Molecular Imaging and Biology

, Volume 13, Issue 1, pp 10–15

Reduced PBR/TSPO Expression After Minocycline Treatment in a Rat Model of Focal Cerebral Ischemia: A PET Study Using [18F]DPA-714

  • Abraham Martín
  • Raphaël Boisgard
  • Michael Kassiou
  • Frédéric Dollé
  • Bertrand Tavitian
Brief Article

Abstract

Background

Many new candidate pharmaceuticals designed to improve recovery after stroke have been proposed recently, but there are still too few molecular imaging methods capable to assess their efficacy. A hallmark of the inflammatory reaction that follows focal cerebral ischemia is overexpression of the mitochondrial peripheral benzodiazepine receptor/18 kDa translocator protein (PBR/TSPO) in the monocytic lineage and astrocytes. This overexpression can be imaged with positron emission tomography (PET) using PBR/TSPO-selective radioligands such as [18F]DPA-714.

Purpose

Here, we tested whether PET with [18F]DPA-714 would evidence the effect of minocycline, a broad spectrum antibiotic presently tested as neuroprotective agent after stroke, on the inflammatory reaction induced in an experimental model of stroke.

Procedures

Ten rats were subjected to a 2-h transient middle cerebral artery occlusion with reperfusion. Minocycline or saline was intravenously administrated 1 h after reperfusion and daily during the following 6 days. PET studies were performed using [18F]DPA-714 at 7 days after cerebral ischemia.

Results

In vivo PET imaging showed a significant decrease in [18F]DPA-714 uptake at 7 days after cerebral ischemia in rats treated with minocycline with respect to saline-treated animals. Minocycline treatment had no effect on the size of the infarcted area.

Conclusion

Minocycline administered daily during 7 days after ischemia decreases [18F]DPA-714 binding, suggesting that the drug exerts an anti-inflammatory activity. [18F]DPA-714 PET is a useful biomarker to study novel anti-inflammatory strategies in experimental cerebral ischemia.

Key words

Minocycline PET Neuroinflammation PBR TSPO DPA-714 Cerebral ischemia 

References

  1. 1.
    The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (1995) Tissue plasminogen activation for acute ischemic stroke. N Engl J Med 333:1581-1587CrossRefGoogle Scholar
  2. 2.
    Montaner J, Rovira A, Molina CA, Arenillas JF, Ribo M, Chacon P, Monasterio J, Alvarez-Sabin (2003) Plasmatic level of neuroinflammatory markers predict the extent of diffusion-weighted image lesions in hyperacute stroke. J Cereb Blood Flow Metab 23:1403-1407CrossRefPubMedGoogle Scholar
  3. 3.
    Emsley HC, Tyrrell PJ (2002) Inflammation and infection in clinical stroke. J Cereb Blood Flow Metab 22:1399-419CrossRefPubMedGoogle Scholar
  4. 4.
    Yrjänheikki J, Keinänen R, Pellikka M, Hökfelt T, Koistinaho J (1998) Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci U S A 95:15769-15774CrossRefPubMedGoogle Scholar
  5. 5.
    Yrjänheikki J, Tikka T, Keinänen 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 96:13496-13500CrossRefPubMedGoogle Scholar
  6. 6.
    Wang CX, Yang T, Shuaib A (2003) Effects of minocycline alone and in combination with mild hypothermia in embolic stroke. Brain Res 963:327-329CrossRefPubMedGoogle Scholar
  7. 7.
    Xu L, Fagan SC, Waller JL, Edwards D, Borlongan CV, Zheng J, Hill WD, Feuerstein G, Hess DC (2004) Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats. BMC Neurol 26:4-7Google Scholar
  8. 8.
    He Y, Appel S, Le W (2001) Minocycline inhibits microglial activation and protects nigral cells after 6-hydroxydopamine injection into mouse striatum. Brain Res 909:187-193CrossRefPubMedGoogle Scholar
  9. 9.
    Wu DC, Jackson-Lewis V, Vila M, Tieu K, Teismann P, Vadseth C, Choi DK, Ischiropoulos H, Przedborski S (2002) Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci 22:1763-1771PubMedGoogle Scholar
  10. 10.
    Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapère JJ, Lindemann P, Norenberg MD, Nutt D, Weizman A, Zhang MR, Gavish M (2006) Trends Pharmacol Sci 27:402-409CrossRefPubMedGoogle Scholar
  11. 11.
    Rojas S, Martín A, Arranz MJ, Pareto D, Purroy J, Verdaguer E, Llop J, Gómez V, Gispert JD, Millán O, Chamorro A, Planas AM (2007) Imaging brain inflammation with [11C]PK11195 by PET and induction of the peripheral-type benzodiazepine receptor after transient focal ischemia in rats. J Cereb Blood Flow Metab 27:1975-1986CrossRefPubMedGoogle Scholar
  12. 12.
    Martín A, Boisgard R, Thézé B, Van Camp N, Kuhnast B, Damont A, Kassiou M, Dollé F, Tavitian B (2010) Evaluation of the PBR/TSPO radioligand [18F]DPA-714 in a rat model of focal cerebral ischemia. J Cereb Blood Flow Metab 30(1):230-241Google Scholar
  13. 13.
    Dollé F, Luus C, Reynolds A, Kassiou M (2009) Radiolabelled molecules for imaging the translocator protein (18 kDa) using Positron Emission Tomography. Curr Med Chem 16:2899-2923CrossRefPubMedGoogle Scholar
  14. 14.
    Chaveau F, Boutin H, Van Camp N, Dollé F, Tavitian T (2008) Nuclear imaging of neuroinflammation: a comprehensive review of [11C]PK11195 challengers. Eur J Nucl Med Mol Imag 35:2304-2319CrossRefGoogle Scholar
  15. 15.
    James ML, Fulton RR, Vercoullie J, Henderson DJ, Garreau L, Chalon S, Dolle F, Costa B, Guilloteau D, Kassiou M (2008) DPA-714, a new translocator protein-specific ligand: synthesis, radiofluorination, and pharmacologic characterization. J Nucl Med 49:814-822CrossRefPubMedGoogle Scholar
  16. 16.
    Doorduin J, Klein HC, Dierckx RA, James M, Kassiou M, de Vries EF (2009) [11C]DPA-713 and [18F]DPA-714 as new PET tracers for TSPO: a comparison with [11C]-(R)-PK11195 in a rat model of herpes encephalitis. Mol Imaging Biol 11:386-398CrossRefPubMedGoogle Scholar
  17. 17.
    Chauveau F, Van Camp N, Dollé F, Kuhnast B, Hinnen F, Damont A, Boutin H, James M, Kassiou M, Tavitian B (2009) Comparative evaluation of the translocator protein radioligands [11C]DPA-713, [18F]DPA-714, and [11C]PK11195 in a rat model of acute neuroinflammation. J Nucl Med 50:468-476CrossRefPubMedGoogle Scholar
  18. 18.
    Justicia C, Martín A, Rojas S, Gironella M, Cervera A, Panés J, Chamorro A, Planas AM (2006) Anti-VCAM-1 antibodies did not protect against ischemic damage either in rats or in mice. J Cereb Blood Flow Metab 26:421-432CrossRefPubMedGoogle Scholar
  19. 19.
    Damont A, Hinnen F, Kunhast B et al. (2008) Radiosynthesis of [18F]DPA-714, a selective radioligand for imaging the translocator protein (18 kDa) with PET. J Labelled Comp Radiopharm 51:286-292CrossRefGoogle Scholar
  20. 20.
    Schweinhardt P, Fransson P, Olson L, Spenger C, Andersson JL (2003) A template for spatial normalisation of MR images of the rat brain. J Neurosci Methods 129:105-113CrossRefPubMedGoogle Scholar
  21. 21.
    Ji B, Maeda J, Sawada M, Ono M, Okauchi T, Inaji M, Zhang MR, Suzuki K, Ando K, Staufenbiel M, Trojanowski JQ, Lee VM, Higuchi M, Suhara T (2008) Imaging of peripheral benzodiazepine receptor expression as biomarkers of detrimental versus beneficial glial responses in mouse models of Alzheimer's and other CNS pathologies. J Neurosci 28:12255-12267CrossRefPubMedGoogle Scholar
  22. 22.
    Koistinaho M, Malm TM, Kettunen MI, Goldsteins G, Starckx S, Kauppinen RA, Opdenakker G, Koistinaho J (2005) Minocycline protects against permanent cerebral ischemia in wild type but not in matrix metalloprotease-9-deficient mice. J Cereb Blood Flow Metab 25:460-467CrossRefPubMedGoogle Scholar
  23. 23.
    Stirling DP, Khodarahmi K, Liu J, McPhail LT, McBride CB, Steeves JD, Ramer MS, Tetzlaff W (2004) Minocycline treatment reduces delayed oligodendrocyte death, attenuates axonal dieback, and improves functional outcome after spinal cord injury. J Neurosci 24:2182-2190CrossRefPubMedGoogle Scholar
  24. 24.
    Power C, Henry S, Del Bigio MR, Larsen PH, Corbett D, Imai Y, Yong VW, Peeling J (2003) Intracerebral hemorrhage induces macrophage activation and matrix metalloproteinases. Ann Neurol 53:731-742CrossRefPubMedGoogle Scholar
  25. 25.
    Murata Y, Rosell A, Scannevin RH, Rhodes KJ, Wang X, Lo EH (2008) Extension of the thrombolytic time window with minocycline in experimental stroke. Stroke 39:3372-3377CrossRefPubMedGoogle Scholar
  26. 26.
    Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, Bian J, Guo L, Farrell LA, Hersch SM, Hobbs W, Vonsattel JP, Cha JH, Friedlander RM (2000) Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 6:797-801CrossRefPubMedGoogle Scholar
  27. 27.
    Du Y, Ma Z, Lin S, Dodel RC, Gao F, Bales KR, Triarhou LC, Chernet E, Perry KW, Nelson DL, Luecke S, Phebus LA, Bymaster FP, Paul SM (2001) Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. Proc Natl Acad Sci U S A 98:14669-14674CrossRefPubMedGoogle Scholar
  28. 28.
    Tikka TM, Vartiainen NE, Goldsteins G, Oja SS, Andersen PM, Marklund SL, Koistinaho J (2002) Minocycline prevents neurotoxicity induced by cerebrospinal fluid from patients with motor neurone disease. Brain 125:722-731CrossRefPubMedGoogle Scholar
  29. 29.
    Jander S, Schroeter M, Peters O, Witte OW, Stoll G (2003) Cortical spreading depression induces proinflammatory cytokine gene expression in the rat brain. J Neurosci 23:11602-11610Google Scholar
  30. 30.
    Fagan SC, Edwards DJ, Borlongan CV, Xu L, Arora A, Feuerstein G, Hess DC (2004) Optimal delivery of minocycline to the brain: implication for human studies of acute neuroprotection. Exp Neurol 186:248-251CrossRefPubMedGoogle Scholar
  31. 31.
    Nessler S, Dodel R, Bittner A, et al (2002) Effect of minocycline in experimental autoimmune encephalomyelitis. Ann Neurol 52:689-690CrossRefPubMedGoogle Scholar
  32. 32.
    Rosell A, Lo EH (2008) Multiphasic roles for matrix metalloproteinases after stroke. Curr Opin Pharmacol 8:82-89CrossRefPubMedGoogle Scholar
  33. 33.
    Yong VW, Wells J, Giuliani F, Casha S, Power C, Metz LM (2004) The promise of minocycline in neurology. Lancet Neurol 3:744-751CrossRefPubMedGoogle Scholar

Copyright information

© Academy of Molecular Imaging and Society for Molecular Imaging 2010

Authors and Affiliations

  • Abraham Martín
    • 1
  • Raphaël Boisgard
    • 1
  • Michael Kassiou
    • 2
  • Frédéric Dollé
    • 3
  • Bertrand Tavitian
    • 1
  1. 1.CEA, DSV, I²BM, SHFJ, Laboratoire Imagerie Moléculaire Expérimentale; INSERM U803Orsay CedexFrance
  2. 2.Department of Medical Radiation Sciences and School of ChemistryUniversity of SydneySydneyAustralia
  3. 3.CEA, DSV, I²BM, SHFJOrsayFrance

Personalised recommendations