title: Modulation of inflammatory mediators in the trigeminal ganglion by botulinum neurotoxin type A: an organ culture study.
abstract: BACKGROUND
  Onabotulinumtoxin type A (BoNT-A) has been found to reduce pain in chronic migraine. The aim of the present study was to ask if BoNT-A can interact directly on sensory mechanisms in the trigeminal ganglion (TG) using an organ culture method.
  
  
  METHODS
  To induce inflammation, rat TGs were incubated for 24 hrs with either the mitogen MEK1/2 inhibitor U0126, BoNT-A or NaCl. After this the TGs were prepared for immunohistochemistry. Sections of the TG were then incubated with primary antibodies against CGRP (neuronal transmitter), iNOS (inflammatory marker), IL-1β (Interleukin 1β), SNAP-25 (synaptic vesicle docking protein) or SV2-A (Botulinum toxin receptor element).
  
  
  RESULTS
  We report that CGRP, iNOS, IL-1β, SNAP-25 and SV2-A were observed in fresh TG with a differential distribution. Interestingly, NaCl organ culture of the TG resulted in enhanced expression of CGRP and SNAP-25 in neurons and iNOS in SGCs. Co-incubation with U0126 or BoNT-A retained the increased expression of SNAP-25, while it decreased the IL-1β immunoreactivity in neurons. The iNOS expression in SGCs returned to levels observed in fresh specimens. Moreover, we observed no alteration SV2-A expression in SGCs. Thus, the overall picture is that both U0126 and BoNT-A have the ability to modify the expression of certain molecules in the TG.
  
  
  CONCLUSIONS
  We hypothesize that chronic migraine might be associated with some degree of inflammation in the TG that could involve both neurons and SGCs. It is clinically well recognized that treatment with corticosteroids will reduce the symptoms of chronic migraine; however this remedy is associated with long-term side effects. Understanding the mechanisms involved in the expressional alterations may suggest novel ways to modify the changes and indicate novel therapeutics. The results of the present work illustrate one way by which BoNT-A may modify these expressional alterations.
authors.affiliation: Department of Medicine, Lund University, Lund, Sweden, jacob.edvinsson@hotmail.com.
authors.forename: Jacob
authors.initials: J
authors.lastname: Edvinsson
authors.forename: Karin
authors.initials: K
authors.lastname: Warfvinge
authors.forename: Lars
authors.initials: L
authors.lastname: Edvinsson
mesh_terms: D000818:Animals; D019274:Botulinum Toxins, Type A / Q000494:pharmacology* / Q000627:therapeutic use; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008297:Male; D008881:Migraine Disorders / Q000188:drug therapy / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques; D010146:Pain / Q000188:drug therapy / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012668:Trigeminal Ganglion / Q000187:drug effects / Q000378:metabolism*
chemical_list: D018836:Inflammation Mediators; D019274:Botulinum Toxins, Type A; C545476:incobotulinumtoxinA