Tyrphostin A9 protects axons in experimental autoimmune encephalomyelitis through activation of ERKs

Xiaodong Dai, Yongmei Wang, Yuexin Li, Yongping Zhong, Min Pei, Jing Long, Xingchen Dong, Yi Li Chen, Qi Wang, Guifeng Wang, Bruce G. Gold, Arthur A. Vandenbark, Kim A. Neve, Halina Offner, Chunhe Wang

Research output: Contribution to journalArticlepeer-review

Abstract

Aims: Small molecule compound tyrphostin A9 (A9), an inhibitor of platelet-derived growth factor (PDGF) receptor, was previously reported by our group to stimulate extracellular signal-regulated kinase 1 (ERK1) and 2 (ERK2) in neuronal cells in a PDGF receptor-irrelevant manner. The study aimed to investigate whether A9 could protect axons in experimental autoimmune encephalomyelitis through activation of ERKs. Main methods: A9 treatment on the protection on neurite outgrowth in SH-SY5Y neuroblastoma cells and primary substantia nigra neuron cultures from the neurotoxin MPP+ were analyzed. Then, clinical symptoms as well as ERK1/2 activation, axonal protection induction, and the abundance increases of the regeneration biomarker GAP-43 in the CNS in the relapsing-remitting experimental autoimmune encephalomyelitis (EAE) model were verified. Key findings: A9 treatment could stimulate neurite outgrowth in SH-SY5Y neuroblastoma cells and protect primary substantia nigra neuron cultures from the neurotoxin MPP+. In the relapsing-remitting EAE model, oral administration of A9 successfully ameliorated clinical symptoms, activated ERK1/2, induced axonal protection, and increased the abundance of the regeneration biomarker GAP-43 in the CNS. Interestingly, gene deficiency of ERK1 or ERK2 disrupted the beneficial effects of A9 in MOG-35-55-induced EAE. Significance: These results demonstrated that small molecule compounds that stimulate persistent ERK activation in vitro and in vivo may be useful in protective or restorative treatment for neurodegenerative diseases.

Original languageEnglish (US)
Article number120383
JournalLife Sciences
Volume294
DOIs
StatePublished - Apr 1 2022
Externally publishedYes

Keywords

  • Experimental autoimmune encephalomyelitis (EAE)
  • Extracellular signal-regulated kinase
  • Multiple sclerosis (MS)
  • Tyrphostin A9

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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