Nonsteroidal anti-inflammatory drugs differentially affect the heat shock response in cultured spinal cord cells.
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to amplify the heat shock response in cell lines by increasing the binding of heat shock transcription factor-1 to heat shock elements within heat shock gene promoters. Because overexpression of the inducible heat shock protein 70 (Hsp70) was neuroprotective in a culture model of motor neuron disease, this study investigated whether NSAIDs induce Hsp70 and confer cytoprotection in motor neurons of dissociated spinal cord cultures exposed to various stresses. Two NSAIDs, sodium salicylate and niflumic acid, lowered the temperature threshold for induction of Hsp70 in glia but failed to do so in motor neurons. At concentrations that increased Hsp70 in heat shocked glial cells, sodium salicylate failed to delay death of motor neurons exposed to hyperthermia, paraquat-mediated oxidative stress, and glutamate excitotoxicity. Neither sodium salicylate nor the cyclooxygenase-2 inhibitor, niflumic acid, protected motor neurons from the toxicity of mutated Cu/Zn-superoxide dismutase (SOD-1) linked to a familial form of the motor neuron disease, amyotrophic lateral sclerosis. Thus, treatment with 2 types of NSAIDs failed to overcome the high threshold for the activation of heat shock response in motor neurons.
Batulan
Zarah
Z
Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
Nalbantoglu
Josephine
J
Durham
Heather D
HD
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002470:Cell Survival; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000378:metabolism; D018869:Heat-Shock Response / Q000187:drug effects*; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D016900:Neurofilament Proteins / Q000032:analysis; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D009544:Niflumic Acid / Q000494:pharmacology*; D010957:Plasmids; D012980:Sodium Salicylate / Q000494:pharmacology*; D013116:Spinal Cord / Q000187:drug effects* / Q000196:embryology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D013696:Temperature
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D005904:Glial Fibrillary Acidic Protein; D018840:HSP70 Heat-Shock Proteins; D016900:Neurofilament Proteins; C051774:neurofilament protein H; D009544:Niflumic Acid; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D012980:Sodium Salicylate