Xiaodong Dai1, Yongmei Wang1, Yuexin Li2, Yongping Zhong3, Min Pei1, Jing Long1, Xingchen Dong1, Yi-Li Chen1, Qi Wang1, Guifeng Wang4, Bruce G Gold3, Arthur A Vandenbark5, Kim A Neve6, Halina Offner7, Chunhe Wang8. 1. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200126, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China. 2. Department of Neurology, Oregon Health & Science University, Portland, OR 97239, United States of America; Research Service, VA Portland Health Care System, Portland, OR 97239, United States of America. 3. Department of Neurology, Oregon Health & Science University, Portland, OR 97239, United States of America. 4. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200126, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China. Electronic address: gfwang@simm.ac.cn. 5. Department of Neurology, Oregon Health & Science University, Portland, OR 97239, United States of America; Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR 97239, United States of America; Research Service, VA Portland Health Care System, Portland, OR 97239, United States of America. 6. Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, United States of America; Research Service, VA Portland Health Care System, Portland, OR 97239, United States of America. 7. Department of Neurology, Oregon Health & Science University, Portland, OR 97239, United States of America; Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR 97239, United States of America; Research Service, VA Portland Health Care System, Portland, OR 97239, United States of America. 8. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200126, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China; Department of Neurology, Oregon Health & Science University, Portland, OR 97239, United States of America; Research Service, VA Portland Health Care System, Portland, OR 97239, United States of America. Electronic address: wangc@simm.ac.cn.
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.
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.
Authors: G Martiny-Baron; M G Kazanietz; H Mischak; P M Blumberg; G Kochs; H Hug; D Marmé; C Schächtele Journal: J Biol Chem Date: 1993-05-05 Impact factor: 5.157