1. Tyrphostin A9 protects axons in experimental autoimmune encephalomyelitis through activation of ERKs.
- Author
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Dai X, Wang Y, Li Y, Zhong Y, Pei M, Long J, Dong X, Chen YL, Wang Q, Wang G, Gold BG, Vandenbark AA, Neve KA, Offner H, and Wang C
- Subjects
- Animals, Encephalomyelitis, Autoimmune, Experimental etiology, Encephalomyelitis, Autoimmune, Experimental metabolism, Encephalomyelitis, Autoimmune, Experimental pathology, Extracellular Signal-Regulated MAP Kinases genetics, Female, Humans, Mice, Mice, Inbred C57BL, Neuroblastoma metabolism, Neuroblastoma pathology, Rats, Rats, Sprague-Dawley, Axons drug effects, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental prevention & control, Extracellular Signal-Regulated MAP Kinases metabolism, Gene Expression Regulation drug effects, Neuroblastoma drug therapy, Tyrphostins pharmacology
- 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., (Copyright © 2022 Elsevier Inc. All rights reserved.)- Published
- 2022
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