Exploring the neuroprotective effects of montelukast on brain inflammation and metabolism in a rat model of quinolinic acid-induced striatal neurotoxicity.

BACKGROUND: One intrastriatal administration of quinolinic acid (QA) in rats induces a lesion with features resembling those observed in Huntington's disease. Our aim is to evaluate the effects of the cysteinyl leukotriene receptor antagonist montelukast (MLK), which exhibited neuroprotection in different preclinical models of neurodegeneration, on QA-induced neuroinflammation and regional metabolic functions. METHODS: The right and left striatum of Sprague Dawley and athymic nude rats were injected with QA and vehicle (VEH), respectively. Starting from the day before QA injection, animals were treated with 1 or 10 mg/kg of MLK or VEH for 14 days. At 14 and 30 days post-lesion, animals were monitored with magnetic resonance imaging (MRI) and positron emission tomography (PET) using [18F]-VC701, a translocator protein (TSPO)-specific radiotracer. Striatal neuroinflammatory response was measured post-mortem in rats treated with 1 mg/kg of MLK by immunofluorescence. Rats treated with 10 mg/kg of MLK also underwent a [18F]-FDG PET study at baseline and 4 months after lesion. [18F]-FDG PET data were then used to assess metabolic connectivity between brain regions by applying a covariance analysis method. RESULTS: MLK treatment was not able to reduce the QA-induced increase in striatal TSPO PET signal and MRI lesion volume, where we only detected a trend towards reduction in animals treated with 10 mg/kg of MLK. Post-mortem immunofluorescence analysis revealed that MLK attenuated the increase in striatal markers of astrogliosis and activated microglia in the lesioned hemisphere. We also found a significant increase in a marker of anti-inflammatory activity (MannR) and a trend towards reduction in a marker of pro-inflammatory activity (iNOS) in the lesioned striatum of MLK-compared to VEH-treated rats. [18F]-FDG uptake was significantly reduced in the striatum and ipsilesional cortical regions of VEH-treated rats at 4 months after lesion. MLK administration preserved glucose metabolism in these cortical regions, but not in the striatum. Finally, MLK was able to counteract changes in metabolic connectivity and measures of network topology induced by QA, in both lesioned and non-lesioned hemispheres. CONCLUSIONS: Overall, MLK treatment produced a significant neuroprotective effect by reducing neuroinflammation assessed by immunofluorescence and preserving regional brain metabolism and metabolic connectivity from QA-induced neurotoxicity in cortical and subcortical regions.

Brain sex-dependent alterations after prolonged high fat diet exposure in mice.

We examined effects of exposing female and male mice for 33 weeks to 45% or 60% high fat diet (HFD). Males fed with either diet were more vulnerable than females, displaying higher and faster increase in body weight and more elevated cholesterol and liver enzymes levels. Higher glucose metabolism was revealed by PET in the olfactory bulbs of both sexes. However, males also displayed altered anterior cortex and cerebellum metabolism, accompanied by a more prominent brain inflammation relative to females. Although both sexes displayed reduced transcripts of neuronal and synaptic genes in anterior cortex, only males had decreased protein levels of AMPA and NMDA receptors. Oppositely, to anterior cortex, cerebellum of HFD-exposed mice displayed hypometabolism and transcriptional up-regulation of neuronal and synaptic genes. These results indicate that male brain is more susceptible to metabolic changes induced by HFD and that the anterior cortex versus cerebellum display inverse susceptibility to HFD.

68Ga-PSMA and 68Ga-DOTA-RM2 PET/MRI in Recurrent Prostate Cancer: Diagnostic Performance and Association with Clinical and Histopathological Data.

The aim of the present study is to investigate and compare the performances of 68Ga-PSMA and 68Ga-DOTA-RM2 PET/MRI in identifying recurrent prostate cancer (PCa) after primary treatment and to explore the association of dual-tracer PET findings with clinical and histopathological characteristics. Thirty-five patients with biochemical relapse (BCR) of PCa underwent 68Ga PSMA PET/MRI for restaging purpose, with 31/35 also undergoing 68Ga-DOTA-RM2 PET/MRI scan within 16 days (mean: 3 days, range: 2-16 days). Qualitative and quantitative image analysis has been performed by comparing 68Ga-PSMA and 68Ga-DOTA-RM2 PET/MRI findings both on a patient and lesion basis. Clinical and instrumental follow-up was used to validate PET findings. Fisher's exact test and Mann-Whitney U test were used to investigate the association between dual-tracer PET findings, clinical and histopathological data. p-value significance was defined below the 0.05 level. Patients' mean age was 70 years (range: 49-84) and mean PSA at time of PET/MR scans was 1.88 ng/mL (range: 0.21-14.4). A higher detection rate was observed for 68Ga-PSMA PET/MRI, with more lesions being detected compared to 68Ga-DOTA-RM2 PET/MRI (26/35 patients, 95 lesions vs. 15/31 patients, 41 lesions; p = 0.016 and 0.002). 68Ga-PSMA and 68Ga-DOTA-RM2 PET/MRI findings were discordant in 11/31 patients; among these, 10 were 68Ga-PSMA positive (9/10 confirmed as true positive and 1/10 as false positive by follow-up examination). Patients with higher levels of PSA and shorter PSA doubling time (DT) presented more lesions on 68Ga-PSMA PET/MRI (p = 0.006 and 0.044), while no association was found between PET findings and Gleason score. 68Ga-PSMA has a higher detection rate than 68Ga-DOTA-RM2 in detecting PCa recurrence. The number of 68Ga-PSMA PET positive lesions is associated with higher levels of PSA and shorter PSA DT, thus representing potential prognostic factors.