PMID- 32890589
OWN - NLM
STAT- MEDLINE
DCOM- 20210827
LR  - 20210827
IS  - 1873-7064 (Electronic)
IS  - 0028-3908 (Linking)
VI  - 180
DP  - 2020 Dec 1
TI  - Novel brain permeant mTORC1/2 inhibitors are as efficacious as rapamycin or 
      everolimus in mouse models of acquired partial epilepsy and tuberous sclerosis 
      complex.
PG  - 108297
LID - S0028-3908(20)30365-8 [pii]
LID - 10.1016/j.neuropharm.2020.108297 [doi]
AB  - Mechanistic target of rapamycin (mTOR) regulates cell proliferation, growth and 
      survival, and is activated in cancer and neurological disorders, including 
      epilepsy. The rapamycin derivative ("rapalog") everolimus, which allosterically 
      inhibits the mTOR pathway, is approved for the treatment of partial epilepsy with 
      spontaneous recurrent seizures (SRS) in individuals with tuberous sclerosis 
      complex (TSC). In contrast to the efficacy in TSC, the efficacy of rapalogs on 
      SRS in other types of epilepsy is equivocal. Furthermore, rapalogs only poorly 
      penetrate into the brain and are associated with peripheral adverse effects, 
      which may compromise their therapeutic efficacy. Here we compare the antiseizure 
      efficacy of two novel, brain-permeable ATP-competitive and selective mTORC1/2 
      inhibitors, PQR620 and PQR626, and the selective dual pan-PI3K/mTORC1/2 inhibitor 
      PQR530 in two mouse models of chronic epilepsy with SRS, the intrahippocampal 
      kainate (IHK) mouse model of acquired temporal lobe epilepsy and Tsc1(GFAP) CKO 
      mice, a well-characterized mouse model of epilepsy in TSC. During prolonged 
      treatment of IHK mice with rapamycin, everolimus, PQR620, PQR626, or PQR530; only 
      PQR620 exerted a transient antiseizure effect on SRS, at well tolerated doses 
      whereas the other compounds were ineffective. In contrast, all of the examined 
      compounds markedly suppressed SRS in Tsc1(GFAP) CKO mice during chronic treatment 
      at well tolerated doses. Thus, against our expectation, no clear differences in 
      antiseizure efficacy were found across the three classes of mTOR inhibitors 
      examined in mouse models of genetic and acquired epilepsies. The main advantage 
      of the novel 1,3,5-triazine derivatives is their excellent tolerability compared 
      to rapalogs, which would favor their development as new therapies for TORopathies 
      such as TSC.
CI  - Copyright (c) 2020 Elsevier Ltd. All rights reserved.
FAU - Theilmann, Wiebke
AU  - Theilmann W
AD  - Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary 
      Medicine Hannover, Germany.
FAU - Gericke, Birthe
AU  - Gericke B
AD  - Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary 
      Medicine Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany.
FAU - Schidlitzki, Alina
AU  - Schidlitzki A
AD  - Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary 
      Medicine Hannover, Germany.
FAU - Muneeb Anjum, Syed Muhammad
AU  - Muneeb Anjum SM
AD  - Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary 
      Medicine Hannover, Germany.
FAU - Borsdorf, Saskia
AU  - Borsdorf S
AD  - Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary 
      Medicine Hannover, Germany.
FAU - Harries, Timon
AU  - Harries T
AD  - Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary 
      Medicine Hannover, Germany.
FAU - Roberds, Steven L
AU  - Roberds SL
AD  - Tuberous Sclerosis Alliance, Silver Spring, MD, USA.
FAU - Aguiar, Dean J
AU  - Aguiar DJ
AD  - Tuberous Sclerosis Alliance, Silver Spring, MD, USA.
FAU - Brunner, Daniela
AU  - Brunner D
AD  - PsychoGenics, Paramus, NJ, USA.
FAU - Leiser, Steven C
AU  - Leiser SC
AD  - PsychoGenics, Paramus, NJ, USA.
FAU - Song, Dekun
AU  - Song D
AD  - PsychoGenics, Paramus, NJ, USA.
FAU - Fabbro, Doriano
AU  - Fabbro D
AD  - PIQUR Therapeutics AG, Basel, Switzerland.
FAU - Hillmann, Petra
AU  - Hillmann P
AD  - PIQUR Therapeutics AG, Basel, Switzerland.
FAU - Wymann, Matthias P
AU  - Wymann MP
AD  - Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058, Basel, 
      Switzerland.
FAU - Loscher, Wolfgang
AU  - Loscher W
AD  - Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary 
      Medicine Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany. 
      Electronic address: wolfgang.loescher@tiho-hannover.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200903
PL  - England
TA  - Neuropharmacology
JT  - Neuropharmacology
JID - 0236217
RN  - 0 (Immunosuppressive Agents)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Disease Models, Animal
MH  - Epilepsies, Partial/*drug therapy/physiopathology
MH  - Everolimus/pharmacology/*therapeutic use
MH  - Immunosuppressive Agents/pharmacology/therapeutic use
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1/*antagonists & inhibitors
MH  - Mechanistic Target of Rapamycin Complex 2/*antagonists & inhibitors
MH  - Mice
MH  - Mice, Knockout
MH  - Sirolimus/*therapeutic use
MH  - Treatment Outcome
MH  - Tuberous Sclerosis/*drug therapy/physiopathology
OTO - NOTNLM
OT  - Acquired epilepsies
OT  - Antiseizure drugs
OT  - Genetic epilepsies
OT  - TORopathies
OT  - Tolerability
EDAT- 2020/09/06 06:00
MHDA- 2021/08/28 06:00
CRDT- 2020/09/05 20:07
PHST- 2020/06/17 00:00 [received]
PHST- 2020/08/27 00:00 [revised]
PHST- 2020/09/01 00:00 [accepted]
PHST- 2020/09/06 06:00 [pubmed]
PHST- 2021/08/28 06:00 [medline]
PHST- 2020/09/05 20:07 [entrez]
AID - S0028-3908(20)30365-8 [pii]
AID - 10.1016/j.neuropharm.2020.108297 [doi]
PST - ppublish
SO  - Neuropharmacology. 2020 Dec 1;180:108297. doi: 10.1016/j.neuropharm.2020.108297. 
      Epub 2020 Sep 3.