Tc-99-HYNIC-annexin VSPECT imaging of acute stroke and its response to neuroprotective therapy with anti-Fas ligand antibody
The first aim of the study was to determine whether (99m)Tc-HYNIC-annexin V, a marker of cellular stress and apoptosis, can detect ischemic injury in patients with acute stroke. Secondly, we wished to test radiolabeled annexin's ability to monitor therapy in a rodent model of focal ischemic injury.
SPECT imaging of patients was performed between 1 and 2 h after intravenous injection of 30 mCi (1,110 MBq) of tracer. Eight MFL4 (anti-FasL) antibody-treated (400 microg i.p. days 0 and 3) and 21 control adult male Sprague-Dawley rats underwent small animal SPECT imaging with 5-10 mCi (185-370 MBq) of tracer, 1 and 6 days after a 2-h intraluminal thread occlusion of the left middle cerebral artery.
Two patients with acute stroke had regions of multifocal annexin uptake that correlated with sites of restricted diffusion on MRI. Anti-FasL antibody treatment significantly reduced annexin uptake by 92% with a 60% decrease in the number of caspase-8 staining (apoptotic) neurons on day 1. On day 6, treated animals had an 80% reduction in tracer uptake with a 75% decrease in infarct size as compared with controls. Annexin uptake in controls and treated animals (day 6) linearly correlated with infarct size (r (2)=0.603, p=0.0036) and the number of TUNEL-positive (apoptotic) nuclei (r (2)=0.728, p=0.00084).
Annexin imaging shows foci of increased uptake at sites of ischemic injury in patients with acute stroke. Annexin imaging can assess the effects of therapy for ischemic cerebral injury in rats, suggesting its potential as a non-invasive indicator of drug efficacy in future clinical trials.
Available from: PubMed Central
- "Expression of Fas and its ligand have been documented in the brain following ischemia (11), and neutralizing FasL with antibody treatment has been demonstrated to be neuroprotective in experimental in vivo models (12, 13). Furthermore, Fas knockout animals have smaller infarct areas than wild-type ones (14, 15). "
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To investigate the effects of local mild hypothermia on the expression of Fas, FasL and MMP-3 after cerebral ischemia-reperfusion in rats.
Materials and Methods:
Male Wistar rats were divided into sham-operated group (Sham), normothermia group (NT), and hypothermia group (HT). MCAO/R model was established by Longa’s method, and reperfusion was allowed after 2 hr occlusion. Mild hypothermia (33±0.5°C) for 6 hr was initiated at the start of reperfusion. Immunohistochemistry was performed to determine expression Fas, FasL, and MMP-3.
Infarct volume was reduced in the hypothermia group (18.43±4.23%) compared with the normothermia group (24.76±5.76%) (P<0.05). In mild hypothermia group, numbers of Fas-positive and MMP-3 positive cells were significantly less than those of normothermia group (P<0.05). Neurological functional scores of mild hypothermia were significantly improved (P<0.05).
Mild hypothermia decreases infarct volume after cerebral ischemia-reperfusion, reduces Fas and MMP-3 expression, but increases FasL in cerebral ischemia-reperfusion rats.
Available from: Tessa Buckle
- "Tc-AnxV) has been used in the clinic to assess the efficacy of therapy in cancer patients, but also to detect apoptosis in acute myocardial infarction, rheumatoid arthritis, acute stroke and Alzheimer's dementia (Blankenberg et al., 2006; Lampl et al., 2006; Narula and Strauss, 2003; Rottey et al., 2006; Thimister et al., 2003). It should be noted that Annexin V imaging also shows physiologically normal apoptosis, for instance in the bone marrow, gastrointestinal mucosae and salivary glands (Kerr et al., 1972). "
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ABSTRACT: Annexin V imaging is suggested to provide a good indication of cancer treatment efficacy. To study the accuracy of (99m)Tc-AnxV imaging, we monitored chemo-sensitive and chemo-resistant tumors in a mouse breast cancer model after treatment with docetaxel. Sensitive tumors showed a slight peak in (99m)Tc-AnxV uptake one day post-treatment, while uptake in resistant tumors remained constant. In contrast to immunohistochemical analysis, (99m)Tc-AnxV imaging could not be used to predict tumor response, due to large variation between animals.
Available from: Marietta Zille
- "Radiolabeled annexin A5 has already been used in animal and human studies of stroke without such a characterization (Blankenberg et al, 2006). Some of the images of these studies are indicative of unspecific signal from the choroid plexus, especially in the paper by Blankenberg et al (2006). The strong signal in the area of the ventricles detected with SPECT can be blood pool, as discussed in the paper or accumulation of the compound in the choroid plexus or both. "
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ABSTRACT: To monitor stroke-induced brain damage and assess neuroprotective therapies, specific imaging of cell death after cerebral ischemia in a noninvasive manner is highly desirable. Annexin A5 has been suggested as a marker for imaging cell death under various disease conditions including stroke. In this study, C57BL6/N mice received middle cerebral artery occlusion (MCAO) and were injected intravenously with either active or inactive Cy5.5-annexin A5 48 hours after reperfusion. Some mice also received propidium iodide (PI), a cell integrity marker. Only in mice receiving active Cy5.5-annexin A5 were fluorescence intensities significantly higher over the hemisphere ipsilateral to MCAO than on the contralateral side. This was detected noninvasively and ex vivo 4 and 8 hours after injection. The majority of cells positive for fluorescent annexin A5 were also positive for PI and fragmented DNA as detected by terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL) staining. This study demonstrates the high specificity of annexin A5 for visualization of cell death in a mouse model of stroke. To our knowledge, this is the first study to compare the distribution of injected active and inactive annexin A5, PI, and TUNEL staining. It provides important information on the experimental and potential clinical applications of annexin A5-based imaging agents in stroke.
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