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The Journal of Neuroscience, September 15, 1998, 18(18):7296-7305
Regional Selective Neuronal Degeneration after Protein Phosphatase Inhibition in Hippocampal Slice Cultures: Evidence for a MAP Kinase-Dependent Mechanism
Elise Rundén1, 2, Per O. Seglen2, Finn-Mogens Haug1, Ole Petter Ottersen1, Tadeusz Wieloch3, Mehrdad Shamloo3, and Jon Henrik Laake1 1 Department of Anatomy, University of Oslo, 0317 Oslo, Norway, 2 Department of Cell Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway, and 3 Laboratory for Experimental Brain Research, Wallenberg Neuroscience Center, Lund University Hospital, 221 85 Lund, Sweden
The regional selectivity and mechanisms underlying the toxicity of the serine/threonine protein phosphatase inhibitor okadaic acid (OA) were investigated in hippocampal slice cultures. Image analysis of propidium iodide-labeled cultures revealed that okadaic acid caused a dose- and time-dependent injury to hippocampal neurons. Pyramidal cells in the CA3 region and granule cells in the dentate gyrus were much more sensitive to okadaic acid than the pyramidal cells in the CA1 region. Electron microscopy revealed ultrastructural changes in the pyramidal cells that were not consistent with an apoptotic process. Treatment with okadaic acid led to a rapid and sustained tyrosine phosphorylation of the mitogen-activated protein kinases ERK1 and ERK2 (p44/42mapk). The phosphorylation was markedly reduced after treatment of the cultures with the microbial alkaloid K-252a (a nonselective protein kinase inhibitor) or the MAP kinase kinase (MEK1/2) inhibitor PD98059. K-252a and PD98059 also ameliorated the okadaic acid-induced cell death. Inhibitors of protein kinase C, Ca2+/calmodulin-dependent protein kinase II, or tyrosine kinase were ineffective. These results indicate that sustained activation of the MAP kinase pathway, as seen after e.g., ischemia, may selectively harm specific subsets of neurons. The susceptibility to MAP kinase activation of the CA3 pyramidal cells and dentate granule cells may provide insight into the observed relationship between cerebral ischemia and dementia in Alzheimer's disease.
Key words: okadaic acid; K-252a; PD98059; KT5926; H7; KN-62; KN-04; KN-92; KN-93; naringin; staurosporine; genistein; MAP kinase; p44/42 MAP kinase; ERK1/2; MEK1/2; CA3; propidium iodide; fluorescence microscopy; nonapoptotic cell death; apoptosis; cytoskeleton; electron microscopy; image analysis
Copyright © 1998 Society for Neuroscience 0270-6474/98/18187296-10$05.00/0
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