PMID- 27917413
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200929
IS  - 2471-2531 (Print)
IS  - 2471-2531 (Electronic)
IS  - 2471-2531 (Linking)
VI  - 1
IP  - 1
DP  - 2016 Jun
TI  - Efficacy of (S)-Lacosamide in preclinical models of cephalic pain.
LID - e565 [pii]
AB  - 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 Ca(2+) channel (CaV2.2) 
      activity and Ca(2+)-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(R)), inhibited CRMP2 phosphorylation by 
      cyclin dependent kinase 5 (Cdk5) in rat TG slices and decreased 
      depolarization-evoked Ca(2+) influx in TG cells in culture. (S)-LCM significantly 
      blocked capsaicin-evoked CGRP release from dural nerve terminals in the rat an ex 
      vivo cranial 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.
FAU - Moutal, Aubin
AU  - Moutal A
AD  - Department of Pharmacology, College of Medicine, University of Arizona, Tucson, 
      AZ 85742, USA.
FAU - Eyde, Nathan
AU  - Eyde N
AD  - Department of Pharmacology, College of Medicine, University of Arizona, Tucson, 
      AZ 85742, USA.
FAU - Telemi, Edwin
AU  - Telemi E
AD  - Department of Pharmacology, College of Medicine, University of Arizona, Tucson, 
      AZ 85742, USA.
FAU - Park, Ki Duk
AU  - Park KD
AD  - 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.
FAU - Xie, Jennifer Y
AU  - Xie JY
AD  - Department of Pharmacology, College of Medicine, University of Arizona, Tucson, 
      AZ 85742, USA.
FAU - Dodick, David W
AU  - Dodick DW
AD  - Department of Neurology, Mayo Clinic, Phoenix, USA.
FAU - Porreca, Frank
AU  - Porreca F
AD  - Department of Pharmacology, College of Medicine, University of Arizona, Tucson, 
      AZ 85742, USA; Department of Collaborative Research, Mayo Clinic, Phoenix, USA.
FAU - Khanna, Rajesh
AU  - Khanna R
AD  - Department of Pharmacology, College of Medicine, University of Arizona, Tucson, 
      AZ 85742, USA.
LA  - eng
GR  - T35 HL007479/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PL  - United States
TA  - Pain Rep
JT  - Pain reports
JID - 101683899
PMC - PMC5127447
MID - NIHMS798573
OTO - NOTNLM
OT  - (S)-Lacosamide
OT  - CGRP
OT  - CRMP2
OT  - CaV2.2
OT  - Cdk5
OT  - calcium imaging
OT  - cutaneous allodynia
OT  - headache-related pain
OT  - migraine
OT  - phosphorylation
OT  - trigeminal ganglia
COIS- - the authors declare no competing interests.
EDAT- 2016/12/06 06:00
MHDA- 2016/12/06 06:01
PMCR- 2016/08/09
CRDT- 2016/12/06 06:00
PHST- 2016/12/06 06:00 [entrez]
PHST- 2016/12/06 06:00 [pubmed]
PHST- 2016/12/06 06:01 [medline]
PHST- 2016/08/09 00:00 [pmc-release]
AID - e565 [pii]
AID - PAINREPORTS-D-16-0003 [pii]
AID - 10.1097/PR9.0000000000000565 [doi]
PST - ppublish
SO  - Pain Rep. 2016 Jun;1(1):e565. doi: 10.1097/PR9.0000000000000565.