Depiction of microglial activation in aging and dementia: Positron emission tomography with [11C]DPA713 versus [11C](R)PK11195

Yokokura, Masamichi; Terada, Tatsuhiro; Bunai, Tomoyasu; Nakaizumi, Kyoko; Takebayashi, Kiyokazu; Iwata, Yasuhide; Yoshikawa, Etsuji; Futatsubashi, Masami; Suzuki, Katsuaki; Mori, Norio; Ouchi, Yasuomi

doi:10.1177/0271678x16646788

Cited by 69 publications

(52 citation statements)

References 43 publications

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“…In the chronic stage of inflammation [6], neurotoxic M1 phenotype microglia are dominant and the TSPO tracer [ 11 C]( R )PK11195 reflects inflammatory rather than anti-inflammatory microglial activity [22]. To support this contention, we recently showed an elevation in the second-generation TSPO tracer [ 11 C]DPA713 for illustrating chronically activated microglia under inflammatory circumstances [39]. …”

Section: Discussionmentioning

confidence: 99%

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

Hosoya

Fukumoto

Kakiuchi

et al. 2017

J Neuroinflammation

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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.

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Section: Discussionmentioning

confidence: 99%

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

Hosoya

Fukumoto

Kakiuchi

et al. 2017

J Neuroinflammation

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“…The potential advantages of new TSPO tracers has been recently illustrated by the study of Yokokura et al . () comparing [ 11 C]DPA‐713 and [ 11 C]‐R‐PK11195 in the same subjects. This study shows that, as supported by the initial preclinical studies, [ 11 C]DPA‐713 has a higher capacity to detect subtle increases in TSPO levels than [ 11 C]‐R‐PK11195.…”

Section: Imaging Biomarkers Of Neuroinflammationmentioning

confidence: 99%

“…This discovery has led to the generic use of genotyping for the polymorphism rs6971 to identify high, low and mixed-affinity binders [high-affinity binders (HAB), lowaffinity binders (LAB) and mixed-affinity binders (MAB)] and to a faster implementation of these new TSPO tracers in clinical studies. The potential advantages of new TSPO tracers has been recently illustrated by the study of Yokokura et al (2017) comparing [ 11 C]DPA-713 and [ 11 C]-R-PK11195 in the same subjects. This study shows that, as supported by the initial preclinical studies, [ 11 C]DPA-713 has a higher capacity to detect subtle increases in TSPO levels than [ 11 C]-R-PK11195.…”

Section: Imaging Biomarkers Of Neuroinflammationmentioning

confidence: 99%

In vivo molecular imaging of neuroinflammation in Alzheimer's disease

Chaney

Williams

Boutin

2018

Journal of Neurochemistry

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It has become increasingly evident that neuroinflammation plays a critical role in the pathophysiology of Alzheimer's disease (AD) and other neurodegenerative disorders. Increased glial cell activation is consistently reported in both rodent models of AD and in AD patients. Moreover, recent genome wide association studies have revealed multiple genes associated with inflammation and immunity are significantly associated with an increased risk of AD development (e.g. TREM2). Non‐invasive in vivo detection and tracking of neuroinflammation is necessary to enhance our understanding of the contribution of neuroinflammation to the initiation and progression of AD. Importantly, accurate methods of quantifying neuroinflammation may aid early diagnosis and serve as an output for therapeutic monitoring and disease management. This review details current in vivo imaging biomarkers of neuroinflammation being explored and summarizes both pre‐clinical and clinical results from molecular imaging studies investigating the role of neuroinflammation in AD, with a focus on positron emission tomography and magnetic resonance spectroscopy (MRS).

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“…Interestingly, a reversal of repeated social stress-induced anxiety-like behavioral outcomes in rodents has been linked to the off-target peripheral effects of the widely used benzodiazepine lorazepam on TSPO activation [39]. More precisely, in vivo positron emission tomography (PET) scanning using the TSPO-specific ligand [ 11 C]DPA713 has demonstrated enhanced signal in select brain areas due to in vivo microglial activation as a result of aging and neuronal degeneration [40,41]. Once ciprofloxacin treatment stops, the behavior returns to normal.…”

Section: Discussionmentioning

confidence: 99%

Antibiotics May Trigger Mitochondrial Dysfunction Inducing Psychiatric Disorders

Stefano¹,

Samuel²,

Kream³

2017

Med Sci Monit

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Clinical usage of several classes of antibiotics is associated with moderate to severe side effects due to the promotion of mitochondrial dysfunction. We contend that this may be due to perturbation of unique evolutionary relationships that link selective biochemical and molecular aspects of mitochondrial biology to conserved enzymatic processes derived from bacterial progenitors. Operationally, stereo-selective conformational matching between mitochondrial respiratory complexes, cytosolic and nuclear signaling complexes appears to support the conservation of a critically important set of chemical messengers required for existential regulation of homeostatic cellular processes. Accordingly, perturbation of normative mitochondrial function by select classes of antibiotics is certainly reflective of the high degree of evolutionary pressure designed to maintain ongoing bidirectional signaling processes between cellular compartments. These issues are of critical importance in evaluating potentially severe side effects of antibiotics on complex behavioral functions mediated by CNS neuronal groups. The CNS is extremely dependent on delivery of molecular oxygen for maintaining a required level of metabolic activity, as reflected by the high concentration of neuronal mitochondria. Thus, it is not surprising to find several distinct behavioral abnormalities conforming to established psychiatric criteria that are associated with antibiotic usage in humans. The manifestation of acute and/or chronic psychiatric conditions following antibiotic usage may provide unique insights into key etiological factors of major psychiatric syndromes that involve rundown of cellular bioenergetics via mitochondrial dysfunction. Thus, a potential window of opportunity exists for development of novel therapeutic agents targeting diminished mitochondrial function as a factor in severe behavioral disorders.

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Depiction of microglial activation in aging and dementia: Positron emission tomography with [¹¹C]DPA713 versus [¹¹C](R)PK11195

Cited by 69 publications

References 43 publications

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

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

In vivo molecular imaging of neuroinflammation in Alzheimer's disease

Antibiotics May Trigger Mitochondrial Dysfunction Inducing Psychiatric Disorders

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