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Kinin-B2 receptor mediated neuroprotection after NMDA excitotoxicity is reversed in the presence of kinin-B1 receptor agonists.
PLoS One. 2012; 7(2):e30755.Plos

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.

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-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+Show Affiliations

Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

22348022

Citation

Martins, Antonio H., et al. "Kinin-B2 Receptor Mediated Neuroprotection After NMDA Excitotoxicity Is Reversed in the Presence of kinin-B1 Receptor Agonists." PloS One, vol. 7, no. 2, 2012, pp. e30755.
Martins AH, Alves JM, Perez D, et al. Kinin-B2 receptor mediated neuroprotection after NMDA excitotoxicity is reversed in the presence of kinin-B1 receptor agonists. PLoS ONE. 2012;7(2):e30755.
Martins, A. H., Alves, J. M., Perez, D., Carrasco, M., Torres-Rivera, W., Eterović, V. A., Ferchmin, P. A., & Ulrich, H. (2012). Kinin-B2 receptor mediated neuroprotection after NMDA excitotoxicity is reversed in the presence of kinin-B1 receptor agonists. PloS One, 7(2), e30755. https://doi.org/10.1371/journal.pone.0030755
Martins AH, et al. Kinin-B2 Receptor Mediated Neuroprotection After NMDA Excitotoxicity Is Reversed in the Presence of kinin-B1 Receptor Agonists. PLoS ONE. 2012;7(2):e30755. PubMed PMID: 22348022.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Kinin-B2 receptor mediated neuroprotection after NMDA excitotoxicity is reversed in the presence of kinin-B1 receptor agonists. AU - Martins,Antonio H, AU - Alves,Janaina M, AU - Perez,Dinely, AU - Carrasco,Marimeé, AU - Torres-Rivera,Wilmarie, AU - Eterović,Vesna A, AU - Ferchmin,Pedro A, AU - Ulrich,Henning, Y1 - 2012/02/10/ PY - 2010/10/19/received PY - 2011/12/21/accepted PY - 2012/2/21/entrez PY - 2012/2/22/pubmed PY - 2012/8/1/medline SP - e30755 EP - e30755 JF - PloS one JO - PLoS ONE VL - 7 IS - 2 N2 - 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. 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-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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/22348022/Kinin_B2_receptor_mediated_neuroprotection_after_NMDA_excitotoxicity_is_reversed_in_the_presence_of_kinin_B1_receptor_agonists_ L2 - http://dx.plos.org/10.1371/journal.pone.0030755 DB - PRIME DP - Unbound Medicine ER -