title: Efficacy of (S)-Lacosamide in preclinical models of cephalic pain.
abstract: Migraine is one of the world's most common neurological disorders. Current acute migraine treatments have sub-optimal efficacy and new therapeutic options are needed. Approaches targeting calcitonin gene related peptide (CGRP) signaling are clinically effective but small molecule antagonists have not been advanced due to toxicity. In this study, we explored the axonal growth/specification collapsin response mediator protein 2 (CRMP2) as a novel "druggable" target for inhibiting CGRP release and for potential relevance for treatment of migraine pain. CRMP2 has been demonstrated to regulate N-type voltage gated Ca2+channel (CaV2.2) activity and Ca2+-dependent CGRP release in sensory neurons. The co-expression of CRMP2 with CaV2.2 and CGRP in trigeminal ganglia (TG) sensory neurons suggested the possibility of a novel approach to regulate CGRP release in the trigeminal system. Screening protocols surprisingly revealed that (S)-Lacosamide ((S)-LCM), an inactive analog of the clinically-approved small molecule anti-epileptic drug (R)-Lacosamide (Vimpat®), inhibited CRMP2 phosphorylation by cyclin dependent kinase 5 (Cdk5) in rat TG slices and decreased depolarization-evoked Ca2+influx in TG cells in culture. (S)-LCM significantly blocked capsaicin-evoked CGRP release from dural nerve terminals in the rat anex vivocranial cup preparation. Additionally, cephalic and extracephalic cutaneous allodynia (CA) induced in rats by activation of dural nociceptors with a cocktail of inflammatory mediators, was inhibited by oral administration of (S)-LCM. The confirmation of CRMP2 as an upstream mediator of CGRP release together with the brain penetrance of this molecule suggest (S)-LCM as a potential therapy for acute migraine.
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85742, USA.
authors.forename: Aubin
authors.initials: A
authors.lastname: Moutal
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85742, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Eyde
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85742, USA.
authors.forename: Edwin
authors.initials: E
authors.lastname: Telemi
authors.affiliation: Department of Biological Chemistry, University of Science and Technology and Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea.
authors.forename: Ki Duk
authors.initials: KD
authors.lastname: Park
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85742, USA.
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Xie
authors.affiliation: Department of Neurology, Mayo Clinic, Phoenix, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Dodick
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85742, USA; Department of Collaborative Research, Mayo Clinic, Phoenix, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85742, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Khanna
keywords: (S)-Lacosamide; CGRP; CRMP2; CaV2.2; Cdk5; calcium imaging; cutaneous allodynia; headache-related pain; migraine; phosphorylation; trigeminal ganglia