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Acute neuroinflammation in a clinically relevant focal cortical ischemic stroke model in rat: longitudinal positron emission tomography and immunofluorescent tracking

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Abstract

Adequate estimation of neuroinflammatory processes following ischemic stroke is essential for better understanding of disease mechanisms, and for the development of treatment strategies. With the TSPO (18 kDa translocator protein) positron emission tomography (PET) radioligand [11C]PBR28, we monitored longitudinally the inflammatory response post-transient cerebral ischemia in rats, using a recently developed rat stroke model that produces isolated focal cortical infarcts with clinical relevance in size and pathophysiology. Six Sprague–Dawley rats were subjected to 90 min transient endovascular occlusion of the M2 segment of the middle cerebral artery (M2CAO). Animals were imaged with a nanoScan® PET/MRI system at 1, 4, 7 and 14 days after M2CAO with a bolus injection of [11C]PBR28. In the infarct region, we found a significantly increased uptake of [11C]PBR28 on day 4, 7 and 14 compared to day 1 as well as compared to the contralateral cortex. No significant increase was detected in the contralateral cortex during the 14 days of imaging. The activation in the infarct region gradually decreased between day 4 and day 14. In an additional group of animals (n = 26), immunofluorescence studies were performed with antibodies for activated microglia/monocytes (Cd11b), phagocytes (Cd68), astrocytes (glial fibrillary acidic protein) and TSPO. The TSPO immunofluorescence signal indicated reactive microgliosis post injury, corresponding to PET findings. The present clinically relevant animal model and TSPO PET ligand appear to be well suited for studies on neuroinflammation after ischemic stroke.

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Acknowledgments

The research leading to these results has received funding from the European Union’s Seventh Framework Programme (FP7/2007–2013, GA 278850, INMiND), Uppdrag Besegra Stroke (supported by the Swedish Heart–Lung Foundation, Karolinska Institutet, Friends of Karolinska Institutet USA and the Swedish order of St John) and Söderbergska Stiftelsen.

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The authors declare that they have no conflict of interest.

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    Authors and Affiliations

    1. Department of Clinical Neuroscience, Karolinska Institutet, 171 76, Stockholm, Sweden

      Miklós Tóth, Philip Little, Fabian Arnberg, Jenny Häggkvist, Christer Halldin, Balázs Gulyás & Staffan Holmin

    2. Department of Neuroradiology, Karolinska University Hospital, 171 76, Stockholm, Sweden

      Philip Little, Fabian Arnberg & Staffan Holmin

    3. Department of Radiology, Karolinska University Hospital, 171 76, Stockholm, Sweden

      Fabian Arnberg

    4. Science for Life Laboratory, Department of Neuroscience, Karolinska Institutet, 17165, Stockholm, Sweden

      Jan Mulder

    5. Imperial College - NTU, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 639798, Singapore

      Christer Halldin & Balázs Gulyás

    6. Imperial College London, Faculty of Medicine, Division of Brain Sciences, London, SW7 2AZ, UK

      Balázs Gulyás

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    1. Miklós Tóth
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    Correspondence to Balázs Gulyás.

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    M. Tóth and P. Little contributed equally.

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    Tóth, M., Little, P., Arnberg, F. et al. Acute neuroinflammation in a clinically relevant focal cortical ischemic stroke model in rat: longitudinal positron emission tomography and immunofluorescent tracking. Brain Struct Funct 221, 1279–1290 (2016). https://doi.org/10.1007/s00429-014-0970-y

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