Screening for inhibitors of the SOD1 gene promoter: pyrimethamine does not reduce SOD1 levels in cell and animal models.

Neuroscience Letters
Paul D WrightRobert H Brown

Abstract

Mutations in the Cu/Zn superoxide dismutase (SOD1) gene are detected in 20% of familial and 3% of sporadic amyotrophic lateral sclerosis (ALS) cases. Although mutant SOD1 is known to induce motor neuron death via multiple adverse acquired functions, its exact pathogenic mechanism is not well defined. SOD1 toxicity is dose dependent; levels of mutant SOD1 protein in transgenic mice determine disease susceptibility, onset and rate of progression. We therefore sought to identify small molecules that reduce SOD1 levels by inhibiting the SOD1 promoter. We tested pyrimethamine (previously reported to suppress SOD1 expression), several compounds currently in trials in human and murine ALS, and a set of 1040 FDA-approved compounds. In a PC12 cell-based assay, no compounds reduced SOD1 promoter activity without concomitant cytotoxicity. Additionally, pyrimethamine failed to repress levels of SOD1 protein in HeLa cells or homogenates of liver, spinal cord and brain of wild-type mice. Thirty-four compounds (including riluzole, ceftriaxone, minocyclin, PBA, lithium, acetylcysteine) in human and mouse ALS trials and an additional set of 1040 FDA-approved compounds also showed no effect on SOD1 promoter activity. This present study thus fail...Continue Reading

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Citations

Jun 15, 2013·Beilstein Journal of Organic Chemistry·Allison S LimpertNicholas D P Cosford
Feb 7, 2012·Expert Opinion on Investigational Drugs·John A Morren, Nestor Galvez-Jimenez
Sep 19, 2012·Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration·Dale J LangeDaniel Benjamin
Feb 19, 2015·Pharmacology Research & Perspectives·Sarina SchulzeKristina Endres
Jul 4, 2016·European Journal of Medicinal Chemistry·Vijay KumarFaizan Ahmad
Jul 19, 2013·Cellular and Molecular Life Sciences : CMLS·Rachna S PandyaXin Wang

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