PMID- 30684511 OWN - NLM STAT- MEDLINE DCOM- 20190826 LR - 20211204 IS - 1872-7549 (Electronic) IS - 0166-4328 (Linking) VI - 363 DP - 2019 May 2 TI - Cannabidiol modulates phosphorylated rpS6 signalling in a zebrafish model of Tuberous Sclerosis Complex. PG - 135-144 LID - S0166-4328(18)31121-5 [pii] LID - 10.1016/j.bbr.2019.01.040 [doi] AB - Tuberous sclerosis complex (TSC) is a rare disease caused by mutations in the TSC1 or TSC2 genes and is characterized by widespread tumour growth, intractable epilepsy, cognitive deficits and autistic behaviour. CBD has been reported to decrease seizures and inhibit tumour cell progression, therefore we sought to determine the influence of CBD on TSC pathology in zebrafish carrying a nonsense mutation in the tsc2 gene. CBD treatment from 6 to 7 days post-fertilization (dpf) induced significant anxiolytic actions without causing sedation. Furthermore, CBD treatment from 3 dpf had no impact on tsc2(-/-) larvae motility nor their survival. CBD treatment did, however, reduce the number of phosphorylated rpS6 positive cells, and their cross-sectional cell size. This suggests a CBD mediated suppression of mechanistic target of rapamycin (mTOR) activity in the tsc2(-/-) larval brain. Taken together, these data suggest that CBD selectively modulates levels of phosphorylated rpS6 in the brain and additionally provides an anxiolytic effect. This is pertinent given the alterations in mTOR signalling in experimental models of TSC. Additional work is necessary to identify upstream signal modulation and to further justify the use of CBD as a possible therapeutic strategy to manage TSC. CI - Copyright (c) 2019 Elsevier B.V. All rights reserved. FAU - Serra, Ines AU - Serra I AD - School of Psychology and Clinical Language Sciences, University of Reading, Reading, UK; School of Pharmacy, University of Reading, Reading, UK. Electronic address: i.serra@pgr.reading.ac.uk. FAU - Scheldeman, Chloe AU - Scheldeman C AD - Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium. Electronic address: chloe.scheldeman@kuleuven.be. FAU - Bazelot, Michael AU - Bazelot M AD - GW Research Ltd. Sovereign House, Vision Park, Histon, Cambridge, UK. Electronic address: mbazelot@gwpharm.com. FAU - Whalley, Benjamin J AU - Whalley BJ AD - School of Pharmacy, University of Reading, Reading, UK. Electronic address: bwhalley@gwpharm.com. FAU - Dallas, Mark L AU - Dallas ML AD - School of Pharmacy, University of Reading, Reading, UK. Electronic address: m.dallas@reading.ac.uk. FAU - de Witte, Peter A M AU - de Witte PAM AD - Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium. Electronic address: peter.dewitte@kuleuven.be. FAU - Williams, Claire M AU - Williams CM AD - School of Psychology and Clinical Language Sciences, University of Reading, Reading, UK. Electronic address: claire.williams@reading.ac.uk. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190123 PL - Netherlands TA - Behav Brain Res JT - Behavioural brain research JID - 8004872 RN - 0 (Cannabinoids) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Ribosomal Protein S6) RN - 0 (Tsc2 protein, zebrafish) RN - 0 (Tuberous Sclerosis Complex 2 Protein) RN - 0 (Zebrafish Proteins) RN - 19GBJ60SN5 (Cannabidiol) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.1 (mTOR protein, zebrafish) MH - Animals MH - Brain/metabolism MH - Cannabidiol/metabolism/*pharmacology MH - Cannabinoids/metabolism/pharmacology MH - Disease Models, Animal MH - Intracellular Signaling Peptides and Proteins/drug effects/genetics MH - Locomotion/drug effects MH - Phosphorylation/drug effects MH - Ribosomal Protein S6/*drug effects MH - Seizures/pathology MH - Signal Transduction/drug effects MH - TOR Serine-Threonine Kinases/drug effects MH - Tuberous Sclerosis/*drug therapy/physiopathology MH - Tuberous Sclerosis Complex 2 Protein/genetics/metabolism MH - Zebrafish/metabolism MH - Zebrafish Proteins/drug effects/genetics/metabolism OTO - NOTNLM OT - Cannabidiol OT - Cannabinoids OT - Tuberous sclerosis complex OT - Zebrafish OT - mTOR OT - rpS6 EDAT- 2019/01/27 06:00 MHDA- 2019/08/27 06:00 CRDT- 2019/01/27 06:00 PHST- 2018/08/07 00:00 [received] PHST- 2019/01/09 00:00 [revised] PHST- 2019/01/22 00:00 [accepted] PHST- 2019/01/27 06:00 [pubmed] PHST- 2019/08/27 06:00 [medline] PHST- 2019/01/27 06:00 [entrez] AID - S0166-4328(18)31121-5 [pii] AID - 10.1016/j.bbr.2019.01.040 [doi] PST - ppublish SO - Behav Brain Res. 2019 May 2;363:135-144. doi: 10.1016/j.bbr.2019.01.040. Epub 2019 Jan 23.