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

• Published in: Life sciences (1973) 2022-04, Vol.294, p.120383-120383, Article 120383
• Main Authors: Dai, Xiaodong, Wang, Yongmei, Li, Yuexin, Zhong, Yongping, Pei, Min, Long, Jing, Dong, Xingchen, Chen, Yi-Li, Wang, Qi, Wang, Guifeng, Gold, Bruce G., Vandenbark, Arthur A., Neve, Kim A., Offner, Halina, Wang, Chunhe
• Format: Article
• Language: English
• Subjects: Animals; Axonogenesis; Axons; Axons - drug effects; Biomarkers; Disease Models, Animal; Encephalomyelitis; Encephalomyelitis, Autoimmune, Experimental - etiology; Encephalomyelitis, Autoimmune, Experimental - metabolism; Encephalomyelitis, Autoimmune, Experimental - pathology; Encephalomyelitis, Autoimmune, Experimental - prevention & control; Experimental allergic encephalomyelitis; Experimental autoimmune encephalomyelitis (EAE); Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; GAP-43 protein; Gene Expression Regulation - drug effects; Growth factors; Health services; Humans; Kinases; Mice; Mice, Inbred C57BL; MPP; Multiple sclerosis (MS); Neuroblastoma; Neuroblastoma - drug therapy; Neuroblastoma - metabolism; Neuroblastoma - pathology; Neuroblastoma cells; Neurodegenerative diseases; Neurotoxins; Oligodendrocyte-myelin glycoprotein; Oral administration; Platelet-derived growth factor; Rats; Rats, Sprague-Dawley; Receptors; Regeneration; Signs and symptoms; Substantia nigra; Toxins; Tyrphostin A9; Tyrphostins - pharmacology
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2022.120383

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. 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. 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. 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.