Abstract
BackgroundRecently, inflammatory cascades have been suggested as a target for epilepsy therapy. Positron emission tomography (PET) imaging offers the unique possibility to evaluate brain inflammation longitudinally in a non-invasive translational manner. This study investigated brain inflammation during early epileptogenesis in the post-kainic acid-induced status epilepticus (KASE) model with post-mortem histology and in vivo with [18F]-PBR111 PET.MethodsStatus epilepticus (SE) was induced (N = 13) by low-dose injections of KA, while controls (N = 9) received saline. Translocator protein (TSPO) expression and microglia activation were assessed with [125I]-CLINDE autoradiography and OX-42 immunohistochemistry, respectively, 7 days post-SE. In a subgroup of rats, [18F]-PBR111 PET imaging with metabolite-corrected input function was performed before post-mortem evaluation. [18F]-PBR111 volume of distribution (Vt) in volume of interests (VOIs) was quantified by means of kinetic modelling and a VOI/metabolite-corrected plasma activity ratio.ResultsAnimals with substantial SE showed huge overexpression of TSPO in vitro in relevant brain regions such as the hippocampus and amygdala (P < 0.001), while animals with mild symptoms displayed a smaller increase in TSPO in amygdala only (P < 0.001). TSPO expression was associated with OX-42 signal but without obvious cell loss. Similar in vivo [18F]-PBR111 increases in Vt and the simplified ratio were found in key regions such as the hippocampus (P < 0.05) and amygdala (P < 0.01).ConclusionBoth post-mortem and in vivo methods substantiate that the brain regions important in seizure generation display significant brain inflammation during epileptogenesis in the KASE model. This work enables future longitudinal investigation of the role of brain inflammation during epileptogenesis and evaluation of anti-inflammatory treatments.
Highlights
Inflammatory cascades have been suggested as a target for epilepsy therapy
The collected radioactive peak was concentrated using a C18-solid phase extraction cartridge with subsequent formulation to a concentration of 20 MBq/100 μL of saline containing less than 1% ethanol for the biological studies. [18F]-PBR111 was produced in 25% to 35% radiochemical yield with radiochemical purity exceeding 97% and specific activity of 215 ± 46 GBq/μmol
There was a small difference between the control and kainic acid-induced status epilepticus (KASE) animals in the percentage of parent compound over time in the plasma, these radioligand metabolism curves were not significantly different (Figure 1)
Summary
Inflammatory cascades have been suggested as a target for epilepsy therapy. TSPO or previously named peripheral benzodiazepine receptor (PBR), which is a marker of activated glia, has been detected in surgically resected brain tissue and most recently in vivo with PET in patients with TLE [5,6,7,8]. Such biomarkers may become of particular value to aide in patient diagnoses and/or stratification, to evaluate the effect of new drug therapies on brain inflammation and for resective surgery of the epileptogenic zone [6,8]
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