Abstract
BackgroundHIV-associated neuroinflammation is believed to be a major contributing factor in the development of HIV-associated neurocognitive disorders (HAND). In this study, we used micropositron emission tomography (PET) imaging to quantify neuroinflammation in HIV-1 transgenic rat (Tg), a small animal model of HIV, known to develop neurological and behavioral problems.MethodsDynamic [18F]DPA-714 PET imaging was performed in Tg and age-matched wild-type (WT) rats in three age groups: 3-, 9-, and 16-month-old animals. As a positive control for neuroinflammation, we performed unilateral intrastriatal injection of quinolinic acid (QA) in a separate group of WT rats. To confirm our findings, we performed multiplex immunofluorescent staining for Iba1 and we measured cytokine/chemokine levels in brain lysates of Tg and WT rats at different ages.Results[18F]DPA-714 uptake in HIV-1 Tg rat brains was generally higher than in age-matched WT rats but this was not statistically significant in any age group. [18F]DPA-714 uptake in the QA-lesioned rats was significantly higher ipsilateral to the lesion compared to contralateral side indicating neuroinflammatory changes. Iba1 immunofluorescence showed no significant differences in microglial activation between the Tg and WT rats, while the QA-lesioned rats showed significant activation. Finally, cytokine/chemokine levels in brain lysates of the Tg rats and WT rats were not significantly different.ConclusionMicroglial activation might not be the primary mechanism for neuropathology in the HIV-1 Tg rats. Although [18F]DPA-714 is a good biomarker of neuroinflammation, it cannot be reliably used as an in vivo biomarker of neurodegeneration in the HIV-1 Tg rat.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0390-9) contains supplementary material, which is available to authorized users.
Highlights
HIV-associated neuroinflammation is believed to be a major contributing factor in the development of HIV-associated neurocognitive disorders (HAND)
The hallmark of neuroinflammation is the activation of naturally quiescent resident microglial cells [9] resulting in the unregulated secretion of multiple neurotoxins and cytotoxins, resulting in neuronal damage leading to cell death [3, 10]
Imaging microglial activation as a surrogate marker for neuroinflammation can be done through the use of specific radiolabeled ligands targeting the translocator protein (TSPO, previously known as the peripheral benzodiazepine receptor (PBR)) [3], an 18 kD outer mitochondrial membrane receptor which is naturally expressed in small amounts in resting microglial cells
Summary
HIV-associated neuroinflammation is believed to be a major contributing factor in the development of HIV-associated neurocognitive disorders (HAND). We used micropositron emission tomography (PET) imaging to quantify neuroinflammation in HIV-1 transgenic rat (Tg), a small animal model of HIV, known to develop neurological and behavioral problems. Methods: Dynamic [18F]DPA-714 PET imaging was performed in Tg and age-matched wild-type (WT) rats in three age groups: 3-, 9-, and 16-month-old animals. Results: [18F]DPA-714 uptake in HIV-1 Tg rat brains was generally higher than in age-matched WT rats but this was not statistically significant in any age group. The contribution of neuroinflammation/microglial activation to neuronal damage in HIV is assumed to play a major role [3] based on multiple cell culture studies [4,5,6,7] as well as direct histological evaluation of brain tissues from untreated HIV or simian immunodeficiency virus-infected animals [8]. Newer higher affinity ligands for TSPO, such as DPA-713 [21], PBR-28 [22], CLINDE [23, 24], and DAA [25], among others, have been developed as a result
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