Detection of neuroinflammation before selective neuronal loss appearance after mild focal ischemia using [18F]DPA-714 imaging

Abstract

BackgroundTranslocator protein (TSPO) imaging can be used to detect neuroinflammation (including microglial activation) after acute cerebral infarction. However, longitudinal changes of TSPO binding after mild ischemia that induces selective neuronal loss (SNL) without acute infarction are not well understood. Here, we performed TSPO imaging with [18F]DPA-714 to determine the time course of neuroinflammation and SNL after mild focal ischemia.ResultsMild focal ischemia was induced by middle cerebral artery occlusion (MCAO) for 20 min. In MCAO rats without acute infarction investigated by 2, 3, 5-triphenyltetrazolium chloride (TTC) staining, in vitro ARG revealed a significant increase of [18F]DPA-714 binding in the ipsilateral striatum compared with that in the contralateral side at 1, 2, 3, and 7 days after MCAO. Increased [18F]DPA-714 binding was observed in the cerebral cortex penumbra, reaching maximal values at 7 days after MCAO. Activation of striatal microglia and astrocytes was observed with immunohistochemistry of ionized calcium binding adaptor molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP) at 2, 3, and 7 days after MCAO. SNL was investigated with Nissl staining and neuronal nuclei (NeuN) immunostaining and observed in the ischemic core region of the striatum on days 3 and 7 after MCAO. We confirmed that total distribution volume of [18F]DPA-714 in the ipsilateral striatum was significantly increased at 2 and 7 days after MCAO using positron emission tomography (PET).Conclusions[18F]DPA-714 binding measured with in vitro ARG was increased before SNL appeared, and this change was detected by in vivo PET. These findings suggest that TSPO PET imaging might be useful for detection of neuroinflammation leading to SNL after focal ischemia.

TSPO imaging in animal models of brain diseases

“…In a very clinically relevant model of focal temporary MCAO using a minimally invasive technique through the insertion of a microwire tip via the ventral tail artery, Toth et al [83] demonstrated significant increases in [ 11 C]PBR28 uptake in the infarct at day 4, 7 and 14 post-MCAO, although [ 11 C]PBR28 uptake started to decrease at day 14. Their results are in line with other studies using more conventional models of stroke in rats [76,65] such as those developed by Miyajima et al [84] described a significant increase in [ 18 F]DPA-714 uptake in the infarct from day 2 maintained up to day 7 post-MCAO (20-min intraluminal MCAO). Taken altogether, these results confirmed that in these models of acute brain injury (permanent or temporary MCAO, SAH or hypoxia), the microglial/macrophage infiltration responsible for the TSPO increase takes approximately 3 days to become detectable, peaks about 1 week after injury and then slowly decreases in intensity afterwards.…”

Recent developments on PET radiotracers for TSPO and their applications in neuroimaging

“…Miyajima et al. 172 monitored [ 18 F] 15 uptake with PET imaging and found that it was markedly increased before selective neuronal loss (SNL) in an ischemic stroke rat model, a change that was also observed by ex vivo autoradiography. Tan et al.…”

Neuronal Loss after Stroke Due to Microglial Phagocytosis of Stressed Neurons

“…Stoke rapidly induces necrosis of all cells within the infarct; however, two types/locations of delayed neuronal death after brain ischemia have also been identified (Figure 1). ( 1) 'Selective neuronal loss' may occur in peri-infact areas 1-7 days after transient middle cerebral artery occlusion (MCAO) in rodent striatum (and to a lesser extent in the cortex), but may increase over the following weeks [4,[7][8][9][10][11][12][13]. (2) 'Secondary neurodegeneration' of the thalamus may occur 0.5-12 months after cortical stroke [2,3,14].…”