2. Academic Validation
  3. The small molecule Erk1/2 signaling pathway inhibitor PD98059 improves DNA repair in an experimental autoimmune encephalomyelitis SJL/J mouse model of multiple sclerosis

The small molecule Erk1/2 signaling pathway inhibitor PD98059 improves DNA repair in an experimental autoimmune encephalomyelitis SJL/J mouse model of multiple sclerosis

  • Mutat Res Genet Toxicol Environ Mutagen. 2023 Jul:889:503650. doi: 10.1016/j.mrgentox.2023.503650.
S M Attia 1,  S F Ahmad 2,  A Nadeem 2,  M S M Attia 2,  M A Ansari 2,  N B Alsaleh 2,  A F Alasmari 2,  M A Al-Hamamah 2,  A Alanazi 2,  A A Alshamrani 2,  S A Bakheet 2,  G I Harisa 3
Affiliations

Affiliations

  • 1 Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, 11451 Riyadh, Saudi Arabia. Electronic address: [email protected].
  • 2 Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, 11451 Riyadh, Saudi Arabia.
  • 3 Department of Pharmaceutics, College of Pharmacy, King Saud University, 11451 Riyadh, Saudi Arabia.
PMID: 37491119 DOI: 10.1016/j.mrgentox.2023.503650
Abstract

Multiple sclerosis (MS) is a demyelinating disorder in which the myelin sheath covering the central nervous system axons is damaged or lost, disrupting action potential conduction and leading to various neurological complications. The pathogenesis of MS remains unclear, and no effective therapies are currently available. MS is triggered by environmental factors in genetically susceptible individuals. DNA damage and DNA repair failure have been proposed as MS genetic risk factors; however, inconsistent evidence has been found in multiple studies. Therefore, more investigations are needed to ascertain whether DNA damage/repair is altered in this disorder. In this context, therapies that prevent DNA damage or enhance DNA repair could be effective strategies for MS treatment. The overactivation of the extracellular-signal-related kinase 1 and 2 (ERK1/2) pathway can lead to DNA damage and has been linked to MS pathogenesis. In our study, we observed substantially elevated oxidative DNA damage and slower DNA repair rates in an experimentally autoimmune encephalomyelitis animal model of MS (EAE). Moreover, statistical decreases in oxidative DNA strand breaks and faster repair rates were observed in EAE Animals injected with the ERK1/2 inhibitor PD98059 (PD). Moreover, the expression of several genes associated with DNA strand breaks and repair changed in EAE mice at both the mRNA and protein levels, as revealed by the RT2 Profiler PCR array and verified by RT-PCR and protein analyses. The treatment with PD mitigated these changes and improved DNA repair gene expression. Our results demonstrate clear associations between ERK1/2 activation, DNA damage/repair, and MS pathology, and further suggest that PD therapy may be a promising Adjuvant therapeutic strategy.

Keywords

DNA damage; Erk1/2 inhibitor PD98059; Modified comet assay; Multiple sclerosis pathology; Oxidative stress.

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