title: The selective p38 inhibitor SB-239063 protects primary neurons from mild to moderate excitotoxic injury.
abstract: Inhibition of the p38 mitogen-activated protein kinase (MAP Kinase) pathway reduces acute ischemic injury in vivo, suggesting a direct role for this signaling pathway in a number of neurodegenerative processes. The present study was designed to evaluate further the role of p38 MAP Kinase in acute excitotoxic neuronal injury using the selective p38 inhibitor SB-239063 (trans-1-(4hydroxycyclohexyl)-4-(fluorophenyl)-5-(2-methoxy-pyrimidin-4-yl) imidazole). Unlike the widely used p38 inhibitor, SB-203580 (4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole), this second generation p38 inhibitor more selectively inhibits p38 MAP Kinase without affecting the activity of other MAP Kinase signaling pathways and provides a more accurate means to selectively assess the role of p38 in excitotoxicity that has not been previously possible. SB-239063 provided substantial protection against cell death induced by either oxygen glucose deprivation (OGD) or magnesium deprivation in cultured neurons. The ability of this compound to block excitotoxicity was not due to direct inhibition of N-methyl-D-aspartate (NMDA) receptor-mediated currents as SB-239063 did not alter NMDA electrophysiological responses. SB-239063 did not protect against a severe excitotoxic insult induced by 60-min exposure to NMDA. However, when tested against a less severe, brief (5 min) NMDA exposure, p38 inhibition provided substantial protection. These data demonstrate that inhibition of p38 MAP Kinase can confer neuroprotection in vitro against mild but not severe excitotoxic exposure, and suggests that other additional pathways/mechanism(s) may be involved in severe excitotoxic cell death.
authors.affiliation: High Throughput Biology, Discovery Research, GlaxoSmithKline, PO Box 1539, Mail Code UW 2523, 709 Swedeland Road, 19406, King of Prussia, PA, USA. Jeffrey_J_Legos@gsk.com
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Legos
authors.forename: BethAnn
authors.initials: B
authors.lastname: McLaughlin
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Skaper
authors.forename: Paul J L M
authors.initials: PJ
authors.lastname: Strijbos
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Parsons
authors.forename: Elias
authors.initials: E
authors.lastname: Aizenman
authors.forename: Greta A
authors.initials: GA
authors.lastname: Herin
authors.forename: Frank C
authors.initials: FC
authors.lastname: Barone
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Erhardt
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000166:cytology; D007093:Imidazoles / Q000494:pharmacology*; D008274:Magnesium / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D016548:Prosencephalon / Q000166:cytology; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D007093:Imidazoles; D018696:Neuroprotective Agents; D011743:Pyrimidines; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C406525:SB 239063; D008274:Magnesium; D005947:Glucose