Control of spasticity in a multiple sclerosis model using central nervous system-excluded CB1 cannabinoid receptor agonists.
The FASEB Journal. 2014-01-01; 28(1): 117-130
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1. FASEB J. 2014 Jan;28(1):117-30. doi: 10.1096/fj.13-239442. Epub 2013 Oct 11.
Control of spasticity in a multiple sclerosis model using central nervous
system-excluded CB1 cannabinoid receptor agonists.
Pryce G(1), Visintin C, Ramagopalan SV, Al-Izki S, De Faveri LE, Nuamah RA, Mein
CA, Montpetit A, Hardcastle AJ, Kooij G, de Vries HE, Amor S, Thomas SA, Ledent
C, Marsicano G, Lutz B, Thompson AJ, Selwood DL, Giovannoni G, Baker D.
(1)1Blizard Institute, Barts and the London School of Medicine and Dentistry,
Queen Mary University of London, 4 Newark St., London E1 2AT, UK.
The purpose of this study was the generation of central nervous system
(CNS)-excluded cannabinoid receptor agonists to test the hypothesis that
inhibition of spasticity, due to CNS autoimmunity, could be controlled by
affecting neurotransmission within the periphery. Procedures included
identification of chemicals and modeling to predict the mode of exclusion;
induction and control of spasticity in the ABH mouse model of multiple sclerosis;
conditional deletion of CB1 receptor in peripheral nerves; side-effect profiling
to demonstrate the mechanism of CNS-exclusion via drug pumps; genome-wide
association study in N2(129×ABH) backcross to map polymorphic cannabinoid drug
pump; and sequencing and detection of cannabinoid drug-pump activity in human
brain endothelial cell lines. Three drugs (CT3, SAB378 and SAD448) were
identified that control spasticity via action on the peripheral nerve CB1
receptor. These were peripherally restricted via drug pumps that limit the CNS
side effects (hypothermia) of cannabinoids to increase the therapeutic window. A
cannabinoid drug pump is polymorphic and functionally lacking in many laboratory
(C57BL/6, 129, CD-1) mice used for transgenesis, pharmacology, and toxicology
studies. This phenotype was mapped and controlled by 1-3 genetic loci. ABCC1
within a cluster showing linkage is a cannabinoid CNS-drug pump. Global and
conditional CB1 receptor-knockout mice were used as controls. In summary,
CNS-excluded CB1 receptor agonists are a novel class of therapeutic agent for
PMID: 24121462 [Indexed for MEDLINE]