Preclinical PET imaging in epileptogenesis: towards identification of biomarkers and therapeutic targets

Abstract

Background: Epilepsy is a neurological disorder that affects a significant portion of the global population. However, its complexity and the lack of biomarkers hinder the study of its etiology, resulting in a lack of effective treatments to slow down or halt disease development, also called epileptogenesis.

Main body: Animal models have proven to be a crucial tool for studying epileptogenesis, many exhibiting cellular, molecular, and functional alterations that resemble those found in human patients. This review examines preclinical studies that have utilized positron emission tomography, a non-invasive neuroimaging technique that has demonstrated correlation with the pathological features and behavioral comorbidities of the disease and a high predictive value for the severity of epileptogenesis.

Conclusion: Positron emission tomography imaging has fostered the knowledge of the mechanisms driving epileptogenesis. This translational technique might be crucial for identifying biomarkers of epilepsy, identifying novel treatment targets and selecting and monitoring patients for potential future therapies.

Keywords: Animal models; Biomarker; Epilepsy; Epileptogenesis; PET.

Fig. 1

Schematic overview of molecular imaging targets for epileptogenesis. Scheme shows known imaging targets (in bold) altered during epileptogenesis and their cellular location in the brain. These targets include: glucose and amino acid metabolism (¹⁸F-FDG and ¹⁸F-FET, respectively) and the transporters at the BBB and the cell membrane for each tracer (GLUT1 and GLUT3 for ¹⁸F-FDG, LAT1 for ¹⁸F-FET); astrocyte (TSPO and MAO-B) and microglia activation (TSPO and P2X7R) indicative of neuroinflammation; extravasation of DTPA as surrogate for BBB leakage; the BBB efflux transporter P-gp limiting access of antiseizure medication to the brain; pre- and post-synaptic neuroreceptors as well as SV2A. FDG: 2-deoxy-2-¹⁸ F-fluoro-D-glucose; GLUT1: glucose transporter 1; GLUT3: glucose transporter 3; FET: O-(2-¹⁸ F-fluoroethyl)-l-tyrosine; LAT1: large neutral amino acid transporter 1; TSPO: translocator protein; MAO-B: monoamine oxidase type B; P2X7R: purinergic P2X7 receptor; BBB: blood-brain barrier; DTPA: Diethylenetriaminepentaacetic acid; P-gp: P-glycoprotein; GABA: gamma aminobutyric acid; mGluR: metabotropic glutamate receptor; 5-HT: serotonin; CB1: cannabinoid receptor 1; SV2A: synaptic vesicle glycoprotein 2A. This figure was created using Servier Medical Art licensed under CC BY 4.0

Fig. 2

Temporal profile of different biomarkers during epileptogenesis according to an integrated interpretation of the data obtained from molecular in vivo imaging techniques in different animal models of epilepsy during early, latent and chronic phases. Color lines show relative level of each molecular marker relative to the baseline values (gray line). MAO-B: monoamine oxidase type B; TSPO: translocator protein; P2X7R: purinergic P2X7 receptor; CB1: cannabinoid receptor 1; mGluR: metabotropic glutamate receptor; 5HT: serotonin; SV2A: synaptic vesicle glycoprotein 2A; AA tur: amino acid turnover; GABA: gamma aminobutyric acid; BBB int: blood-brain barrier integrity; D: day