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Evidence that Brain‐Derived Neurotrophic Factor Neuroprotection Is Linked to Its Ability to Reverse the NMDA‐Induced Inactivation of Protein Kinase C in Cortical Neurons

Abstract : Several lines of evidence indicate that a rapid loss of neuronal protein kinase C (PKC) activity is a characteristic feature of cerebral ischemia and is a necessary step in the NMDA‐induced death of cultured neurons. Exposing embryonic day 18 primary rat cortical neurons to 50 μM NMDA or 50 μM glutamate for 10 min caused ~80% cell death over the next 24 h, but excitotoxic death was largely averted, i.e., by 70‐80%, in cells pretreated with brain‐derived neurotrophic factor (BDNF). An 8‐h preexposure to BDNF (50‐100 ng/ml) maximally protected cortical cells from the effects of NMDA and glutamate, although the transient application of BDNF between 8 and 4 h before NMDA was equally protective. These effects of BDNF were abolished at supralethal, i.e., >100 μM, NMDA concentrations. It is significant that BDNF pretreatment prevented the inactivation of PKC in cortical cells normally seen 30 min to 2 h following lethal NMDA or glutamate exposure. This BDNF effect did not arise from changes in NMDA channel activity because neither whole‐cell NMDA current amplitudes nor increases in intracellular free Ca2+ concentration were altered by the 8‐h BDNF pretreatment. Furthermore, BDNF offered no neuroprotection to cells treated with the PKC inhibitors staurosporine (10‐20 nM), calphostin C (1‐2.5 μM), or GF‐109203X (100 nM) at the time of NMDA addition. These results underscore the importance of PKC inactivation in glutamate‐induced neuronal death. They also suggest that BDNF neuroprotection arises, at least in part, via its ability to block the mechanism by which pathophysiological Ca2+ influx through the NMDA receptor causes membrane PKC inactivation.