title: Promethazine inhibits NMDA-induced currents - new pharmacological aspects of an old drug.
abstract: OBJECTIVE
  The phenothiazine derivative promethazine was first introduced into clinical practice as an antiallergic drug owing to its H1-receptor antagonizing properties. Nowadays, promethazine is primarily used as a sedative and/or as an antiemetic. The spectrum of clinically relevant effects is mediated by different molecular targets. Since glutamate is the predominant excitatory transmitter in the vertebrate brain and involved in alertness control, pain processing, and neurotoxicity we tested the hypothesis that promethazine interacts with excitatory ionotropic glutamate receptors.
  
  
  METHODS
  Electrophysiological experiments were performed by means of the patch-clamp technique at glutamate receptors heterologously expressed in human TsA cells.
  
  
  RESULTS
  Promethazine selectively inhibited NMDA receptors whereas AMPA- and kainate receptors were hardly affected. Inhibition of NMDA-induced membrane currents occurred in a reversible manner with a half-maximal effect at around 20 μM promethazine. The inhibition occurred in a non-competitive manner as it did neither vary with the glutamate nor the glycine concentration. Analysis of the underlying mechanism revealed only a weak dependency on receptor usage, pH value (pH 6.8-7.8), and membrane potential (zδ = 0.44 ± 0.04 according to the Woodhull-model). In line with the latter finding, promethazine did not interact with the Mg(2+) binding site. However, the displacement of promethazine by 9-aminoacridine indicates that promethazine may interact with the channel pore more externally in relation to the Mg(2+) binding site.
  
  
  CONCLUSIONS
  Promethazine inhibits NMDA-mediated membrane currents in a reversible and concentration-dependent manner. The results presented here provide evidence that the NMDA receptor antagonism may contribute to clinically relevant effects of promethazine like sedation, analgesia or neuroprotection.
authors.affiliation: University Hospital of Ulm, Department of Anesthesiology, Steinhoevelstrasse 9, 89075 Ulm, Germany. oliver.adolph@uniklinik-ulm.de
authors.forename: Oliver
authors.initials: O
authors.lastname: Adolph
authors.forename: Sarah
authors.initials: S
authors.lastname: Köster
authors.forename: Michael
authors.initials: M
authors.lastname: Georgieff
authors.forename: Eva-Marie
authors.initials: EM
authors.lastname: Georgieff
authors.forename: Wasim
authors.initials: W
authors.lastname: Moulig
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Föhr
mesh_terms: D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects*; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D011398:Promethazine / Q000494:pharmacology*; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016202:N-Methylaspartate; D011398:Promethazine; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate