ISSN:
1471-4159
Source:
Blackwell Publishing Journal Backfiles 1879-2005
Topics:
Medicine
Notes:
Abstract : Several lines of evidence indicate that a rapid loss ofneuronal protein kinase C (PKC) activity is a characteristic feature ofcerebral ischemia and is a necessary step in the NMDA-induced death ofcultured neurons. Exposing embryonic day 18 primary rat cortical neurons to 50μM NMDA or 50 μM glutamate for 10 min caused ~80% celldeath over the next 24 h, but excitotoxic death was largely averted, i.e., by70-80%, in cells pretreated with brain-derived neurotrophic factor (BDNF). An8-h preexposure to BDNF (50-100 ng/ml) maximally protected cortical cells fromthe effects of NMDA and glutamate, although the transient application of BDNFbetween 8 and 4 h before NMDA was equally protective. These effects of BDNFwere abolished at supralethal, i.e., 〉100 μM, NMDAconcentrations. It is significant that BDNF pretreatment prevented theinactivation of PKC in cortical cells normally seen 30 min to 2 h followinglethal NMDA or glutamate exposure. This BDNF effect did not arise from changesin NMDA channel activity because neither whole-cell NMDA current amplitudesnor increases in intracellular free Ca2+ concentration were alteredby the 8-h BDNF pretreatment. Furthermore, BDNF offered no neuroprotection tocells treated with the PKC inhibitors staurosporine (10-20 nM),calphostin C (1-2.5 μM), or GF-109203X (100 nM) at thetime of NMDA addition. These results underscore the importance of PKCinactivation in glutamate-induced neuronal death. They also suggest that BDNFneuroprotection arises, at least in part, via its ability to block themechanism by which pathophysiological Ca2+ influx through the NMDA receptor causes membrane PKC inactivation.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1046/j.1471-4159.1999.0720102.x
