Dataset Information

[(18)F]DPA-714 PET imaging of AMD3100 treatment in a mouse model of stroke.

ABSTRACT: Chemokine receptor 4 and stromal-cell-derived factor 1 have been found to be related to the initiation of neuroinflammation in ischemic brain. Herein, we aimed to monitor the changes of neuorinflammation after AMD3100 treatment using a translocator protein (TSPO) specific PET tracer in a mouse model of stroke. The transient MCAO model was established with Balb/C mice. The success of the model was confirmed by magnetic resonance imaging and FDG PET. The treatment started the same day after surgery via daily intraperitoneal injection of 1 mg of AMD3100/kg for three consecutive days. [(18)F]DPA-714 was used as the TSPO imaging tracer. In vivo PET was performed at different time points after surgery in both control and treated mice. Ex vivo histological and immunofluorescence staining of brain slices was performed to confirm the lesion site and inflammatory cell activation. The TSPO level was also evaluated using Western blotting. Longitudinal PET scans revealed that the level of [(18)F]DPA-714 uptake was significantly increased in the ischemic brain area with a peak accumulation at around day 10 after surgery, and the level of uptake remained high until day 16. The in vivo PET data were consistent with those from ex vivo immunofluorescence staining. After AMD3100 treatment, the signal intensity was significantly decreased compared with that of normal saline-treated control group. In conclusion, TSPO-targeted PET imaging using [(18)F]DPA-714 can be used to monitor inflammatory response after stroke and provide a useful method for evaluating the efficacy of anti-inflammation treatment.

SUBMITTER: Wang Y

PROVIDER: S-EPMC4186675 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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[(18)F]DPA-714 PET imaging of AMD3100 treatment in a mouse model of stroke.

Wang Yu Y Yue Xuyi X Kiesewetter Dale O DO Wang Zhe Z Lu Jie J Niu Gang G Teng Gaojun G Chen Xiaoyuan X

Molecular pharmaceutics 20140904 10

Chemokine receptor 4 and stromal-cell-derived factor 1 have been found to be related to the initiation of neuroinflammation in ischemic brain. Herein, we aimed to monitor the changes of neuorinflammation after AMD3100 treatment using a translocator protein (TSPO) specific PET tracer in a mouse model of stroke. The transient MCAO model was established with Balb/C mice. The success of the model was confirmed by magnetic resonance imaging and FDG PET. The treatment started the same day after surger ...[more]

PMID: 25157648

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Project description:BACKGROUND:Cerebral stroke is a severe and frequent condition that requires rapid and reliable diagnosis. If administered shortly after the first symptoms manifest themselves, IV thrombolysis has been shown to increase the functional prognosis by restoring brain reperfusion. However, a better understanding of the pathophysiology of stroke should help to identify potential new therapeutic targets. Stroke is known to induce an inflammatory brain reaction that involves overexpression of the 18-kDa translocator protein (TSPO) in glial cells and infiltrated leukocytes, which can be visualised by positron emission tomography (PET). We aimed to evaluate post-stroke neuroinflammation using the PET TSPO radioligand (18)?F-DPA-714. METHODS:Nine patients underwent (18)?F-DPA-714 PET and magnetic resonance imaging (MRI) between 8 and 18 days after the ictus. Co-registration of MRI and PET images was used to define three volumes of interest (VOIs): core infarction, contralateral region, and cerebellum ipsilateral to the stroke lesion. Time activity curves were obtained from each VOI, and ratios of mean and maximum activities between the VOIs were calculated. RESULTS:We observed an increased uptake of (18)?F-DPA-714 co-localised with the infarct tissue and extension beyond the region corresponding to the damage in the blood brain barrier. No correlation was identified between (18)?F-DPA-714 uptake and infarct volume. (18)?F-DPA-714 uptake in ischemic lesion (mainly associated with TSPO expression in the infarct area and in the surrounding neighbourhood) slowly decreased from 10 min pi to the end of the PET acquisition, remaining higher than that in both contralateral region and ipsilateral cerebellum. CONCLUSION:Our results show that (18)?F-DPA-714 uptake after acute ischemia is mainly associated with TSPO expression in the infarct area and in the surrounding neighbourhood. We also demonstrated that the kinetics of (18)?F-DPA-714 differs in injured tissue compared to normal tissue. Therefore, (18)?F-DPA-714 may be useful in assessing the extent of neuroinflammation associated with acute stroke and could also help to predict clinical outcomes and functional recovery, as well as to assess therapeutic strategies, such as the use of neuroprotective/anti-inflammatory drugs.

Project description:Background: Activation and dysregulation of innate, adaptive and resident immune cells in response to damage determine the pathophysiology of demyelinating disorders. Among the plethora of involved cells, microglia/macrophages and astrocytes play an important role in the pathogenesis of demyelinating disorders. The in-depth investigation of the spatio-temporal profile of these cell types in vivo may inform about the exact disease state and localization as well as may allow to monitor therapeutic modulation of the components of the neuroinflammatory response during the course of multiple sclerosis (MS). In this study, we aimed to non-invasively decipher the degree and temporal profile of neuroinflammation (TSPO - [18F]DPA-714 PET) in relation to selected magnetic resonance imaging (MRI) parameters (T2 maps) in the cuprizone (CPZ)-induced model of demyelination. Methods: C57Bl6 (n=30) mice were fed with a standard chow mixed with 0.2% (w/w) CPZ for 4 (n=10; demyelination) and 6 weeks (n=10; spontaneous remyelination). The degree of neuroinflammation at de- and remyelination was assessed by [18F]DPA-714 PET, multi-echo T2 MRI, autoradiography and immunohistochemistry. Results: CPZ-induced brain alterations were confirmed by increase of T2 relaxation times in both white and grey matter after 3 and 5 weeks of CPZ. Peak [18F]DPA-714 was found in the corpus callosum (CC, white matter), the hippocampus (HC, grey matter) and thalamus (grey matter) after 4 weeks of CPZ treatment and declined after 6 weeks of CPZ. Ex vivo autoradiography and dedicated immunofluorescence showed demyelination/remyelination with corresponding increased/decreased TSPO levels in the CC and hippocampus, confirming the spatial distribution of [18F]DPA-714 in vivo. The expression of TSPO microglia and astrocytes is time-dependent in this model. Microglia predominantly express TSPO at demyelination, while the majority of astrocytes express TSPO during remyelination. The combination of PET- and MRI-based imaging biomarkers demonstrated the regional and temporal development of the CPZ model-associated neuroinflammatory response in grey and white matter regions. Conclusions: The combination of [18F]DPA-714 PET and T2 mapping may allow to further elucidate the regional and temporal profile of inflammatory signals depending on the myelination status, although the underlying inflammatory microenvironment changes. A combination of the described imaging biomarkers may facilitate the development of patient-tailored strategies for immunomodulatory and neuro-restorative therapies in MS.

Project description:(18)F-DPA-714 is a PET tracer that recognizes macrophage translocator protein (TSPO), and (18)F-Alfatide II ((18)F-AlF-NOTA-E[PEG4-c(RGDfk)]2) is specific for integrin ?v?3. This study aims to apply these two tracers for longitudinal PET imaging of muscular inflammation, and evaluate the value of (18)F-DPA-714 in differentiating inflammation from tumor.RAW264.7 mouse macrophage cells were used for cell uptake analysis of (18)F-DPA-714. A mouse hind limb muscular inflammation model was established by intramuscular injection of turpentine oil. For the inflammation model, PET imaging was performed at different days using (18)F-DPA-714 and (18)F-Alfatide II. The specificity of the imaging probes was tested by co- or pre-injection of PK11195 or unlabeled RGD (Arg-Gly-Asp) peptide. PET imaging using (18)F-DPA-714 was performed in A549, HT29, U87MG, INS-1, and 4T1 xenograft models. Immunofluorescence staining was performed to evaluate infiltrated macrophages and angiogenesis in inflammation and/or tumors.Uptake of (18)F-DPA-714 in RAW264.7 cells was 45.5% at 1 h after incubation, and could be blocked by PK11195. PET imaging showed increased (18)F-DPA-714 and (18)F-Alfatide II uptake at inflammatory muscles. Peak uptake of (18)F-DPA-714 was seen on day 6 (4.02 ± 0.64 %ID/g), and peak uptake of (18)F-Alfatide II was shown on day 12 (1.87 ± 0.35 %ID/g) at 1 h p.i.. Tracer uptakes could be inhibited by PK11195 for (18)F-DPA-714 or cold RGD for (18)F-Alfatide II. Moreover, macrophage depletion with liposomal clodronate also reduced the local accumulation of both tracers. A549, HT29, U87MG, INS-1, and 4T1 tumor uptakes of (18)F-DPA-714 (0.46 ± 0.28, 0.91 ± 0.08, 1.69 ± 0.67, 1.13 ± 0.33, 1.22 ± 0.55 %ID/g at 1 h p.i., respectively) were significantly lower than inflammation uptake (All P < 0.05).PET imaging using (18)F-DPA-714 as a TSPO targeting tracer could evaluate the dynamics of macrophage activation and infiltration in different stages of inflammatory diseases. The concomitant longitudinal PET imaging with both (18)F-DPA-714 and (18)F-Alfatide II matched the causal relationship between macrophage infiltration and angiogenesis. Moreover, we found (18)F-DPA-714 uptake in several types of tumors is significantly lower than that in inflammatory muscles, suggesting (18)F-DPA-714 PET has the potential for better differentiation of tumor and non-tumor inflammation.

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[(18)F]DPA-714 PET imaging of AMD3100 treatment in a mouse model of stroke.

Publications

[(18)F]DPA-714 PET imaging of AMD3100 treatment in a mouse model of stroke.

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