Kinin-B2 receptor exerted neuroprotection after diisopropylfluorophosphate-induced neuronal damage

The kinin-B2 receptor (B2BKR) activated by its endogenous ligand bradykinin participates in various metabolic processes including the control of arterial pressure and inflammation. Recently, functions for this receptor in brain development and protection against glutamate-provoked excitotoxicity have been proposed. Here, we report neuroprotective properties for bradykinin against organophosphate poisoning using acute hippocampal slices as an in vitro model. Following slice perfusion for 10min with diisopropylfluorophosphate (DFP) to initiate the noxious stimulus, responses of pyramidal neurons upon an electric impulse were reduced to less than 30% of control amplitudes. Effects on synaptic-elicited population spikes were reverted when preparations had been exposed to bradykinin 30min after challenging with DFP. Accordingly, bradykinin-induced population spike recovery was abolished by HOE-140, a B2BKR antagonist. However, the kinin-B1 receptor (B1BKR) agonist Lys-des-Arg(9)-bradykinin, inducing the phosphorylation of mitogen-activated protein kinase (MEK/MAPK) and cell death, abolished bradykinin-mediated neuroprotection, an effect, which was reverted by the ERK inhibitor PD98059. In agreement with pivotal B1BKR functions in this process, antagonism of endogenous B1BKR activity alone was enough for restoring population spike activity. On the other hand pralidoxime, an oxime, reactivating acetylcholinesterase (AChE) after organophosphate poisoning, induced population spike recovery after DFP exposure in the presence of bradykinin and Lys-des-Arg(9)-bradykinin. Lys-des-Arg(9)-bradykinin did not revert protection exerted by pralidoxime, however when instead bradykinin and Ly-des-Arg(9)-bradykinin were superfused together, recovery of population spikes diminished. These findings again confirm the neuroprotective feature of bradykinin, which is, diminished by its endogenous metabolites, stimulating the B1BKR, providing a novel understanding of the physiological roles of these receptors.