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Regional selective neuronal degeneration after protein phosphatase inhibition in hippocampal slice cultures : Evidence for a MAP kinase-dependent mechanism

Rundén, Elise; Seglen, Per O.; Haug, Finn Mogens; Ottersen, Ole Petter; Wieloch, Tadeusz LU ; Shamloo, Mehrdad LU and Laake, Jon Henrik (1998) In Journal of Neuroscience 18(18). p.7296-7305
Abstract

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... (More)

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 (p44/42 (mapk)). 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.

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keywords
Apoptosis, CA3, Cytoskeleton, Electron microscopy, ERK1/2, Fluorescence microscopy, Genistein, H7, Image analysis, K-252a, KN- 93, KN-04, KN-62, KN-92, KT5926, MAP kinase, MEK1/2, Naringin, Nonapoptotic cell death, Okadaic acid, P44/42 MAP kinase, PD98059, Propidium iodide, Staurosporine
in
Journal of Neuroscience
volume
18
issue
18
pages
10 pages
publisher
Society for Neuroscience
external identifiers
  • Scopus:0032530577
ISSN
0270-6474
language
English
LU publication?
yes
id
f876431b-dae1-41df-abaa-00f28de0bbfa
date added to LUP
2016-10-05 16:07:23
date last changed
2016-11-30 14:37:56
@misc{f876431b-dae1-41df-abaa-00f28de0bbfa,
  abstract     = {<p>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 (p44/42 (mapk)). 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, Ca<sup>2+</sup>/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.</p>},
  author       = {Rundén, Elise and Seglen, Per O. and Haug, Finn Mogens and Ottersen, Ole Petter and Wieloch, Tadeusz and Shamloo, Mehrdad and Laake, Jon Henrik},
  issn         = {0270-6474},
  keyword      = {Apoptosis,CA3,Cytoskeleton,Electron microscopy,ERK1/2,Fluorescence microscopy,Genistein,H7,Image analysis,K-252a,KN- 93,KN-04,KN-62,KN-92,KT5926,MAP kinase,MEK1/2,Naringin,Nonapoptotic cell death,Okadaic acid,P44/42 MAP kinase,PD98059,Propidium iodide,Staurosporine},
  language     = {eng},
  month        = {09},
  number       = {18},
  pages        = {7296--7305},
  publisher    = {ARRAY(0x8ee4068)},
  series       = {Journal of Neuroscience},
  title        = {Regional selective neuronal degeneration after protein phosphatase inhibition in hippocampal slice cultures : Evidence for a MAP kinase-dependent mechanism},
  volume       = {18},
  year         = {1998},
}