Inhibition of the p44/42 MAP kinase pathway protects hippocampal neurons in a cell-culture model of seizure activity

• DOI: 10.1073/pnas.95.20.11975
• Publication Date: 2002-07-26T14:40:11Z
• Authors: Beverley Murray; Alessandro Alessa...; Andrew J. Cole; Ann G. Yee; Edwin J. Furshpan
• Keywords: Flavonoids; Neurons; 0301 basic medicine; Mitogen-Activated Protein Kinase 3; Cell Death; Kynurenic Acid; Hippocampus; Models, Biological; Synaptic Transmission; Rats; 03 medical and health sciences; Seizures; Calcium-Calmodulin-Dependent Protein Kinases; Animals; Enzyme Inhibitors; Mitogen-Activated Protein Kinases; Phosphorylation; Microscopy, Immunoelectron; Excitatory Amino Acid Antagonists; Cells, Cultured; Signal Transduction

Excessive release of glutamate and the subsequent influx calcium are associated with a number neurological insults that result in neuronal death. The calcium-activated intracellular signaling pathways responsible for this excitotoxic injury largely unknown. Here, we report PD098059, selective inhibitor p44/42 mitogen-activated protein kinase (MAP kinase) pathway, reduces death cell-culture model seizure activity. Dissociated hippocampal neurons grown chronically presence kynurenate, broad spectrum glutamate-receptor antagonist, elevated amounts magnesium exhibit intense seizure-like activity after removal these blockers excitatory synaptic transmission. A 30-min produced extensive within 24 h as assayed by uptake trypan blue lactate dehydrogenase. Phospho-p44/42 MAP immunoreactivity 30 min was present many somata dendrites well some terminals, consistent both presynaptic postsynaptic effects pathway. addition PD098059 (40 μM; EC 50 = 10 μM) during washout inhibited phosphorylation reduced trypan-blue staining ( n 13) dehydrogenase 16) 73% ± 18% 75% 19% (mean SD), respectively. observed neuroprotection could be caused an effect on events or downstream activated events. Either possibility suggests heretofore unknown function pathway neurons.