In vivo TSPO and cannabinoid receptor type 2 availability early in post-stroke neuroinflammation in rats: a positron emission tomography study

Abstract

BackgroundUpregulated levels of 18-kDa translocator proteins (TSPO) and type 2 endocannabinoid receptors (CB2) are considered to reflect different aspects of microglia-related neuroinflammatory responses in the brain. Relative to the increase in the TSPO expression that occurs slightly later during neuroinflammation in a proinflammatory fashion, CB2 activation is considered to relate to the neuroprotective responses that occurs predominantly at an early stage of brain disorders. These findings, however, were deduced from studies with different animal samples under different experimental settings. Here, we aimed to examined the differences in TSPO binding and CB2 availability at an early stage of stroke in the same animal using positron emission tomography (PET).MethodsWe used a total of eight Sprague-Dawley rats that underwent photothrombotic stroke surgery. The binding levels of a TSPO tracer [11C](R)PK11195 and a CB2 tracer [11C]NE40 were measured at 24 h after the surgery in the same animal using PET in combination with immunohistochemistry for CB2 and several other markers. A morphological inspection was also performed with X-ray computed tomography for small animals.ResultsThe levels of [11C]NE40 binding potential (BPND) were significantly higher in the cerebral cortical region on the lesion side than those on the non-lesion side, whereas no difference was found in the levels of [11C](R)PK11195 BPND between hemispheres. The tracer influx index (R1) data were all reduced on the lesion side irrespective of tracers. This increase in [11C]NE40 BPND was concomitant with an elevation in CB2 expression mainly within the microglia in the peri-infarct area, as shown by immunohistochemical examinations with Iba-1, CD11b/c+, and NG2+ staining.ConclusionsThe present results provide in vivo evidence of different responses of microglia occurring in the acute state of stroke. The use of the CB2 tracer [11C]NE40 allows us to evaluate the roles played by the neuroprotective aspect of microglia in acute neuroinflammatory processes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0851-4) contains supplementary material, which is available to authorized users.

Coexistence of cerebral hypometabolism and neuroinflammation in the thalamo-limbic-brainstem region in young women with functional somatic syndrome

“…Interestingly, our direct comparison between [ 18 F]FDG SUVR and [ 11 C]DPA713 BP ND showed a positive correlation in the right hippocampus and amygdala. Since it was reported that TSPO-based PET findings in chronic, but not early, brain disease reflect a proinflammatory state [35,36], it seems theoretically possible that lower cerebral metabolism couples with higher proinflammatory responses, i.e., [ 18 [37], from aerobic glycolysis, the current result suggested that the higher [ 18 F]FDG uptake accompanied greater glycolysis in the hippocampus and amygdala, which subserve memory and emotion in patients with FSS. In the present study, a significant reduction in glucose metabolism was found in patients with FSS compared with healthy subjects.…”

Positron emission tomography of type 2 cannabinoid receptors for detecting inflammation in the central nervous system

“…(5) Imaging results using CB 2 R and TSPO tracers should be compared head to head. Given that CB 2 R more closely represents anti-inflammatory features, additional knowledge of the inflammatory status in the CNS will be provided by PET imaging using both CB 2 R and TSPO tracers [43]. 6The mRNA expression of CB 2 R should be measured.…”

“…Thus, they might not be the most suitable for evaluating of CB 2 R. CB 2 R imaging in an animal model of stroke Ischemic stroke involves a cascade of hemodynamic, vascular, structural, and inflammatory responses in a time-dependent manner [54][55][56]. Inflammation is implicated in the initial neuronal loss and consists mainly of pro-inflammatory responses and the extension of the lesion in the penumbra; the subsequent [43] was reported in an SD rat model of photothrombotic stroke at 24 h after surgery. Another study using [ 11 C]NE40 imaging did not show an upregulated signal in a Wistar rat model of photothrombotic stroke [48], despite the minor increase in the level of CB 2 R seen by immunostaining.…”

“…Few clinical evaluations of CB 2 R PET imaging have been reported [45,47]. The hurdles in CB 2 R tracer development and translation may include: (1) species differences between humans and rodents in their immune systems, microglia subtypes, and levels of CB 2 R expression [68], as well as distinct age-related changes, with a more pro-inflammatory type in humans [69] according to transcriptomic analysis; (2) low expression level of CB 2 R in the brain, even under inflammatory conditions [70]; (3) lack of specific CB 2 R antibody for post-mortem validation of in vivo imaging results [43,55,71]; (4) lack of full CB 2 R knock-out mice [72]; and 5) developing a reference region for modeling [73]. CB 2 R imaging in patients with amyotrophic lateral sclerosis ALS is a progressive and fatal motor neuron disease [74].…”

Radiosynthesis of a Novel 11C‐Labeled Derivative of 4’‐O‐Methylhonokiol and Its Preliminary Evaluation in an LPS Rat Model of Neuroinflammation

“…Positron emission tomography (PET) based on operation of biologically active compounds labeled with short‐lived isotopes 11 C (T 1/2 =20.4 min) and 18 F (T 1/2 =109.8 min) provides a non‐invasive and direct method for assessing neuroinflammatory changes in the brain . Recently, significant progress was achieved in the development of PET radiotracers for inflammatory protein targets, including enzymes (translocator protein 18 kDa, glycogen synthase kinase 3, monoamine oxidase‐B, cyclooxygenase), cannabinoid (CB2) and purine (P2X7) receptors . Cyclooxygenase type 2 (COX‐2) is an inducible enzyme involved in the prostaglandin biosynthesis, it is minimally expressed at baseline in several peripheral tissues and brain, and overexpressed at sites of inflammation.…”