Kinin-B2 receptor mediated neuroprotection after NMDA excitotoxicity is reversed in the presence of Kinin-B1 receptor agonists
| Autor: | Antonio H. Martins, Henning Ulrich, Pedro A. Ferchmin, Janaina Maria Alves, Dinely Pérez, Marimée Carrasco, Wilmarie Torres-Rivera, Vesna A. Eterovic |
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| Rok vydání: | 2012 |
| Předmět: |
Receptor
Bradykinin B2 Excitotoxicity lcsh:Medicine Carboxypeptidases Pharmacology medicine.disease_cause Receptor Bradykinin B1 Biochemistry chemistry.chemical_compound 0302 clinical medicine Molecular Cell Biology Pathology Membrane Receptor Signaling lcsh:Science 0303 health sciences Multidisciplinary Kinin Receptor antagonist Neuroprotective Agents NMDA receptor Medicine Research Article Signal Transduction Agonist N-Methylaspartate medicine.drug_class Immunology Bradykinin Biology Neuroprotection Signaling Pathways 03 medical and health sciences Diagnostic Medicine medicine Animals Bradykinin receptor NEUROTRANSMISSORES CA1 Region Hippocampal 030304 developmental biology Brain Chemistry lcsh:R Immunologic Subspecialties Rats chemistry Anatomical Pathology lcsh:Q Clinical Immunology 030217 neurology & neurosurgery Neuroscience |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP PLoS ONE PLoS ONE, Vol 7, Iss 2, p e30755 (2012) |
| Popis: | Background Kinins, with bradykinin and des-Arg9-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-Arg9-bradykinin as well as Lys-des-Arg9-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. Principal Findings 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-Arg9-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-Arg9-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. |
| Databáze: | OpenAIRE |
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