Reduced PBR/TSPO Expression After Minocycline Treatment in a Rat Model of Focal Cerebral Ischemia: A PET Study Using [18F]DPA-714
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.
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.
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.
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.
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 wordsMinocycline PET Neuroinflammation PBR TSPO DPA-714 Cerebral ischemia
We thank A. Blossier for technical assistance in the PET studies. This work was funded in part by the EU-FP6 network EMIL (LSHC-CT-2004-503569) and the EU-FP6 network DiMI (LSHB-CT-2005-512146).
- 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
- 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.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
- 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
- 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
- 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.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
- 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