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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
Author(s) -
Tremblay R,
Hewitt K.,
Lesiuk H.,
Mealing G.,
Morley P,
Durkin J. P.
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.0720102.x
Subject(s) - neuroprotection , nmda receptor , staurosporine , glutamate receptor , brain derived neurotrophic factor , neurotrophic factors , protein kinase c , neurotrophin , neuroscience , programmed cell death , biology , chemistry , microbiology and biotechnology , pharmacology , kinase , biochemistry , apoptosis , receptor
: 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 50μ M NMDA or 50 μ M 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 μ M , 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 Ca 2+ concentration were alteredby the 8‐h BDNF pretreatment. Furthermore, BDNF offered no neuroprotection tocells treated with the PKC inhibitors staurosporine (10‐20 n M ),calphostin C (1‐2.5 μ M ), or GF‐109203X (100 n M ) 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 Ca 2+ influx through the NMDA receptor causes membrane PKC inactivation.