TY - JOUR
T1 - Curcumin reduces development of seizurelike events in the hippocampal-entorhinal cortex slice culture model for epileptogenesis
AU - Drion, Cato M.
AU - Kooijman, Lieneke
AU - Aronica, Eleonora
AU - van Vliet, Erwin A.
AU - Wadman, Wytse J.
AU - Chameau, Pascal
AU - Gorter, Jan A.
N1 - With supplementary files
PY - 2019/4/1
Y1 - 2019/4/1
N2 - Objective: Inhibition of the mammalian target of rapamycin (mTOR) pathway could be antiepileptogenic in temporal lobe epilepsy (TLE), possibly via anti-inflammatory actions. We studied effects of the mTOR inhibitor rapamycin and the anti-inflammatory compound curcumin—also reported to inhibit the mTOR pathway—on epileptogenesis and inflammation in an in vitro organotypic hippocampal-entorhinal cortex slice culture model. Methods: Brain slices containing hippocampus and entorhinal cortex were obtained from 6-day-old rat pups and maintained in culture for up to 3 weeks. Rapamycin or curcumin was added to the culture medium from day 2 in vitro onward. Electrophysiological recordings revealed epileptiformlike activity that developed over 3 weeks. Results: In week 3, spontaneous seizurelike events (SLEs) could be detected using whole cell recordings from CA1 principal neurons. The percentage of recorded CA1 neurons displaying SLEs was lower in curcumin-treated slice cultures compared to vehicle-treated slices (25.8% vs 72.5%), whereas rapamycin did not reduce SLE occurrence significantly (52%). Western blot for phosphorylated-S6 (pS6) and phosphorylated S6K confirmed that rapamycin inhibited the mTOR pathway, whereas curcumin only lowered pS6 expression at one phosphorylation site. Real-time quantitative polymerase chain reaction results indicated a trend toward lower expression of inflammatory markers IL-1β and IL-6 and transforming growth factor β after 3 weeks of treatment with rapamycin and curcumin compared to vehicle. Significance: Our results show that curcumin suppresses SLEs in the combined hippocampal-entorhinal cortex slice culture model and suggest that its antiepileptogenic effects should be further investigated in experimental models of TLE.
AB - Objective: Inhibition of the mammalian target of rapamycin (mTOR) pathway could be antiepileptogenic in temporal lobe epilepsy (TLE), possibly via anti-inflammatory actions. We studied effects of the mTOR inhibitor rapamycin and the anti-inflammatory compound curcumin—also reported to inhibit the mTOR pathway—on epileptogenesis and inflammation in an in vitro organotypic hippocampal-entorhinal cortex slice culture model. Methods: Brain slices containing hippocampus and entorhinal cortex were obtained from 6-day-old rat pups and maintained in culture for up to 3 weeks. Rapamycin or curcumin was added to the culture medium from day 2 in vitro onward. Electrophysiological recordings revealed epileptiformlike activity that developed over 3 weeks. Results: In week 3, spontaneous seizurelike events (SLEs) could be detected using whole cell recordings from CA1 principal neurons. The percentage of recorded CA1 neurons displaying SLEs was lower in curcumin-treated slice cultures compared to vehicle-treated slices (25.8% vs 72.5%), whereas rapamycin did not reduce SLE occurrence significantly (52%). Western blot for phosphorylated-S6 (pS6) and phosphorylated S6K confirmed that rapamycin inhibited the mTOR pathway, whereas curcumin only lowered pS6 expression at one phosphorylation site. Real-time quantitative polymerase chain reaction results indicated a trend toward lower expression of inflammatory markers IL-1β and IL-6 and transforming growth factor β after 3 weeks of treatment with rapamycin and curcumin compared to vehicle. Significance: Our results show that curcumin suppresses SLEs in the combined hippocampal-entorhinal cortex slice culture model and suggest that its antiepileptogenic effects should be further investigated in experimental models of TLE.
KW - antiepileptogenesis
KW - inflammation
KW - mammalian target of rapamycin
KW - mitogen-activated protein kinase
KW - rat
KW - seizurelike event
UR - http://www.scopus.com/inward/record.url?scp=85061441656&partnerID=8YFLogxK
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85061441656&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30747999
UR - https://pure.uva.nl/ws/files/34033258/epi14667_sup_0001_figs1.pdf
UR - https://pure.uva.nl/ws/files/34033260/epi14667_sup_0002_figs2.pdf
UR - https://pure.uva.nl/ws/files/34033262/epi14667_sup_0003_figs3.pdf
UR - https://pure.uva.nl/ws/files/34033264/epi14667_sup_0004_appendixs1.docx
U2 - https://doi.org/10.1111/epi.14667
DO - https://doi.org/10.1111/epi.14667
M3 - Article
C2 - 30747999
SN - 0013-9580
VL - 60
SP - 605
EP - 614
JO - Epilepsia
JF - Epilepsia
IS - 4
ER -