TSPO PET Using [18F]PBR111 Reveals Persistent Neuroinflammation Following Acute Diisopropylfluorophosphate Intoxication in the Rat

Abstract

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.

[11C]PBR28 MR–PET imaging reveals lower regional brain expression of translocator protein (TSPO) in young adult males with autism spectrum disorder

“…Reverse translation in the disease-specific context will be required to determine what changes in TSPO expression reflect. Studies conducted in other disease contexts have had success combining in vivo TSPO PET imaging and post mortem histological characterization [ 82 ]. Studies with a focus on post mortem tissue analysis will need to be conducted, and will benefit from the information obtained through in vivo TSPO imaging in terms of selecting brain regions to investigate.…”

Effects of early life exposure to traffic-related air pollution on brain development in juvenile Sprague-Dawley rats

“…At approximately PND 50, animals were transported back to the UC Davis campus. After 18 h recovery, behaviorally tested animals were imaged by MR, while untested animals were euthanized as previously described 31 . Briefly, whole blood was collected via cardiac puncture, animals were transcardially perfused, and left and right brain hemispheres were collected for cytokine analyses and immunohistochemistry, respectively.…”

Positron Emission Tomography Imaging of Macrophages in Cancer

“…The translocator protein (TSPO) is primarily found on the outer mitochondrial membrane of various different types of cells such as macrophages, neutrophils, and lymphocytes. There have been numerous studies in literature in which TSPO has been used as a target for PET imaging of inflammation [ 50 , 51 , 52 ]. Although not specifically targeting TAMs, Wu and colleagues carried out a study in 2014 in which they used N, N-Diethyl-2-(2-(4-(2-[ 18 F] fluoroethoxy) phenyl)-5, 7-dimethylpyrazolo [1, 5-a] pyrimidin-3-yl) acetamide ([ 18 F]-DPA-714), a tracer targeting TSPO, to differentiate inflammation from tumor [ 48 ].…”