Alternative methods of the therapy in the brain ischemia such as preconditioning seem more interesting because of the lack of the clinical applicable effective pharmacological neuroprotection. The role of NMDA receptor activation in triggering of this phenomenon was suggested, but it is not clear. Our recent in vitro studies (Kuszczyk et al. 2010) disclosed tolerance to the excitotoxic challenge by preconditioning with different NMDA receptor antagonists including MK-801 and memantine. The aim of the present study was to check if NMDA receptor antagonism induces also brain tolerance in vivo in different models of experimental brain ischemia. They included hypoxia-ischemia (H-I) in 7-dayold rats and 3-min global forebrain ischemia of Mongolian gerbils. In the neonatal rats exposure to 7% O2 in N2 was used for hypoxic preconditioning (H-P) as a positive control, while for pharmacological preconditioning two NMDA receptor antagonists MK-801 (3 mg/kg) and memantine (5 mg/kg) were injected i.p. Gerbils were pretreated with MK-801. The animals were preconditioned 24, 48, 72 and 96 hours before the insults, and the brain damage or deficit of CA1 pyramidal neurons was evaluated two weeks later. Our results demonstrated that MK-801 administered in all studied time points almost completely reduced brain damage compared to the H-I group, while H-P and preconditioning with memantine were less effective. In gerbils MK-801 was effective only 24 h before global ischemia. These data demonstrate for the first time ischemic tolerance induced by MK-801 and memantine preconditioning in vivo. Known neuroprotective effects of the NMDA receptor antagonists in various models of brain ischemia may be partially ascribed to induced tolerance. We consider a role of mild oxidative stress and enhanced production of trophic factors in its mechanisms. Supported by the MNiSW grant #0664/B/ P01/2010/38.
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