title: A Novel Approach for the Control of Inflammatory Pain: Prostaglandin E2 Complexation by Randomly Methylated β-Cyclodextrins.
abstract: Inhibitors of cyclooxygenase, which block the formation of prostaglandin (PG) E2, are the standard treatment of inflammatory pain. These drugs, however, have serious gastrointestinal, renal, and cardiovascular side effects that limit their clinical use. Cyclodextrins are neutral glucose oligomers that form a hydrophilic outer and a hydrophobic interior cavity used to carry hydrophilic substances. Methyl-β-cyclodextrins are used currently in several drugs as enhancers and also to deliver PGs. We therefore hypothesized that randomly methylated β-cyclodextrins (RAMEB) could be used for pain treatment.
  
  
  
  An in silico screening for important inflammatory mediators (eg, PGE2, substance P, bradykinin, and calcitonin gene-related peptide) was performed to predict the probability of these molecules binding to RAMEB. Thereafter, a comprehensive in vitro study investigated the complexation affinity of the best target toward RAMEB or its RAMEB-fraction L (FL) using capillary electrophoresis.Wistar rats were injected intraplantarly with complete Freund's adjuvant (CFA) for 96 hours to induce inflammatory hyperalgesia. Subsequently, rats were treated intraplantarly or intravenously either with RAMEB or RAMEB FL and compared with the respective controls. Parecoxib was used as positive control. Mechanical (paw pressure threshold, PPT) and thermal (paw withdrawal latency) nociceptive thresholds were determined before injection and at the indicated time points thereafter. Paw tissue was collected after treatments, and PGE2 and PGD2 contents were measured. Analysis of variance was used for data analysis followed by appropriate post hoc comparisons.
  
  
  
  In silico screening indicated that PGE2, with the highest affinity, was the best candidate for RAMEB binding. Likewise, in capillary electrophoresis experiments, RAMEB had a high affinity to form inclusion complexes with the PGE2 (stability constant [K], 360 1/M; 95% confidence interval [C]: 347.58-372.42 M). Local treatment with RAMEB alleviated CFA-induced mechanical (PPT: 76.25 g; 95% CI: 56.24-96.25 g) and thermal hyperalgesia (PPT: 8.50 seconds; 95% CI: 6.76-10.23 seconds). Moreover, a systemic administration of RAMEB decreased CFA-induced mechanical (PPT: 126.66 g; 95% CI: 114.54-138.77 g) and thermal hyperalgesia (paw withdrawal latency: 11.47 seconds; 95% CI: 9.26-13.68 seconds). RAMEB FL resulted in greater in vitro PGE2-binding capacity and decreased PG content as well as hyperalgesia in vivo to a similar extent. Motor activity of the rats was not altered by RAMEB or RAMEB FL.
  
  
  
  Capture of PGs by cyclodextrins could be a novel and innovative tool for the treatment of inflammatory pain and bypassing some unwanted side effects of cyclooxygenase inhibitors.
authors.affiliation: From the *Department of Anesthesiology, University Hospital of Wüerzburg, Wüerzburg, Germany; and †Cyclolab Ltd., Budapest, Hungary.
authors.forename: Reine-Solange
authors.initials: RS
authors.lastname: Sauer
authors.forename: Heike Lydia
authors.initials: HL
authors.lastname: Rittner
authors.forename: Norbert
authors.initials: N
authors.lastname: Roewer
authors.forename: Tamás
authors.initials: T
authors.lastname: Sohajda
authors.forename: Sergey
authors.initials: S
authors.lastname: Shityakov
authors.forename: Alexander
authors.initials: A
authors.lastname: Brack
authors.forename: Jens-Albert
authors.initials: JA
authors.lastname: Broscheit
mesh_terms: D000818:Animals; D003198:Computer Simulation; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use; D015232:Dinoprostone / Q000737:chemistry* / Q000627:therapeutic use*; D019075:Electrophoresis, Capillary; D006930:Hyperalgesia / Q000188:drug therapy; D007249:Inflammation / Q000188:drug therapy*; D018836:Inflammation Mediators; D007555:Isoxazoles / Q000627:therapeutic use; D008297:Male; D008745:Methylation; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D004856:Postural Balance / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D018836:Inflammation Mediators; D007555:Isoxazoles; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; C409945:parecoxib; D015232:Dinoprostone