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

Chem Biol. 2004 Nov;11(11):1489-93. doi: 10.1016/j.chembiol.2004.08.024.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Cyclic AMP Response Element-Binding Protein
  • Cyclooxygenase Inhibitors / pharmacology
  • Drug Evaluation, Preclinical
  • Female
  • Fibroblasts / enzymology
  • Humans
  • Indoprofen / pharmacokinetics
  • Indoprofen / pharmacology*
  • Mice
  • Nerve Tissue Proteins / biosynthesis*
  • Nerve Tissue Proteins / genetics
  • Pregnancy
  • Prostaglandin-Endoperoxide Synthases / physiology
  • RNA-Binding Proteins
  • SMN Complex Proteins
  • Survival of Motor Neuron 1 Protein
  • Survival of Motor Neuron 2 Protein
  • Up-Regulation

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclic AMP Response Element-Binding Protein
  • Cyclooxygenase Inhibitors
  • Nerve Tissue Proteins
  • RNA-Binding Proteins
  • SMN Complex Proteins
  • SMN1 protein, human
  • SMN2 protein, human
  • Smn1 protein, mouse
  • Survival of Motor Neuron 1 Protein
  • Survival of Motor Neuron 2 Protein
  • Indoprofen
  • Prostaglandin-Endoperoxide Synthases