(R)-[11C]PK11195 brain uptake as a biomarker of inflammation and antiepileptic drug resistance: evaluation in a rat epilepsy model.

Abstract

Neuroinflammation has been suggested as a key determinant of the intrinsic severity of epilepsy. Glial cell activation and associated inflammatory signaling can influence seizure thresholds as well as the pharmacodynamics and pharmacokinetics of antiepileptic drugs. Based on these data, we hypothesized that molecular imaging of microglia activation might serve as a tool to predict drug refractoriness of epilepsy. Brain uptake of (R)-[11C]PK11195, a ligand of the translocator protein 18 kDa and molecular marker of microglia activation, was studied in a chronic model of temporal lobe epilepsy in rats with selection of phenobarbital responders and non-responders. In rats with drug-sensitive epilepsy, (R)-[11C]PK11195 brain uptake values were comparable to those in non-epileptic controls. Analysis in non-responders revealed enhanced brain uptake of up to 39% in different brain regions. The difference might be related to the fact that non-responders exhibited higher baseline seizure frequencies than responders indicating a more pronounced intrinsic disease severity. In hippocampal sections, ED1 immunostaining argued against a general difference in microglia activation between both groups. Our data suggest that TSPO PET imaging might serve as a biomarker for drug resistance in temporal lobe epilepsy. However, it needs to be considered that our findings indicate that the TSPO PET data might merely reflect seizure frequency. Future experimental and clinical studies should further evaluate the validity of TSPO PET data to predict the response to phenobarbital and other antiepileptic drugs in longitudinal studies with scanning before drug exposure and with a focus on the early phase following an epileptogenic brain insult.

• Authors: Renée Marie Bogdanović, Stina Syvänen, Christina Michler, Vera Russmann, Jonas Eriksson, Albert D Windhorst, Adriaan A Lammertsma, Elisabeth C de Lange, Rob A Voskuyl, Heidrun Potschka
• Journal: Neuropharmacology (Neuropharmacology) Vol. 85 Pg. 104-12 (Oct 2014) ISSN: 1873-7064 [Electronic] England
• PMID: 24880085 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Anticonvulsants
• Carbon Radioisotopes
• Carrier Proteins
• Isoquinolines
• Radiopharmaceuticals
• Receptors, GABA-A
• Tspo protein, rat
• PK 11195
• Phenobarbital

Topics

• Animals
• Anticonvulsants (blood, pharmacology)
• Brain (diagnostic imaging, drug effects, pathology, physiopathology)
• Carbon Radioisotopes
• Carrier Proteins (metabolism)
• Chronic Disease
• Disease Models, Animal
• Drug Resistance (physiology)
• Electrodes, Implanted
• Epilepsy, Temporal Lobe (diagnostic imaging, drug therapy, pathology, physiopathology)
• Female
• Isoquinolines
• Microglia (drug effects, metabolism, pathology)
• Neuroimmunomodulation (physiology)
• Phenobarbital (blood, pharmacology)
• Positron-Emission Tomography
• Radiopharmaceuticals
• Random Allocation
• Rats, Sprague-Dawley
• Receptors, GABA-A (metabolism)
• Status Epilepticus (diagnostic imaging, drug therapy, pathology, physiopathology)