Serial Quantitative TSPO-Targeted PET Reveals Peak Microglial Activation up to 2 Weeks After an Epileptogenic Brain Insult

Abstract

Experimental and clinical evidence suggests that neuroinflammation, triggered by epileptogenic insults, contributes to seizure development. We used translocator protein-targeted molecular imaging to obtain further insights into the role of microglial activation during epileptogenesis. Methods: As epileptogenic insult, a status epilepticus (SE) was induced in rats by lithium pilocarpine. Rats were subjected to 11 C-PK11195 PET scans before SE; at 4 h after SE; at 1, 2, 5, 7, 14, and 22 d after SE; and at 14-16 wk after SE. For data evaluation, brain regions were outlined by coregistration with a standard rat brain atlas, and percentage injected dose/cm 3 and binding potential (simplified reference tissue model with cerebellar gray matter as a reference region) were calculated. For autoradiography and immunohistochemical evaluation, additional rats were decapitated without prior SE or 2, 5, or 14 d after SE. Results: After SE, increases in 11 C-PK11195 uptake and binding potential were evident in epileptogenesis-associated brain regions, such as the hippocampus, thalamus, or piriform cortex, but not in the cerebellum beginning at 2-5 d and persisting at least 3 wk after SE. Maximal regional signal was observed at 1-2 wk after SE. Autoradiography confirmed the spatiotemporal profile. Immunohistochemical evaluation revealed microglial and astroglial activation as well as neuronal cell loss in epileptogenesis-associated brain regions at all investigated time points. The time course of microglial activation was consistent with that demonstrated by tracer techniques. Conclusion: Translocator protein-targeted PET is a reliable tool for identifying brain inflammation during epileptogenesis. Neuroinflammation mainly affects brain regions commonly associated with seizure generation and spread. Definition of the time profile of neuroinflammation may facilitate the development of inflammation-targeted, antiepileptogenic therapy.

[18F]GE180 positron emission tomographic imaging indicates a potential double‐hit insult in the intrahippocampal kainate mouse model of temporal lobe epilepsy

“…6,8,9 Similar to the findings in the present study, TSPO up-regulation was evident within days and for a few weeks after SE-induced epileptogenesis, which was confirmed by in vitro autoradiography and immunohistochemistry. 6,8,9 Similar to the findings in the present study, TSPO up-regulation was evident within days and for a few weeks after SE-induced epileptogenesis, which was confirmed by in vitro autoradiography and immunohistochemistry.…”

“…9 As the mice of the present study were examined longitudinally, we have no individual tissue available directly matching the in vivo data. This protocol was established because the longitudinal design of the study prohibited the generation of arterial blood sample-based input function, and it was not possible to extract a reliable image-derived input function.…”

“…4 As serial imaging with dedicated small animal PET scanners has become an available technique also for laboratory rodents, 3,5 TSPO PET represents a noninvasive and quantitative tool with high translational potential. 9 Furthermore, a recent paper demonstrates the predictive potential of TSPO PET at epilepsy onset in a rat model of temporal lobe epilepsy. 9 Furthermore, a recent paper demonstrates the predictive potential of TSPO PET at epilepsy onset in a rat model of temporal lobe epilepsy.…”

Biomarkers of Epileptogenesis: The Focus on Glia and Cognitive Dysfunctions

“…Similar approaches were used to monitor microglia activation by measuring TSPO binding with Positron Emission Tomography (PET) in the hippocampus of adult rats injected with kainic acid [42] or pilocarpine [43]. However, no attempts were made to correlate changes in microglia activation during epileptogenesis with the chronic functional outcomes.…”

“…However, no attempts were made to correlate changes in microglia activation during epileptogenesis with the chronic functional outcomes. Activation of microglia and astrocytes were measured within 2-4 days post-SE by in vivo imaging [38,43,44]. However, there is immunohistochemical evidence that both cell types are already activated within the first 24 h after SE [40,45].…”