Nuclear Medicine and Molecular Imaging

, Volume 52, Issue 3, pp 224–228 | Cite as

A Single Intraperitoneal Injection of Endotoxin Changes Glial Cells in Rats as Revealed by Positron Emission Tomography Using [11C]PK11195

  • Miho OtaEmail author
  • Jun Ogura
  • Shintaro Ogawa
  • Koichi Kato
  • Hiroshi Matsuda
  • Hiroshi Kunugi
Original Article



Intracranial administration of lipopolysaccharide (LPS) is known to elicit a rapid innate immune response, activate glial cells in the brain, and induce depression-like behavior. However, no study has focused on the changes in glial cells induced by intraperitoneal injection of LPS in vivo.


Ten adult male Fischer F344 rats underwent [11C]PK11195 PET before and 2 days after intraperitoneal injection of LPS to evaluate the changes in glial cells. The difference in standardized uptake values (SUV) of [11C]PK11195 between before and after injection was determined.


There was a cluster of brain regions that showed significant reductions in SUV. This cluster included the bilateral striata and bilateral frontal regions, especially the somatosensory areas.


Changes in activity of glial cells induced by the intraperitoneal injection of LPS were detected in vivo by [11C]PK11195 PET. Intraperitoneal injection of LPS is known to induce depression, and further studies with [11C]PK11195 PET would clarify the relationships between neuroinflammation and depression.


[11C]PK11195 Glial cells Lipopolysaccharides Positron emission tomography Somatosensory area 



The authors thank Mr. Makoto Funasaka for his expert technical assistance with the PET experiments.

Compliance with Ethical Standards

Conflicts of Interest

Miho Ota was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (C) (16 K10234). Jun Ogura, Shintaro Ogawa, Koichi Kato, Hiroshi Matsuda, and Hiroshi Kunugi declare that they have no conflicts of interest.

Ethical Approval

All experimental procedures were in accordance with the guidelines of the United State’s National Institutes of Health (1996) ( and were approved by the Ethics Review Committee for Animal Experimentation at the National Institute of Neuroscience, National Center of Neurology and Psychiatry, Japan, and performed with every effort to minimize the number of animals and their suffering.

Informed Consent

The Ethics Review Committee for Animal Experimentation of our institution approved this study, and the requirement to obtain informed consent was waived.


  1. 1.
    Kunugi H, Hori H, Ogawa S. Biochemical markers subtyping major depressive disorder. Psychiatry Clin Neurosci. 2015;69:597–608.CrossRefPubMedGoogle Scholar
  2. 2.
    Pollak Y, Yirmiya R. Cytokine-induced changes in mood and behaviour: implications for 'depression due to a general medical condition', immunotherapy and antidepressive treatment. Int J Neuropsychopharmacol. 2002;5:389–99.CrossRefPubMedGoogle Scholar
  3. 3.
    Reichenberg A, Yirmiya R, Schuld A, Kraus T, Haack M, Morag A, et al. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry. 2001;58:445–52.CrossRefPubMedGoogle Scholar
  4. 4.
    Martin SA, Dantzer R, Kelley KW, Woods JA. Voluntary wheel running does not affect lipopolysaccharide-induced depressive-like behavior in young adult and aged mice. Neuroimmunomodulation. 2014;21:52–63.CrossRefPubMedGoogle Scholar
  5. 5.
    Sulakhiya K, Kumar P, Jangra A, Dwivedi S, Hazarika NK, Baruah CC, et al. Honokiol abrogates lipopolysaccharide-induced depressive like behavior by impeding neuroinflammation and oxido-nitrosative stress in mice. Eur J Pharmacol. 2014;744:124–31.CrossRefPubMedGoogle Scholar
  6. 6.
    Bay-Richter C, Janelidze S, Hallberg L, Brundin L. Changes in behaviour and cytokine expression upon a peripheral immune challenge. Behav Brain Res. 2011;222:193–9.CrossRefPubMedGoogle Scholar
  7. 7.
    De La Garza R II, Fabrizio KR, Radoi G-E, Vlad T, Asnis GM. The non-steroidal anti-inflammatory drug diclofenac sodium attenuates lipopolysaccharide-induced alterations to reward behavior and corticosterone release. Behav Brain Res. 2004;149:77–85.CrossRefGoogle Scholar
  8. 8.
    Engeland CG, Kavaliers M, Ossenkopp KP. Sex differences in the effects of muramyl dipeptide and lipopolysaccharide on locomotor activity and the development of behavioral tolerance in rats. Pharmacol Biochem Behav. 2003;74:433–47.CrossRefPubMedGoogle Scholar
  9. 9.
    Moraes MM, Galvão MC, Cabral D, Coelho CP, Queiroz-Hazarbassanov N, Martins MF, et al. Propentofylline prevents sickness behavior and depressive-like behavior induced by lipopolysaccharide in rats via neuroinflammatory pathway. PLoS One. 2017;12:e0169446.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Tonelli LH, Holmes A, Postolache TT. Intranasal immune challenge induces sex-dependent depressive-like behavior and cytokine expression in the brain. Neuropsychopharmacology. 2008;33:1038–48.CrossRefPubMedGoogle Scholar
  11. 11.
    Sasayama D, Hattori K, Wakabayashi C, Teraishi T, Hori H, Ota M, et al. Increased cerebrospinal fluid interleukin-6 levels in patients with schizophrenia and those with major depressive disorder. J Psychiatr Res. 2013;47:401–6.CrossRefPubMedGoogle Scholar
  12. 12.
    Hoogland IC, Houbolt C, van Westerloo DJ, van Gool WA, van de Beek D. Systemic inflammation and microglial activation: systematic review of animal experiments. J Neuroinflammation. 2015;12:114.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Ng YK, Ling EA. Induction of major histocompatibility class II antigen on microglial cells in postnatal and adult rats following intraperitoneal injections of lipopolysaccharide. Neurosci Res. 1997;28:111–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Cazareth J, Guyon A, Heurteaux C, Chabry J, Petit-Paitel A. Molecular and cellular neuroinflammatory status of mouse brain after systemic lipopolysaccharide challenge: importance of CCR2/CCL2 signaling. J Neuroinflammation. 2014;11:132.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Wu SY, Chen YW, Tsai SF, Wu SN, Shih YH, Jiang-Shieh YF, et al. Estrogen ameliorates microglial activation by inhibiting the Kir2.1 inward-rectifier K(+) channel. Sci Rep. 2016;6:22864.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Hannestad J, DellaGioia N, Gallezot JD, Lim K, Nabulsi N, Esterlis I, et al. The neuroinflammation marker translocator protein is not elevated in individuals with mild-to-moderate depression: a [11C]PBR28 PET study. Brain Behav Immun. 2013;33:131–8.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Setiawan E, Wilson AA, Mizrahi R, Rusjan PM, Miler L, Rajkowska G, et al. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiat. 2015;72:268–75.CrossRefGoogle Scholar
  18. 18.
    Su L, Faluyi YO, Hong YT, Fryer TD, Mak E, Gabel S, et al. Neuroinflammatory and morphological changes in late-life depression: the NIMROD study. Br J Psychiatry. 2016;209:525–6.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Haarman BC, Burger H, Doorduin J, Renken RJ, Sibeijn-Kuiper AJ, Marsman JB, et al. Volume, metabolites and neuroinflammation of the hippocampus in bipolar disorder – a combined magnetic resonance imaging and positron emission tomography study. Brain Behav Immun. 2016;56:21–33.CrossRefPubMedGoogle Scholar
  20. 20.
    van Berckel BN, Bossong MG, Boellaard R, Kloet R, Schuitemaker A, Caspers E, et al. Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study. Biol Psychiatry. 2008;64:820–2.CrossRefPubMedGoogle Scholar
  21. 21.
    Dickens AM, Vainio S, Marjamäki P, Johansson J, Lehtiniemi P, Rokka J, et al. Detection of microglial activation in an acute model of neuroinflammation using PET and radiotracers 11C-(R)-PK11195 and 18F-GE-180. J Nucl Med. 2014;55:466–72.CrossRefPubMedGoogle Scholar
  22. 22.
    Sridharan S, Lepelletier FX, Trigg W, Banister S, Reekie T, Kassiou M, et al. Comparative evaluation of three TSPO PET radiotracers in a LPS-induced model of mild neuroinflammation in rats. Mol Imaging Biol. 2017;19:77–89.CrossRefPubMedGoogle Scholar
  23. 23.
    Shah F, Hume SP, Pike VW, Ashworth S, McDermott J. Synthesis of the enantiomers of [N-methyl-11C]PK 11195 and comparison of their behaviours as radioligands for PK binding sites in rats. Nucl Med Biol. 1994;21:573–81.CrossRefPubMedGoogle Scholar
  24. 24.
    Mizuta T, Kitamura K, Iwata H, Yamagishi Y, Ohtani A, Tanaka K, et al. Performance evaluation of a high-sensitivity large-aperture small-animal PET scanner: ClairvivoPET. Ann Nucl Med. 2008;22:447–55.CrossRefPubMedGoogle Scholar
  25. 25.
    Tanaka E, Kudo H. Subset-dependent relaxation in block-iterative algorithms for image reconstruction in emission tomography. Phys Med Biol. 2003;48:1405–22.CrossRefPubMedGoogle Scholar
  26. 26.
    de Paula FD, de Vries EF, Sijbesma JW, Buchpiguel CA, Dierckx RA, Copray SC. PET imaging of glucose metabolism, neuroinflammation and demyelination in the lysolecithin rat model for multiple sclerosis. Mult Scler. 2014;20:1443–52.CrossRefGoogle Scholar
  27. 27.
    Ito S. Visceral region in the rat primary somatosensory cortex identified by vagal evoked potential. J Comp Neurol. 2002;444:10–24.CrossRefPubMedGoogle Scholar
  28. 28.
    Schweighöfer H, Rummel C, Roth J, Rosengarten B. Modulatory effects of vagal stimulation on neurophysiological parameters and the cellular immune response in the rat brain during systemic inflammation. Intensive Care Med Exp. 2016;4:19.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Wolff S, Klatt S, Wolff JC, Wilhelm J, Fink L, Kaps M, et al. Endotoxin-induced gene expression differences in the brain and effects of iNOS inhibition and norepinephrine. Intensive Care Med. 2009;35:730–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Kropholler MA, Boellaard R, van Berckel BN, Schuitemaker A, Kloet RW, Lubberink MJ, et al. Evaluation of reference regions for (R)-[11C]-PK11195 studies in Alzheimer’s disease and mild cognitive impairment. J Cereb Blood Flow Metab. 2007;27:1965–74.CrossRefPubMedGoogle Scholar
  31. 31.
    Nakatomi Y, Mizuno K, Ishii A, Wada Y, Tanaka M, Tazawa S, et al. Neuroinflammation in patients with chronic fatigue syndrome/myalgic encephalomyelitis: an 11C-(R)-PK11195 PET study. J Nucl Med. 2014;55:945–50.CrossRefPubMedGoogle Scholar
  32. 32.
    Vas A, Shchukin Y, Karrenbauer VD, Cselényi Z, Kostulas K, Hillert J, et al. Functional neuroimaging in multiple sclerosis with radiolabelled glia markers: preliminary comparative PET studies with [11C]vinpocetine and [11C]PK11195 in patients. J Neurol Sci. 2008;264:9–17.Google Scholar
  33. 33.
    Koyama M, Kawashima R, Ito H, Ono S, Sato K, Goto R, et al. SPECT imaging of normal subjects with technetium-99m-HMPAO and technetium-99m-ECD. J Nucl Med. 1997;38:587–92.PubMedGoogle Scholar
  34. 34.
    Steiner J, Walter M, Gos T, Guillemin GJ, Bernstein HG, Sarnyai Z, et al. Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission? J Neuroinflammation. 2011;8:94.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Van Otterloo ES, Miguel-Hidalgo JJ, Stockmeier CA, Rajkowska G. Microglia immunoreactivity is unchanged in the white matter of orbitofrontal cortex in elderly depressed patients. Program no. 9152. Neuroscience 2005 Abstracts. Washington DC. Society for Neuroscience. 2005Google Scholar
  36. 36.
    Czeh M, Gressens P, Kaindl AM. The yin and yang of microglia. Dev Neurosci. 2011;33:199–209.CrossRefPubMedGoogle Scholar
  37. 37.
    Wee Yong V. Inflammation in neurological disorders: a help or a hindrance? Neuroscientist. 2010;16:408–20.CrossRefPubMedGoogle Scholar
  38. 38.
    Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N, et al. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci. 2006;9:268–75.CrossRefPubMedGoogle Scholar
  39. 39.
    Koizumi S, Ohsawa K, Inoue K, Kohsaka S. Purinergic receptors in microglia: functional modal shifts of microglia mediated by P2 and P1 receptors. Glia. 2013;61:47–54.CrossRefPubMedGoogle Scholar
  40. 40.
    Gavish M, Bachman I, Shoukrun R, Katz Y, Veenman L, Weisinger G, et al. Enigma of the peripheral benzodiazepine receptor. Pharmacol Rev. 1999;51:629–50.Google Scholar

Copyright information

© Korean Society of Nuclear Medicine 2018

Authors and Affiliations

  1. 1.Department of Mental Disorder Research, National Institute of NeuroscienceNational Center of Neurology and PsychiatryKodairaJapan
  2. 2.Organic Radiochemistry Section, Department of Advanced Neuroimaging, Integrative Brain Imaging CenterNational Center Hospital of Neurology and PsychiatryKodairaJapan
  3. 3.Integrative Brain Imaging CenterNational Center Hospital of Neurology and PsychiatryKodairaJapan

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