Macrophages and microglia in HSV-1 infected mouse brain

Esiri, Margaret M.; Drummond, Cláudia; Morris, Christine S.

doi:10.1016/0165-5728(95)00123-8

Cited by 38 publications

(18 citation statements)

References 19 publications

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“…In this study, the performance of 11 C-PBR28 for the preclinical imaging of neuroinflammation was evaluated with the HSE model, with (R)-11 C-PK11195 tracer used for comparison purposes. In the HSE model, nasal infection with HSV-1 induces strong activation of microglia 6-7 d after infection, in particular in the pons and medulla (15,16,24). 11 C-PBR28 was able to detect the activation of microglia in more brain regions and proved to be more sensitive than (R)-11 C-PK11195.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Analysis of ¹¹C-PBR28 in the Rat Model of Herpes Encephalitis: Comparison with (R)-¹¹C-PK11195

et al. 2016

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11 C-PBR28 is a second-generation translocator protein (TSPO) tracer with characteristics supposedly superior to the most commonly used tracer for neuroinflammation, (R)-11 C-PK11195. Despite its use in clinical research, no studies on the imaging properties and pharmacokinetic analysis of 11 C-PBR28 in rodent models of neuroinflammation have been published yet. Therefore, this study aimed to evaluate 11 C-PBR28 as a tool for detection and quantification of neuroinflammation in preclinical research and to compare its imaging properties with (R)-11 C-PK11195. The herpes simplex encephalitis (HSE) model was used for induction of neuroinflammation in male Wistar rats. Six or 7 d after virus inoculation, a dynamic 11 C-PBR28 or (R)-11 C-PK11195 PET scan with arterial blood sampling was obtained. Pharmacokinetic modeling was performed on the PET data and analyzed using volumes of interest and a voxel-based approach. Volume-of-interest-and voxel-based analysis of 11 C-PBR28 images showed overexpression of TSPO in brain regions known to be affected in the HSE rat model. 11 C-PBR28 was metabolized faster than (R)-11 C-PK11195, with a metabolic half-life in plasma of 5 and 21 min, respectively. Overall, 11 C-PBR28 was more sensitive than (R)-11 C-PK11195 in detecting neuroinflammation. The binding potential (BP ND ) of 11 C-PBR28 was significantly higher (P , 0.05) in the medulla (176%), pons (146%), midbrain (101%), hippocampus (85%), thalamus (73%), cerebellum (54%), and hypothalamus (49%) in HSE rats than in control rats, whereas (R)-11 C-PK11195 showed a higher BP ND only in the medulla (32%). The BP ND in control animals was not significantly different between tracers, suggesting that the nonspecific binding of both tracers is similar. 11 C-PBR28 was more sensitive than (R)-11 C-PK11195 in the detection of TSPO overexpression in the HSE rat model, because more brain regions with significantly increased tracer uptake could be found, irrespective of the data analysis method used. These results suggest that 11 C-PBR28 should be able to detect more subtle changes in microglial activation in preclinical models of neuroinflammation.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Analysis of ¹¹C-PBR28 in the Rat Model of Herpes Encephalitis: Comparison with (R)-¹¹C-PK11195

et al. 2016

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“…Viral products tend to disappear after the first 3 weeks, and often viral genome can not be detected consistently. 62,63 This might suggest that late increases of [ 11 C](R)-PK11195 signals reflect primarily a delayed neuroinflammatory response to Wallerian-type degeneration of axons and synaptic terminals of the initially damaged neurons. Microglial activation may be involved in long-lasting modifications of the architecture of neuronal network after an acute insult by contributing to neuroplasticity and remodeling of distributed neuronal network.…”

Section: Post-herpetic Encephalitismentioning

confidence: 99%

Positron Emission Tomography Imaging of Neuroinflammation

et al. 2007

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In the diseased brain, upon activation microglia express binding sites for synthetic ligands designed to recognize the 18-kDa translocator protein TP-18, which is part of the so-called peripheral benzodiazepine receptor complex. PK11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide], the prototype synthetic ligand, has been widely used for the functional characterization of TP-18. Its cellular source in activated microglia has been established using high-resolution, single-cell autoradiography with the R-enantiomer [3H](R)-PK11195. Radiolabeled [11C](R)-PK11195 has been used to image active brain disease with positron emission tomography. Consistent with experimental and postmortem observations of a characteristically distributed pattern of microglia activation in areas of focal pathology, as well as in anterograde and retrograde projection areas, the in vivo regional [11C](R)-PK11195 signal is found in active focal lesions and over time also along the affected neural tracts and their respective cortical and subcortical projection areas. Thus, a profile of active disease emerges that matches some of the typical distribution patterns known from structural neuroimaging techniques, but additionally shows involvement of brain regions linked through neural pathways. In the context of cell-based in vivo neuropathology, the image data are thus best interpreted in the context of the emerging cellular understanding of brain disease or damage, rather than the definitions of clinical diagnosis. One important observation, borne out by experiment, is the long latency with which activated microglia or increased PK11195 retention appear to gradually emerge and remain in distal areas secondarily affected by disease, supporting speculations that the presence of activated microglia is an important corollary of brain plasticity

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“…Microglial cells express increased MHC class I and class II glycoproteins and have a wide distribution throughout the brain, including areas separate from the productive infection. In some instances, this focal microglial cell reaction remains for several weeks (105).…”

Section: Virusesmentioning

confidence: 99%

“…Human HSV encephalitis has been modeled in rats experimentally by inoculation of virus in peripheral nerves (105,370). HSV moves along peripheral neurons, achieving widespread distribution in the brain by days 8 to 10 postinfection.…”

Section: Virusesmentioning

confidence: 99%

Role of Microglia in Central Nervous System Infections

et al. 2004

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The nature of microglia fascinated many prominent researchers in the 19th and early 20th centuries, and in a classic treatise in 1932, Pio del Rio-Hortega formulated a number of concepts regarding the function of these resident macrophages of the brain parenchyma that remain relevant to this day. However, a renaissance of interest in microglia occurred toward the end of the 20th century, fueled by the recognition of their role in neuropathogenesis of infectious agents, such as human immunodeficiency virus type 1, and by what appears to be their participation in other neurodegenerative and neuroinflammatory disorders. During the same period, insights into the physiological and pathological properties of microglia were gained from in vivo and in vitro studies of neurotropic viruses, bacteria, fungi, parasites, and prions, which are reviewed in this article. New concepts that have emerged from these studies include the importance of cytokines and chemokines produced by activated microglia in neurodegenerative and neuroprotective processes and the elegant but astonishingly complex interactions between microglia, astrocytes, lymphocytes, and neurons that underlie these processes. It is proposed that an enhanced understanding of microglia will yield improved therapies of central nervous system infections, since such therapies are, by and large, sorely needed

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Macrophages and microglia in HSV-1 infected mouse brain

Cited by 38 publications

References 19 publications

Pharmacokinetic Analysis of ¹¹C-PBR28 in the Rat Model of Herpes Encephalitis: Comparison with (R)-¹¹C-PK11195

Pharmacokinetic Analysis of ¹¹C-PBR28 in the Rat Model of Herpes Encephalitis: Comparison with (R)-¹¹C-PK11195

Positron Emission Tomography Imaging of Neuroinflammation

Role of Microglia in Central Nervous System Infections

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Macrophages and microglia in HSV-1 infected mouse brain

Cited by 38 publications

References 19 publications

Pharmacokinetic Analysis of 11C-PBR28 in the Rat Model of Herpes Encephalitis: Comparison with (R)-11C-PK11195

Pharmacokinetic Analysis of 11C-PBR28 in the Rat Model of Herpes Encephalitis: Comparison with (R)-11C-PK11195

Positron Emission Tomography Imaging of Neuroinflammation

Role of Microglia in Central Nervous System Infections

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Pharmacokinetic Analysis of ¹¹C-PBR28 in the Rat Model of Herpes Encephalitis: Comparison with (R)-¹¹C-PK11195

Pharmacokinetic Analysis of ¹¹C-PBR28 in the Rat Model of Herpes Encephalitis: Comparison with (R)-¹¹C-PK11195