Kinin-B2 Receptor Mediated Neuroprotection after NMDA Excitotoxicity Is Reversed in the Presence of Kinin-B1 Receptor Agonists

Abstract

BackgroundKinins, 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 FindingsBradykinin 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.ConclusionsBradykinin 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.

Kinin-B2 Receptor Activity Determines the Differentiation Fate of Neural Stem Cells

“…The observed effects can be explained by the increased availability of Bk and subsequent activation of B2BkR, because they were reversed by pretreatment with HOE-140. Such neuroprotective features were recently described for an in vitro model of hippocampal neurons where Bk reversed apoptosis induced by NMDA-mediated excitotoxicity (62).…”

Kinin B2 receptor can play a neuroprotective role in Alzheimer's disease

“…PKA and PKC may phosphorylate NMDA or AMPA receptor subunits, changing the membrane traffic and their kinetic properties (voltage-dependent block, channel open time, burst behavior), triggering an increase in synaptic effectiveness (Kohno et al, 2008). Very recently, it was shown that B2R stimulation leads to neuroprotection after NMDA excitotoxicity in the CA1 area of rat hippocampal slices via phosphatidylinositol 3-kinase and not by MEK/MAPK signaling (Martins et al, 2012).…”

Neuroprotection Against Diisopropylfluorophosphate in Acute Hippocampal Slices

“…The same group described that a fluorescence live/dead confocal viability assay was consistent with the PSs assessment of neuronal damage after several pharmacological neuroprotective treatments [8]. PS have been successfully used to study the mechanism of neurotoxicity and neuroprotection [7, 9-13]. …”