Lack of neuroinflammation in the HIV-1 transgenic rat: an [ 18F]-DPA714 PET imaging study

Journal of Neuroinflammation

Dima A. Hammoud³  William C. Reid³  Dragan Maric¹  Michael Kassiou²  Elaine M. Jagoda⁴  Kristin L. Peterson³  Margaret R. Lentz³  Wael G. Ibrahim³  Xuyi Yue⁵  Dianne E. Lee³ 

[1] Division of Intermural Research (DIR), National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, Bethesda, MD, USA;Chemistry Department, The University of Sydney, Sydney, Australia;Center for Infectious Disease Imaging (CIDI), Radiology and Imaging Sciences, National Institutes of Health/Clinical Center, 10 Center Drive, Room 1C368, Bethesda 20814-9692, MD, USA;Molecular Imaging Program (MIP), National Cancer Institute (NCI), Bethesda, MD, USA;Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA

关键词: Neuroinflammation;    Positron emission tomography;    Transgenic rat;    HIV;   

Others  :  1227054
DOI  :  10.1186/s12974-015-0390-9

 received in 2015-07-11, accepted in 2015-09-02,  发布年份 2015

【 摘 要 】

Background

HIV-associated neuroinflammation is believed to be a major contributing factor in the development of HIV-associated neurocognitive disorders (HAND). In this study, we used micropositron emission tomography (PET) imaging to quantify neuroinflammation in HIV-1 transgenic rat (Tg), a small animal model of HIV, known to develop neurological and behavioral problems.

Methods

Dynamic [ ¹⁸ F]DPA-714 PET imaging was performed in Tg and age-matched wild-type (WT) rats in three age groups: 3-, 9-, and 16-month-old animals. As a positive control for neuroinflammation, we performed unilateral intrastriatal injection of quinolinic acid (QA) in a separate group of WT rats. To confirm our findings, we performed multiplex immunofluorescent staining for Iba1 and we measured cytokine/chemokine levels in brain lysates of Tg and WT rats at different ages.

Results

[ ¹⁸ F]DPA-714 uptake in HIV-1 Tg rat brains was generally higher than in age-matched WT rats but this was not statistically significant in any age group. [ ¹⁸ F]DPA-714 uptake in the QA-lesioned rats was significantly higher ipsilateral to the lesion compared to contralateral side indicating neuroinflammatory changes. Iba1 immunofluorescence showed no significant differences in microglial activation between the Tg and WT rats, while the QA-lesioned rats showed significant activation. Finally, cytokine/chemokine levels in brain lysates of the Tg rats and WT rats were not significantly different.

Conclusion

Microglial activation might not be the primary mechanism for neuropathology in the HIV-1 Tg rats. Although [ ¹⁸ F]DPA-714 is a good biomarker of neuroinflammation, it cannot be reliably used as an in vivo biomarker of neurodegeneration in the HIV-1 Tg rat.

【 授权许可】

   
2015 Lee et al.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

【 参考文献 】

• [1]McArthur JC, Steiner J, Sacktor N, Nath A: Human immunodeficiency virus-associated neurocognitive disorders: mind the gap. Ann Neurol 2010, 67(6):699-714.
• [2]Tan IL, McArthur JC: HIV-associated neurological disorders: a guide to pharmacotherapy. CNS drugs 2012, 26(2):123-34.
• [3]Venneti S, Lopresti BJ, Wiley CA: The peripheral benzodiazepine receptor (translocator protein 18 kDa) in microglia: from pathology to imaging. Prog Neurobiol 2006, 80(6):308-22.
• [4]Lu SM, Tremblay ME, King IL, Qi J, Reynolds HM, Marker DF, et al.: HIV-1 Tat-induced microgliosis and synaptic damage via interactions between peripheral and central myeloid cells. PLoS One 2011, 6(9):e23915.
• [5]Guha D, Nagilla P, Redinger C, Srinivasan A, Schatten GP, Ayyavoo V: Neuronal apoptosis by HIV-1 Vpr: contribution of proinflammatory molecular networks from infected target cells. J Neuroinflammation 2012, 9:138. BioMed Central Full Text
• [6]Kramer-Hammerle S, Rothenaigner I, Wolff H, Bell JE, Brack-Werner R: Cells of the central nervous system as targets and reservoirs of the human immunodeficiency virus. Virus Res 2005, 111(2):194-213.
• [7]Renner NA, Sansing HA, Morici LA, Inglis FM, Lackner AA, MacLean AG: Microglia activation by SIV-infected macrophages: alterations in morphology and cytokine secretion. J Neurovirol 2012, 18(3):213-21.
• [8]Cosenza-Nashat M, Zhao ML, Suh HS, Morgan J, Natividad R, Morgello S, et al.: Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain. Neuropathol Appl Neurobiol 2009, 35(3):306-28.
• [9]Scarf AM, Kassiou M: The translocator protein. J Nucl Med 2011, 52(5):677-80.
• [10]Dheen ST, Kaur C, Ling EA: Microglial activation and its implications in the brain diseases. Curr Med Chem 2007, 14(11):1189-97.
• [11]Cagnin A, Kassiou M, Meikle SR, Banati RB: In vivo evidence for microglial activation in neurodegenerative dementia. Acta Neurol Scand Suppl 2006, 185:107-14.
• [12]Banati RB, Newcombe J, Gunn RN, Cagnin A, Turkheimer F, Heppner F, et al.: The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity. Brain 2000, 123(Pt 11):2321-37.
• [13]Cagnin A, Myers R, Gunn RN, Lawrence AD, Stevens T, Kreutzberg GW, et al.: In vivo visualization of activated glia by [11C] (R)-PK11195-PET following herpes encephalitis reveals projected neuronal damage beyond the primary focal lesion. Brain 2001, 124(Pt 10):2014-27.
• [14]Tai YF, Pavese N, Gerhard A, Tabrizi SJ, Barker RA, Brooks DJ, et al.: Imaging microglial activation in Huntington’s disease. Brain Res Bull 2007, 72(2–3):148-51.
• [15]Gerhard A, Trender-Gerhard I, Turkheimer F, Quinn NP, Bhatia KP, Brooks DJ: In vivo imaging of microglial activation with [11C](R)-PK11195 PET in progressive supranuclear palsy. Mov Disord 2006, 21(1):89-93.
• [16]Gerhard A, Watts J, Trender-Gerhard I, Turkheimer F, Banati RB, Bhatia K, et al.: In vivo imaging of microglial activation with [11C](R)-PK11195 PET in corticobasal degeneration. Mov Disord 2004, 19(10):1221-6.
• [17]Chauveau F, Van Camp N, Dolle F, Kuhnast B, Hinnen F, Damont A, et al.: 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 2009, 50(3):468-76.
• [18]Doorduin J, Klein HC, Dierckx RA, James M, Kassiou M, de Vries EF: [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 2009, 11(6):386-98.
• [19]James ML, Fulton RR, Vercoullie J, Henderson DJ, Garreau L, Chalon S, et al.: DPA-714, a new translocator protein-specific ligand: synthesis, radiofluorination, and pharmacologic characterization. J Nucl Med 2008, 49(5):814-22.
• [20]Martin A, Boisgard R, Theze B, Van Camp N, Kuhnast B, Damont A, et al.: Evaluation of the PBR/TSPO radioligand [(18)F]DPA-714 in a rat model of focal cerebral ischemia. J Cereb Blood Flow Metab 2010, 30(1):230-41.
• [21]Endres CJ, Pomper MG, James M, Uzuner O, Hammoud DA, Watkins CC, et al.: Initial evaluation of 11C-DPA-713, a novel TSPO PET ligand, in humans. J Nucl Med 2009, 50(8):1276-82.
• [22]Brown AK, Fujita M, Fujimura Y, Liow JS, Stabin M, Ryu YH, et al.: Radiation dosimetry and biodistribution in monkey and man of 11C-PBR28: a PET radioligand to image inflammation. J Nucl Med 2007, 48(12):2072-9.
• [23]Arlicot N, Katsifis A, Garreau L, Mattner F, Vergote J, Duval S, et al.: Evaluation of CLINDE as potent translocator protein (18 kDa) SPECT radiotracer reflecting the degree of neuroinflammation in a rat model of microglial activation. Eur J Nucl Med Mol Imaging 2008, 35(12):2203-11.
• [24]Mattner F, Bandin DL, Staykova M, Berghofer P, Gregoire MC, Ballantyne P, et al.: Evaluation of [(1)(2)(3)I]-CLINDE as a potent SPECT radiotracer to assess the degree of astroglia activation in cuprizone-induced neuroinflammation. Eur J Nucl Med Mol Imaging 2011, 38(8):1516-28.
• [25]Venneti S, Wang G, Wiley CA: The high affinity peripheral benzodiazepine receptor ligand DAA1106 binds to activated and infected brain macrophages in areas of synaptic degeneration: implications for PET imaging of neuroinflammation in lentiviral encephalitis. Neurobiol Dis 2008, 29(2):232-41.
• [26]Martin A, Boisgard R, Kassiou M, Dolle F, Tavitian B: Reduced PBR/TSPO expression after minocycline treatment in a rat model of focal cerebral ischemia: a PET study using [(18)F]DPA-714. Mol Imaging Biol 2011, 13(1):10-5.
• [27]Schweinhardt P, Fransson P, Olson L, Spenger C, Andersson JL: A template for spatial normalisation of MR images of the rat brain. J Neurosci Methods 2003, 129(2):d105-13.
• [28]Paxinos G, Watson C. The Rat Brain: In Stereotaxic Coordinates. Academic Press, Incorporated: London, UK; 1998.
• [29]Lee DE, Gallezot JD, Zheng MQ, Lim K, Ding YS, Huang Y, et al.: Test-retest reproducibility of [11C]-(+)-propyl-hexahydro-naphtho-oxazin positron emission tomography using the bolus plus constant infusion paradigm. Mol Imaging 2013, 12(2):77-82.
• [30]Kleiber M: Body size and metabolic rate. Physiol Rev 1947, 27(4):511-41.
• [31]Drake C, Boutin H, Jones MS, Denes A, McColl BW, Selvarajah JR, et al.: Brain inflammation is induced by co-morbidities and risk factors for stroke. Brain Behav Immun 2011, 25(6):1113-22.
• [32]Tang D, Hight MR, McKinley ET, Fu A, Buck JR, Smith RA, et al.: Quantitative preclinical imaging of TSPO expression in glioma using N, N-diethyl-2-(2-(4-(2-18F-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimi din-3-yl)acetamide. J Nucl Med 2012, 53(2):287-94.
• [33]Mocchetti I, Bachis A, Avdoshina V: Neurotoxicity of human immunodeficiency virus-1: viral proteins and axonal transport. Neurotox Res 2011.
• [34]Kovalevich J, Langford D: Neuronal toxicity in HIV CNS disease. Futur Virol 2012, 7(7):687-98.
• [35]Rao JS, Kim HW, Kellom M, Greenstein D, Chen M, Kraft AD, et al.: Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in brain of HIV-1 transgenic rats. J Neuroinflammation 2011, 8(1):101. BioMed Central Full Text
• [36]Agrawal L, Louboutin JP, Reyes BA, Van Bockstaele EJ, Strayer DS: HIV-1 Tat neurotoxicity: a model of acute and chronic exposure, and neuroprotection by gene delivery of antioxidant enzymes. Neurobiol Dis 2012, 45(2):657-70.
• [37]Hu S, Sheng WS, Lokensgard JR, Peterson PK, Rock RB: Preferential sensitivity of human dopaminergic neurons to gp120-induced oxidative damage. J Neurovirol 2009, 15(5–6):401-10.
• [38]Bezzi P, Domercq M, Brambilla L, Galli R, Schols D, De Clercq E, et al.: CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity. Nat Neurosci 2001, 4(7):702-10.
• [39]Radja F, Kay DG, Albrecht S, Jolicoeur P: Oligodendrocyte-specific expression of human immunodeficiency virus type 1 Nef in transgenic mice leads to vacuolar myelopathy and alters oligodendrocyte phenotype in vitro. J Virol 2003, 77(21):11745-53.
• [40]Garvey LJ, Pavese N, Politis M, Ramlackhansingh A, Brooks DJ, Taylor-Robinson SD et al. Increased microglia activation in neurologically asymptomatic HIV-infected patients receiving effective ART; An 11C-PK11195 PET study. AIDS (London, England). 2013. doi:10.1097/01.aids.0000432467.54003.f7.
• [41]Hammoud DA, Endres CJ, Chander AR, Guilarte TR, Wong DF, Sacktor NC, et al.: Imaging glial cell activation with [11C]-R-PK11195 in patients with AIDS. J Neurovirol 2005, 11(4):346-55.
• [42]Wiley CA, Lopresti BJ, Becker JT, Boada F, Lopez OL, Mellors J, et al.: Positron emission tomography imaging of peripheral benzodiazepine receptor binding in human immunodeficiency virus-infected subjects with and without cognitive impairment. J Neurovirol 2006, 12(4):262-71.
• [43]Reid W, Sadowska M, Denaro F, Rao S, Foulke J Jr, Hayes N, et al.: An HIV-1 transgenic rat that develops HIV-related pathology and immunologic dysfunction. Proc Natl Acad Sci U S A 2001, 98(16):9271-6.
• [44]Lashomb AL, Vigorito M, Chang SL: Further characterization of the spatial learning deficit in the human immunodeficiency virus-1 transgenic rat. J Neurovirol 2009, 15(1):14-24.
• [45]Moran LM, Booze RM, Mactutus CF: Modeling deficits in attention, inhibition, and flexibility in HAND. J Neuroimmune Pharmacol 2014, 9(4):508-21.
• [46]Vigorito M, Connaghan KP, Chang SL: The HIV-1 transgenic rat model of neuroHIV. Brain Behav Immun 2015.
• [47]Wayman WN, Chen L, Persons AL, Napier TC: Cortical consequences of HIV-1 Tat exposure in rats are enhanced by chronic cocaine. Curr HIV Res 2015, 13(1):80-7.
• [48]Basselin M, Ramadan E, Igarashi M, Chang L, Chen M, Kraft AD, et al.: Imaging upregulated brain arachidonic acid metabolism in HIV-1 transgenic rats. J Cereb Blood Flow Metab 2011, 31(2):486-93.
• [49]Repunte-Canonigo V, Lefebvre C, George O, Kawamura T, Morales M, Koob GF, et al.: Gene expression changes consistent with neuroAIDS and impaired working memory in HIV-1 transgenic rats. Mol Neurodegener 2014, 9:26. BioMed Central Full Text
• [50]Homji NF, Mao X, Langsdorf EF, Chang SL: Endotoxin-induced cytokine and chemokine expression in the HIV-1 transgenic rat. J Neuroinflammation 2012, 9:3. BioMed Central Full Text
• [51]Boutin H, Prenant C, Maroy R, Galea J, Greenhalgh AD, Smigova A et al. [18F]DPA-714: direct comparison with [11C]PK11195 in a model of cerebral ischemia in rats. PLoS One. 2013;8(2):e56441. doi:10.1371/journal.pone.0056441.
• [52]Harhausen D, Sudmann V, Khojasteh U, Muller J, Zille M, Graham K, et al.: Specific imaging of inflammation with the 18 kDa translocator protein ligand DPA-714 in animal models of epilepsy and stroke. PLoS One 2013, 8(8):e69529.
• [53]Lavisse S, Guillermier M, Herard AS, Petit F, Delahaye M, Van Camp N, et al.: Reactive astrocytes overexpress TSPO and are detected by TSPO positron emission tomography imaging. J Neurosci 2012, 32(32):10809-18.
• [54]Awde AR, Boisgard R, Theze B, Dubois A, Zheng J, Dolle F, et al.: The translocator protein radioligand 18F-DPA-714 monitors antitumor effect of erufosine in a rat 9L intracranial glioma model. J Nucl Med 2013, 54(12):2125-31.
• [55]Winkeler A, Boisgard R, Awde AR, Dubois A, Theze B, Zheng J, et al.: The translocator protein ligand [(1)(8)F]DPA-714 images glioma and activated microglia in vivo. Eur J Nucl Med Mol Imaging 2012, 39(5):811-23.
• [56]Smith G: Animal models of Alzheimer’s disease: experimental cholinergic denervation. Brain Res 1988, 472(2):103-18.
• [57]Lee DE, Reid WC, Ibrahim WG, Peterson KL, Lentz MR, Maric D, et al.: Imaging dopaminergic dysfunction as a surrogate marker of neuropathology in a small-animal model of HIV. Mol Imaging 2014, 13:1-10.
• [58]Lentz MR, Peterson KL, Ibrahim WG, Lee DE, Sarlls J, Lizak MJ, et al.: Diffusion tensor and volumetric magnetic resonance measures as biomarkers of brain damage in a small animal model of HIV. PLoS One 2014, 9(8):e105752.
• [59]Royal W 3rd, Zhang L, Guo M, Jones O, Davis H, Bryant JL: Immune activation, viral gene product expression and neurotoxicity in the HIV-1 transgenic rat. J Neuroimmunol 2012, 247(1–2):16-24.
• [60]Doorduin J, de Vries EF, Dierckx RA, Klein HC: PET imaging of the peripheral benzodiazepine receptor: monitoring disease progression and therapy response in neurodegenerative disorders. Curr Pharm Des 2008, 14(31):3297-315.
• [61]Vicidomini C, Panico M, Greco A, Gargiulo S, Coda AR, Zannetti A, et al.: In vivo imaging and characterization of [(18)F]DPA-714, a potential new TSPO ligand, in mouse brain and peripheral tissues using small-animal PET. Nucl Med Biol 2015, 42(3):309-16.
• [62]Zinnhardt B, Viel T, Wachsmuth L, Vrachimis A, Wagner S, Breyholz HJ, et al.: Multimodal imaging reveals temporal and spatial microglia and matrix metalloproteinase activity after experimental stroke. J Cereb Blood Flow Metab 2015.
• [63]Toth M, Doorduin J, Haggkvist J, Varrone A, Amini N, Halldin C, et al.: Positron emission tomography studies with [11C]PBR28 in the healthy rodent brain: validating SUV as an outcome measure of neuroinflammation. PLoS One 2015, 10(5):e0125917.
• [64]Moran LM, Booze RM, Webb KM, Mactutus CF: Neurobehavioral alterations in HIV-1 transgenic rats: evidence for dopaminergic dysfunction. Exp Neurol 2013, 239:139-47.
• [65]Peng J, Vigorito M, Liu X, Zhou D, Wu X, Chang SL: The HIV-1 transgenic rat as a model for HIV-1 infected individuals on HAART. J Neuroimmunol 2010, 218(1–2):94-101.
• [66]Blanchard HC, Taha AY, Rapoport SI, Yuan ZX: Low-dose aspirin (acetylsalicylate) prevents increases in brain PGE2, 15-epi-lipoxin A4 and 8-isoprostane concentrations in 9 month-old HIV-1 transgenic rats, a model for HIV-1 associated neurocognitive disorders. Prostaglandins Leukot Essent Fat Acids 2015, 96:25-30.
• [67]Davinelli S, Scapagnini G, Denaro F, Calabrese V, Benedetti F, Krishnan S, et al.: Altered expression pattern of Nrf2/HO-1 axis during accelerated-senescence in HIV-1 transgenic rat. Biogerontology 2014, 15(5):449-61.
• [68]Pang X, Panee J: Roles of glutathione in antioxidant defense, inflammation, and neuron differentiation in the thalamus of HIV-1 transgenic rats. J Neuroimmune Pharmacol 2014, 9(3):413-23.
• [69]Walker MD, Dinelle K, Kornelsen R, Lee NV, Miao Q, Adam M et al. [C]PBR28 PET imaging is sensitive to neuroinflammation in the aged rat. J Cereb Blood Flow Metab. 2015. doi:10.1038/jcbfm.2015.54.
• [70]Li MD, Cao J, Wang S, Wang J, Sarkar S, Vigorito M, et al.: Transcriptome sequencing of gene expression in the brain of the HIV-1 transgenic rat. PLoS One 2013, 8(3):e59582.