TSPO PET Identifies Different Anti-inflammatory Minocycline Treatment Response in Two Rodent Models of Epileptogenesis

Bettina J Wolf,Pablo Bascuñana,B Laura N Langer,Tobias L Ross,Ina Leiter,Marion Bankstahl,Mirjam Brackhan,Jens P Bankstahl

doi:10.1007/s13311-020-00834-5

Abstract

Epileptogenesis-associated brain inflammation might be a promising target to prevent or attenuate epileptogenesis. Positron emission tomography (PET) imaging targeting the translocator protein (TSPO) was applied here to quantify effects of different dosing regimens of the anti-inflammatory drug minocycline during the latent phase in two rodent models of epileptogenesis. After induction of epileptogenesis by status epilepticus (SE), rats were treated with minocycline for 7 days (25 or 50 mg/kg) and mice for 5 or 10 days (50 or 100 mg/kg). All animals were subjected to scans at 1 and 2 weeks post-SE. Radiotracer distribution was analyzed and statistical parametric mapping (SPM) was performed, as well as histological analysis of astroglial activation and neuronal cell loss. Atlas-based analysis of [18F]GE180 PET in rats revealed a dose-dependent regional decrease of TSPO expression at 2 weeks post-SE. Results of SPM analysis depicted a treatment effect already at 1 week post-SE in rats treated with the higher minocycline dose. In mice, TSPO PET imaging did not reveal any treatment effects whereas histology identified only a treatment-related reduction in dispersion of dentate gyrus neurons. TSPO PET served as an auspicious tool for temporal monitoring and quantification of anti-inflammatory effects during epileptogenesis. Importantly, the findings underline the need to applying more than one animal model to avoid missing treatment effects. For future studies, the setup is ready to be applied in combination with seizure monitoring to investigate the relationship between individual early treatment response and disease outcome.

Highlights

As increased translocator protein (TSPO) Positron emission tomography (PET) signals were confirmed by immunohistochemistry of activated microglia during epileptogenesis before [18, 40], here, we focused on immunohistochemical staining of astrocytes, for which TSPO expression under certain conditions has been shown [40]
After status epilepticus (SE), [11C]PK11195 uptake was elevated in most brain regions, including those associated with epileptogenesis but not the cerebellum
We demonstrate by molecular in vivo imaging that minocycline treatment significantly reduces TSPO expression after pilocarpine-induced SE in rats, it has no TSPO-reducing effect in the intrahippocampal kainate mouse model

Summary

Introduction

Despite the availability of numerous anti-epileptic drugs, in approximately 30% of all epilepsy patients, these medications fail to suppress the spontaneously recurring epileptic seizures [2]. It is desirable to develop therapeutic strategies that target the mechanisms underlying disease development rather than the symptoms of epilepsy [3]. The most drug-refractory type of epilepsy [4], is frequently preceded by brain insults, which initiate a cascade of changes in the brain resulting in epilepsy development [5, 6]. The period between the initiating insult and the first clinically obvious seizures, termed “latent period,” offers a window of opportunity for anti-epileptogenic treatment. No epilepsy-preventive therapeutic strategies have been identified to date [8]

Methods

Results

Conclusion