TY - JOUR
T1 - Increased expression of (immuno)proteasome subunits during epileptogenesis is attenuated by inhibition of the mammalian target of rapamycin pathway
AU - Broekaart, Diede W.M.
AU - van Scheppingen, Jackelien
AU - Geijtenbeek, Karlijne W.
AU - Zuidberg, Mark R.J.
AU - Anink, Jasper J.
AU - Baayen, Johannes C.
AU - Mühlebner, Angelika
AU - Aronica, Eleonora
AU - Gorter, Jan A.
AU - van Vliet, Erwin A.
PY - 2017/8/1
Y1 - 2017/8/1
N2 - 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.
AB - 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.
KW - Animals
KW - Astrocytes
KW - Brain inflammation
KW - Cells, Cultured
KW - Disease Models, Animal
KW - Epilepsy, Temporal Lobe
KW - Epileptogenesis
KW - Fetus
KW - Gene Expression Regulation
KW - Glial Fibrillary Acidic Protein
KW - Hippocampus
KW - Humans
KW - Interleukin-1beta
KW - Journal Article
KW - Male
KW - Phosphopyruvate Hydratase
KW - Proteasome Endopeptidase Complex
KW - Protein Subunits
KW - Rats
KW - Rats, Sprague-Dawley
KW - Signal Transduction
KW - Sirolimus
KW - Status epilepticus
KW - TOR Serine-Threonine Kinases
KW - Temporal lobe epilepsy
KW - Time Factors
KW - mTOR
UR - http://www.scopus.com/inward/record.url?scp=85021310506&partnerID=8YFLogxK
UR - https://pure.uva.nl/ws/files/17676560/Increased_expression_suppl._1.tif
UR - https://pure.uva.nl/ws/files/17676562/Increased_expression_suppl._2.tif
UR - https://pure.uva.nl/ws/files/17676564/Increased_expression_suppl._3.tif
UR - https://pure.uva.nl/ws/files/17676566/Increased_expression_suppl._4.tif
UR - https://pure.uva.nl/ws/files/17676568/Increased_expression_suppl._5.tif
UR - https://pure.uva.nl/ws/files/17676570/Increased_expression_suppl._6.tif
UR - https://pure.uva.nl/ws/files/17676572/Increased_expression_suppl._7.tif
UR - https://pure.uva.nl/ws/files/17676574/Increased_expression_suppl._8.tif
UR - https://pure.uva.nl/ws/files/17676576/Increased_expression_suppl._9.pdf
U2 - https://doi.org/10.1111/epi.13823
DO - https://doi.org/10.1111/epi.13823
M3 - Article
C2 - 28643873
SN - 0013-9580
VL - 58
SP - 1462
EP - 1472
JO - Epilepsia
JF - Epilepsia
IS - 8
ER -