title: Regional selective neuronal degeneration after protein phosphatase inhibition in hippocampal slice cultures: evidence for a MAP kinase-dependent mechanism.
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 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.
authors.affiliation: Department of Anatomy, University of Oslo, 0317 Oslo, Norway.
authors.forename: E
authors.initials: E
authors.lastname: Rundén
authors.forename: P O
authors.initials: PO
authors.lastname: Seglen
authors.forename: F M
authors.initials: FM
authors.lastname: Haug
authors.forename: O P
authors.initials: OP
authors.lastname: Ottersen
authors.forename: T
authors.initials: T
authors.lastname: Wieloch
authors.forename: M
authors.initials: M
authors.lastname: Shamloo
authors.forename: J H
authors.initials: JH
authors.lastname: Laake
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001596:Benzylamines / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044950:Flavanones; D005419:Flavonoids / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D026121:Indole Alkaloids; D008297:Male; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D009410:Nerve Degeneration / Q000139:chemically induced / Q000201:enzymology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D019319:Okadaic Acid / Q000494:pharmacology; D009924:Organ Culture Techniques; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors*; D011419:Propidium; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D019311:Staurosporine / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000975:Antioxidants; D001596:Benzylamines; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002227:Carbazoles; D004791:Enzyme Inhibitors; D044950:Flavanones; D005419:Flavonoids; D019833:Genistein; D026121:Indole Alkaloids; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D019319:Okadaic Acid; D010744:Phosphoric Monoester Hydrolases; D011419:Propidium; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D019311:Staurosporine; D013449:Sulfonamides; C065344:KN 04; C072105:KN 93; D000096926:Benzenesulfonamides; C063302:KN 62; C049985:staurosporine aglycone; C005274:naringin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one