Celecoxib increases SMN and survival in a severe spinal muscular atrophy mouse model via p38 pathway activation

Abstract

The loss of functional SurvivalMotor Neuron (SMN) protein due tomutations or deletion in theSMN1 gene causes autosomal recessive neurodegenerative spinalmuscle atrophy (SMA).Apotential treatment strategy forSMAis to upregulate the amount of SMNprotein originating fromthe highly homologousSMN2 gene, compensating in part for the absence of the functionalSMN1gene.We have previously shownthat in vitro activation of the p38 pathway stabilizes and increases SMNmRNA levels leading to increased SMN protein levels. In this report, we explore the impact of the p38 activating, FDA-approved, bloodbrain barrier permeatingcompound celecoxibonSMNlevels 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-dependentmanner. Furthermore, celecoxib treatment induces SMN expression in brain and spinal cord samples of wild-type mice in vivo. Critically, celecoxib treatment increasedSMNlevels, improvedmotor function and enhanced survival in a severeSMAmousemodel.Our results identify low dose celecoxib as a potential new member of the SMA therapeutic armamentarium. © The Author 2013. Published by Oxford University Press. All rights reserved.