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TSPO PET detects acute neuroinflammation but not diffuse chronically activated MHCII microglia in the rat.

ABSTRACT: BACKGROUND:Accurate and sensitive imaging biomarkers are required to study the progression of white matter (WM) inflammation in neurodegenerative diseases. Radioligands targeting the translocator protein (TSPO) are considered sensitive indicators of neuroinflammation, but it is not clear how well the expression of TSPO coincides with major histocompatibility complex class II (MHCII) molecules in WM. This study aimed to test the ability of TSPO to detect activated WM microglia that are immunohistochemically positive for MHCII in rat models of prodromal Alzheimer's disease and acute subcortical stroke. METHODS:Fischer 344 wild-type (n?=?12) and TgAPP21 (n?=?11) rats were imaged with [18F]FEPPA PET and MRI to investigate TSPO tracer uptake in the corpus callosum, a WM region known to have high levels of MHCII activated microglia in TgAPP21 rats. Wild-type rats subsequently received an endothelin-1 (ET1) subcortical stroke and were imaged at days 7 and 28 post-stroke before immunohistochemistry of TSPO, GFAP, iNOS, and the MHCII rat antigen, OX6. RESULTS:[18F]FEPPA PET was not significantly affected by genotype in WM and only detected increases near the ET1 infarct (P?=?0.033, infarct/cerebellum uptake ratio: baseline?=?0.94?±?0.16; day 7?=?2.10?±?0.78; day 28?=?1.77?±?0.35). Immunohistochemistry confirmed that only the infarct (TSPO cells/mm2: day 7?=?555?±?181; day 28?=?307?±?153) and WM that is proximal to the infarct had TSPO expression (TSPO cells/mm2: day 7?=?113?±?93; day 28?=?5?±?7). TSPO and iNOS were not able to detect the chronic WM microglial activation that was detected with MHCII in the contralateral corpus callosum (day 28 OX6% area: saline?=?0.62?±?0.38; stroke?=?4.30?±?2.83; P?=?.029). CONCLUSION:TSPO was only expressed in the stroke-induced insult and proximal tissue and therefore was unable to detect remote and non-insult-related chronically activated microglia overexpressing MHCII in WM. This suggests that research in neuroinflammation, particularly in the WM, would benefit from MHCII-sensitive radiotracers.

SUBMITTER: Al-Khishman NU

PROVIDER: S-EPMC7524910 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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TSPO PET detects acute neuroinflammation but not diffuse chronically activated MHCII microglia in the rat.

Al-Khishman Nassir U NU Qi Qi Q Roseborough Austyn D AD Levit Alexander A Allman Brian L BL Anazodo Udunna C UC Fox Matthew S MS Whitehead Shawn N SN Thiessen Jonathan D JD

EJNMMI research 20200929 1

<h4>Background</h4>Accurate and sensitive imaging biomarkers are required to study the progression of white matter (WM) inflammation in neurodegenerative diseases. Radioligands targeting the translocator protein (TSPO) are considered sensitive indicators of neuroinflammation, but it is not clear how well the expression of TSPO coincides with major histocompatibility complex class II (MHCII) molecules in WM. This study aimed to test the ability of TSPO to detect activated WM microglia that are im ...[more]

PMID: 32990808

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Project description:Acute intoxication with organophosphates (OPs) can trigger status epilepticus followed by persistent cognitive impairment and/or electroencephalographic abnormalities. Neuroinflammation is widely posited to influence these persistent neurological consequences. However, testing this hypothesis has been challenging, in part because traditional biometrics preclude longitudinal measures of neuroinflammation within the same animal. Therefore, we evaluated the performance of noninvasive positron emission tomography (PET), using the translocator protein (TSPO) radioligand [18F]PBR111 against classic histopathologic measures of neuroinflammation in a preclinical model of acute intoxication with the OP diisopropylfluorophosphate (DFP). Adult male Sprague Dawley rats administered pyridostigmine bromide (0.1 mg/kg, im) 30 min prior to administration of DFP (4 mg/kg, sc), atropine sulfate (2 mg/kg, im) and 2-pralidoxime (25 mg/kg, im) exhibited moderate-to-severe seizure behavior. TSPO PET performed prior to DFP exposure and at 3, 7, 14, 21, and 28 days postexposure revealed distinct lesions, as defined by increased standardized uptake values (SUV). Increased SUV showed high spatial correspondence to immunohistochemical evidence of neuroinflammation, which was corroborated by cytokine gene and protein expression. Regional SUV metrics varied spatiotemporally with days postexposure and correlated with the degree of neuroinflammation detected immunohistochemically. Furthermore, SUV metrics were highly correlated with seizure severity, suggesting that early termination of OP-induced seizures may be critical for attenuating subsequent neuroinflammatory responses. Normalization of SUV values to a cerebellar reference region improved correlations to all outcome measures and seizure severity. Collectively, these results establish TSPO PET using [18F]PBR111 as a robust, noninvasive tool for longitudinal monitoring of neuroinflammation following acute OP intoxication.

Project description:Brain-related disorders have outmatched cancer and cardiovascular diseases worldwide as the leading cause of morbidity and mortality. The lack of effective therapies and the relatively dry central nervous system (CNS) drug pipeline pose formidable challenge. Superior, targeted delivery of current clinically approved drugs may offer significant potential. Minocycline has shown promise for the treatment of neurological diseases owing to its ability to penetrate the blood-brain barrier (BBB) and potency. Despite its potential in the clinic and in preclinical models, the high doses needed to affect a positive therapeutic response have led to side effects. Targeted delivery of minocycline to the injured site and injured cells in the brain can be highly beneficial. Systemically administered hydroxyl poly(amidoamine) (PAMAM) generation-6 (G6) dendrimers have a longer blood circulation time and have been shown to cross the impaired BBB. We have successfully prepared and characterized the in vitro efficacy and in vivo targeting ability of hydroxyl-G6 PAMAM dendrimer-9-amino-minocycline conjugate (D-mino). Minocycline is a challenging drug to carry out chemical transformations due to its inherent instability. We used a combination of a highly efficient and mild copper catalyzed azide-alkyne click reaction (CuAAC) along with microwave energy to conjugate 9-amino-minocycline (mino) to the dendrimer surface via enzyme responsive linkages. D-mino was further evaluated for anti-inflammatory and antioxidant activity in lipopolysaccharides-activated murine microglial cells. D-mino conjugates enhanced the intracellular availability of the drug due to their rapid uptake, suppressed inflammatory cytokine tumor necrosis factor ? (TNF-?) production, and reduced oxidative stress by suppressing nitric oxide production, all significantly better than the free drug. Fluorescently labeled dendrimer conjugate (Cy5-D-mino) was systematically administered (intravenous, 55 mg/kg) on postnatal day 1 to rabbit kits with a clinically relevant phenotype of cerebral palsy. The in vivo imaging study indicates that Cy5-D-mino crossed the impaired blood-brain barrier and co-localized with activated microglia at the periventricular white matter areas, including the corpus callosum and the angle of the lateral ventricle, with significant implications for positive therapeutic outcomes. The enhanced efficacy of D-mino, when combined with the inherent neuroinflammation-targeting capability of the PAMAM dendrimers, may provide new opportunities for targeted drug delivery to treat neurological disorders.

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Project description:PURPOSE:Over the past 20 years, neuroinflammation (NI) has increasingly been recognised as having an important role in many neurodegenerative diseases, including Alzheimer's disease. As such, being able to image NI non-invasively in patients is critical to monitor pathological processes and potential therapies targeting neuroinflammation. The translocator protein (TSPO) has proven a reliable NI biomarker for positron emission tomography (PET) imaging. However, if TSPO imaging in acute conditions such as stroke provides strong and reliable signals, TSPO imaging in neurodegenerative diseases has proven more challenging. Here, we report results comparing the recently developed TSPO tracers [18F]GE-180 and [18F]DPA-714 with (R)-[11C]PK11195 in a rodent model of subtle focal inflammation. PROCEDURES:Adult male Wistar rats were stereotactically injected with 1 ?g lipopolysaccharide in the right striatum. Three days later, animals underwent a 60-min PET scan with (R)-[11C]PK11195 and [18F]GE-180 (n = 6) or [18F]DPA-714 (n = 6). Ten animals were scanned with either [18F]GE-180 (n = 5) or [18F]DPA-714 (n = 5) only. Kinetic analysis of PET data was performed using the simplified reference tissue model (SRTM) with a contralateral reference region or a novel data-driven input to estimate binding potential BPND. Autoradiography and immunohistochemistry were performed to confirm in vivo results. RESULTS:At 40-60 min post-injection, [18F]GE-180 dual-scanned animals showed a significantly increased core/contralateral uptake ratio vs. the same animals scanned with (R)-[11C]PK11195 (3.41 ± 1.09 vs. 2.43 ± 0.39, p = 0.03); [18]DPA-714 did not (2.80 ± 0.69 vs. 2.26 ± 0.41). Kinetic modelling with a contralateral reference region identified significantly higher binding potential (BPND) in the core of the LPS injection site with [18F]GE-180 but not with [18F]DPA-714 vs. (R)-[11C]PK11195. A cerebellar reference region and novel data-driven input to the SRTM were unable to distinguish differences in tracer BPND. CONCLUSIONS:Second-generation TSPO-PET tracers are able to accurately detect mild-level NI. In this model, [18F]GE-180 shows a higher core/contralateral ratio and BPND when compared to (R)-[11C]PK11195, while [18F]DPA-714 did not.

Dataset Information

TSPO PET detects acute neuroinflammation but not diffuse chronically activated MHCII microglia in the rat.

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TSPO PET detects acute neuroinflammation but not diffuse chronically activated MHCII microglia in the rat.

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