Increased expression of (immuno)proteasome subunits during epileptogenesis is attenuated by inhibition of the mammalian target of rapamycin pathway

• Published in: Epilepsia (Copenhagen) 2017-08, Vol.58 (8), p.1462-1472
• Main Authors: Broekaart, Diede W. M., Scheppingen, Jackelien, Geijtenbeek, Karlijne W., Zuidberg, Mark R. J., Anink, Jasper J., Baayen, Johannes C., Mühlebner, Angelika, Aronica, Eleonora, Gorter, Jan A., Vliet, Erwin A.
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Astrocytes; Astrocytes - drug effects; Astrocytes - metabolism; Brain inflammation; Cells, Cultured; Cortex (piriform); Cortex (temporal); Disease Models, Animal; Drug resistance; Epilepsy; Epilepsy, Temporal Lobe - chemically induced; Epilepsy, Temporal Lobe - metabolism; Epilepsy, Temporal Lobe - pathology; Epileptogenesis; Fetus; Gene expression; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Glial Fibrillary Acidic Protein - metabolism; Hippocampus; Hippocampus - metabolism; Humans; Immunohistochemistry; Inflammation; Interleukin 1; Interleukin-1beta - pharmacology; Male; mTOR; Phosphopyruvate Hydratase - metabolism; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Protein Subunits - metabolism; Rapamycin; Rats; Rats, Sprague-Dawley; Rodents; Seizures; Signal Transduction - drug effects; Sirolimus - pharmacology; Status epilepticus; Temporal lobe; Temporal lobe epilepsy; Time Factors; TOR protein; TOR Serine-Threonine Kinases - metabolism
• ISSN: 0013-9580; 1528-1167
• DOI: 10.1111/epi.13823

Summary Objective Inhibition of the mammalian target of rapamycin (mTOR) pathway reduces epileptogenesis in various epilepsy models, possibly by inhibition of inflammatory processes, which may include the proteasome system. To study the role of mTOR inhibition in the regulation of the proteasome system, we investigated (immuno)proteasome expression during epileptogenesis, as well as the effects of the mTOR inhibitor rapamycin. Methods The expression of constitutive (β1, β5) and immunoproteasome (β1i, β5i) subunits was investigated during epileptogenesis using immunohistochemistry in the electrical post‐status epilepticus (SE) rat model for temporal lobe epilepsy (TLE). The effect of rapamycin was studied on (immuno)proteasome subunit expression in post‐SE rats that were treated for 6 weeks. (Immuno)proteasome expression was validated in the brain tissue of patients who had SE or drug‐resistant TLE and the effect of rapamycin was studied in primary human astrocyte cultures. Results In post‐SE rats, increased (immuno)proteasome expression was detected throughout epileptogenesis in neurons and astrocytes within the hippocampus and piriform cortex and was most evident in rats that developed a progressive form of epilepsy. Rapamycin‐treated post‐SE rats had reduced (immuno)proteasome protein expression and a lower number of spontaneous seizures compared to vehicle‐treated rats. (Immuno)proteasome expression was also increased in neurons and astrocytes within the human hippocampus after SE and in patients with drug‐resistant TLE. In vitro studies using cultured human astrocytes showed that interleukin (IL)‐1β‐induced (immuno)proteasome gene expression could be attenuated by rapamycin. Significance Because dysregulation of the (immuno)proteasome system is observed before the occurrence of spontaneous seizures in rats, is associated with progression of epilepsy, and can be modulated via the mTOR pathway, it may represent an interesting novel target for drug treatment in epilepsy.