Indoprofen upregulates the survival motor neuron protein through a cyclooxygenase-independent mechanism.

Mitchell R Lunn, David E Root, Allison M Martino, Stephen P Flaherty, Brian P Kelley, Daniel D Coovert, Arthur H Burghes, Nguyen Thi Man, Glenn E Morris, Jianhua Zhou, Elliot J Androphy, Charlotte J Sumner, Brent R Stockwell

Index: Chem. Biol. 11(11) , 1489-93, (2004)

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Abstract

Most patients with the pediatric neurodegenerative disease spinal muscular atrophy have a homozygous deletion of the survival motor neuron 1 (SMN1) gene, but retain one or more copies of the closely related SMN2 gene. The SMN2 gene encodes the same protein (SMN) but produces it at a low efficiency compared with the SMN1 gene. We performed a high-throughput screen of approximately 47,000 compounds to identify those that increase production of an SMN2-luciferase reporter protein, but not an SMN1-luciferase reporter protein. Indoprofen, a nonsteroidal anti-inflammatory drug (NSAID) and cyclooxygenase (COX) inhibitor, selectively increased SMN2-luciferase reporter protein and endogenous SMN protein and caused a 5-fold increase in the number of nuclear gems in fibroblasts from SMA patients. No other NSAIDs or COX inhibitors tested exhibited this activity.