title: Celecoxib increases SMN and survival in a severe spinal muscular atrophy mouse model via p38 pathway activation.
abstract: The loss of functional Survival Motor Neuron (SMN) protein due to mutations or deletion in the SMN1 gene causes autosomal recessive neurodegenerative spinal muscle atrophy (SMA). A potential treatment strategy for SMA is to upregulate the amount of SMN protein originating from the highly homologous SMN2 gene, compensating in part for the absence of the functional SMN1 gene. We have previously shown that in vitro activation of the p38 pathway stabilizes and increases SMN mRNA levels leading to increased SMN protein levels. In this report, we explore the impact of the p38 activating, FDA-approved, blood brain barrier permeating compound celecoxib on SMN levels in vitro and in a mouse model of SMA. We demonstrate a significant induction of SMN protein levels in human and mouse neuronal cells upon treatment with celecoxib. We show that activation of the p38 pathway by low doses celecoxib increases SMN protein in a HuR protein-dependent manner. Furthermore, celecoxib treatment induces SMN expression in brain and spinal cord samples of wild-type mice in vivo. Critically, celecoxib treatment increased SMN levels, improved motor function and enhanced survival in a severe SMA mouse model. Our results identify low dose celecoxib as a potential new member of the SMA therapeutic armamentarium.
authors: University of Ottawa, Ottawa, Canada K1H 8M5. faraz@arc.cheo.ca
authors: Faraz
authors: F
authors: Farooq
authors: Francisco
authors: F
authors: Abadía-Molina
authors: Duncan
authors: D
authors: MacKenzie
authors: Jeremiah
authors: J
authors: Hadwen
authors: Fahad
authors: F
authors: Shamim
authors: Sean
authors: S
authors: O'Reilly
authors: Martin
authors: M
authors: Holcik
authors: Alex
authors: A
authors: MacKenzie
mesh_terms: D000293:Adolescent; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D000068579:Celecoxib; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D051959:ELAV Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007223:Infant; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D014897:Spinal Muscular Atrophies of Childhood / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051959:ELAV Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D000068579:Celecoxib