Exploring the neuroprotective effects of montelukast on brain inflammation and metabolism in a rat model of quinolinic acid-induced striatal neurotoxicity
In this study, 18F-FDG PET-CT was used to evaluate the metabolic connectivity between brain regions in rat models for neurodegeneration. Thanks to the high spatial resolution of the B-CUBE, the researchers were able to visualize and quantify regional brain metabolism and connectivity in cortical and subcortical regions in a non-invasive manner.
Research question
One intrastriatal administration of quinolinic acid (QA) in rats induces a lesion with features resembling those observed in Huntington’s disease. The aim of the current study 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.
Experiment
Sprague Dawley and athymic nude rats were injected with QA and vehicle, respectively. Starting from the day before QA injection, animals were treated with 1 or 10 mg/kg of MLK or vehicle for 14 days. At 14 and 30 days post-lesion, animals were monitored with MRI and PET using [18F]-VC701, a translocator protein (TSPO)-specific radiotracer, in order to detect a potential neuroinflammatory response. Striatal neuroinflammatory response was also measured post-mortem in rats treated with 1 mg/kg of MLK by immunofluorescence. Rats treated with 10 mg/kg of MLK also underwent [18F]-FDG PET imaging at baseline and 4 months after induction of the 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. The researchers also found a significant increase in a marker of anti-inflammatory activity and a trend towards reduction in a marker of pro-inflammatory activity in the lesioned striatum of MLK—compared to vehicle treated rats.
[18F]-FDG uptake was significantly reduced in the striatum and ipsilesional cortical regions of vehicle-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.
In conclusion, 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, which was assessed by FDG PET-CT.