

    Article  CAS  PubMed  Google Scholar 

  27. Lain KY, Powers RW, Krohn MA, Ness RB, Crombleholme WR, Roberts JM (1999) Urinary cotinine concentration confirms the reduced risk of preeclampsia with tobacco exposure. Am J Obstet Gynecol 181(5 Pt 1):1192–1196

    Article  CAS  PubMed  Google Scholar 

  28. Hjern A, Hedberg A, Haglund B, Rosen M (2001) Does tobacco smoke prevent atopic disorders? A study of two generations of Swedish residents. Clin Exp Allergy 31(6):908–914

    Article  CAS  PubMed  Google Scholar 

  29. Gonzalez CL, Gharbawie OA, Kolb B (2006) Chronic low-dose administration of nicotine facilitates recovery and synaptic change after focal ischemia in rats. Neuropharmacology 50(7):777–787

    Article  CAS  PubMed  Google Scholar 

  30. Kagitani F, Uchida S, Hotta H, Sato A (2000) Effects of nicotine on blood flow and delayed neuronal death following intermittent transient ischemia in rat hippocampus. Jpn J Physiol 50(6):585–595

    Article  CAS  PubMed  Google Scholar 

  31. Wang L, Kittaka M, Sun N, Schreiber SS, Zlokovic BV (1997) Chronic nicotine treatment enhances focal ischemic brain injury and depletes free pool of brain microvascular tissue plasminogen activator in rats. J Cereb Blood Flow Metab 17(2):136–146

    Article  CAS  PubMed  Google Scholar 

  32. Pohanka M, Snopkova S, Havlickova K, Bostik P, Sinkorova Z, Fusek J, Kuca K, Pikula J (2011) Macrophage-assisted inflammation and pharmacological regulation of the cholinergic anti-inflammatory pathway. Curr Med Chem 18(4):539–551

    Article  CAS  PubMed  Google Scholar 

  33. Schilling M, Besselmann M, Leonhard C, Mueller M, Ringelstein EB, Kiefer R (2003) Microglial activation precedes and predominates over macrophage infiltration in transient focal cerebral ischemia: a study in green fluorescent protein transgenic bone marrow chimeric mice. Exp Neurol 183(1):25–33

    Article  PubMed  Google Scholar 

  34. Imai F, Suzuki H, Oda J, Ninomiya T, Ono K, Sano H, Sawada M (2007) Neuroprotective effect of exogenous microglia in global brain ischemia. J Cereb Blood Flow Metab 27(3):488–500

    Article  CAS  PubMed  Google Scholar 

  35. Lalancette-Hebert M, Gowing G, Simard A, Weng YC, Kriz J (2007) Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci 27(10):2596–2605

    Article  CAS  PubMed  Google Scholar 

  36. Ghosheh OA, Dwoskin LP, Miller DK, Crooks PA (2001) Accumulation of nicotine and its metabolites in rat brain after intermittent or continuous peripheral administration of [2′-(14)C]nicotine. Drug Metab Dispos 29(5):645–651

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was partly supported by the National Natural Science Foundation of China (81030022, 81329003, U1201225, 81371463, 81374007), the Guangzhou Science and Technology Project (7411802013939), Program for Changjiang Scholars and Innovative Research Team in University (IRT1142), the Heilongjiang Science Projects for Returnees of Oversea Scholar (LC2011C40), the Programs for Returnees of Oversea Scholar supported by Department of Education of Heilongjiang Province in China (1251H005), and the project supported by Heilongjiang Human resources and Social Security bureau.

Conflict of Interest

None

Author information

Authors and Affiliations

  1. State Key Laboratory of Organ Failure Research, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China

    Yan-Zhong Guan, Hua-Cheng Yan, Pu Wang, Zhi Gong, Shu-Ji Li, Xiong Cao, Yan-Li Xing & Tian-Ming Gao

  2. Department of Physiology and Pharmacology, Mudanjiang Medical University, Mudanjiang, China

    Yan-Zhong Guan, Xiu-Dong Jin & Li-Xin Guan

Authors
  1. Yan-Zhong Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiu-Dong Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Li-Xin Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hua-Cheng Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhi Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shu-Ji Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiong Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yan-Li Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tian-Ming Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tian-Ming Gao.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guan, YZ., Jin, XD., Guan, LX. et al. Nicotine Inhibits Microglial Proliferation and Is Neuroprotective in Global Ischemia Rats. Mol Neurobiol 51, 1480–1488 (2015). https://doi.org/10.1007/s12035-014-8825-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-014-8825-3

Keywords

Search

Navigation