title: Kinin-B2 receptor mediated neuroprotection after NMDA excitotoxicity is reversed in the presence of kinin-B1 receptor agonists.
abstract: BACKGROUND
  Kinins, with bradykinin and des-Arg(9)-bradykinin being the most important ones, are pro-inflammatory peptides released after tissue injury including stroke. Although the actions of bradykinin are in general well characterized; it remains controversial whether the effects of bradykinin are beneficial or not. Kinin-B2 receptor activation participates in various physiological processes including hypotension, neurotransmission and neuronal differentiation. The bradykinin metabolite des-Arg(9)-bradykinin as well as Lys-des-Arg(9)-bradykinin activates the kinin-B1 receptor known to be expressed under inflammatory conditions. We have investigated the effects of kinin-B1 and B2 receptor activation on N-methyl-D-aspartate (NMDA)-induced excitotoxicity measured as decreased capacity to produce synaptically evoked population spikes in the CA1 area of rat hippocampal slices.
  
  
  RESULTS
  Bradykinin at 10 nM and 1 µM concentrations triggered a neuroprotective cascade via kinin-B2 receptor activation which conferred protection against NMDA-induced excitotoxicity. Recovery of population spikes induced by 10 nM bradykinin was completely abolished when the peptide was co-applied with the selective kinin-B2 receptor antagonist HOE-140. Kinin-B2 receptor activation promoted survival of hippocampal neurons via phosphatidylinositol 3-kinase, while MEK/MAPK signaling was not involved in protection against NMDA-evoked excitotoxic effects. However, 100 nM Lys-des-Arg(9)-bradykinin, a potent kinin-B1 receptor agonist, reversed bradykinin-induced population spike recovery. The inhibition of population spikes recovery was reversed by PD98059, showing that MEK/MAPK was involved in the induction of apoptosis mediated by the B1 receptor.
  
  
  CONCLUSIONS
  Bradykinin exerted protection against NMDA-induced excitotoxicity which is reversed in the presence of a kinin-B1 receptor agonist. As bradykinin is converted to the kinin-B1 receptor metabolite des-Arg(9)-bradykinin by carboxypeptidases, present in different areas including in brain, our results provide a mechanism for the neuroprotective effect in vitro despite of the deleterious effect observed in vivo.
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Antonio H
authors.initials: AH
authors.lastname: Martins
authors.forename: Janaina M
authors.initials: JM
authors.lastname: Alves
authors.forename: Dinely
authors.initials: D
authors.lastname: Perez
authors.forename: Marimeé
authors.initials: M
authors.lastname: Carrasco
authors.forename: Wilmarie
authors.initials: W
authors.lastname: Torres-Rivera
authors.forename: Vesna A
authors.initials: VA
authors.lastname: Eterović
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Ferchmin
authors.forename: Henning
authors.initials: H
authors.lastname: Ulrich
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity*; D001923:Brain Chemistry; D056547:CA1 Region, Hippocampal; D002268:Carboxypeptidases / Q000378:metabolism; D016202:N-Methylaspartate; D018696:Neuroprotective Agents; D051381:Rats; D043783:Receptor, Bradykinin B1 / Q000819:agonists* / Q000502:physiology; D043782:Receptor, Bradykinin B2 / Q000502:physiology*
chemical_list: D018696:Neuroprotective Agents; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; C024626:bradykinin, des-Arg(9)-; D016202:N-Methylaspartate; D002268:Carboxypeptidases; D001920:Bradykinin