Serial quantitative TSPO-targeted PET reveals peak microglial activation up to two weeks after an epileptogenic brain insult.

Experimental and clinical evidence suggests that neuroinflammation, triggered by epileptogenic insults, contributes to seizure development. We employed TSPO-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 [¹¹C]PK11195 PET scans before SE, immediately after SE, at 1, 2, 5, 7, 14, and 22 days, and 14-16 weeks post SE. For data evaluation, brain regions were outlined by co-registration with a standard rat brain atlas, and % injected dose/cc and binding potential (simplified reference tissue model with cerebellar gray matter as reference region) were calculated. For autoradiography and immunohistochemical evaluation, additional rats were decapitated without prior SE or 2, 5 or 14 days post SE. Results: Following SE, increases in [¹¹C]PK11195 uptake and binding potential were evident in epileptogenesis-associated brain regions, such as hippocampus, thalamus or piriform cortex, but not in the cerebellum beginning at 2-5 days and persisting at least 3 weeks after SE. Maximal regional signal was observed at 1-2 weeks 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. Principal Conclusion: TSPO-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, anti-epileptogenic therapy.

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