title: Restoration of axon conduction and motor deficits by therapeutic treatment with glatiramer acetate.
abstract: Glatiramer acetate (GA; Copaxone) is an approved drug for the treatment of multiple sclerosis (MS). The underlying multifactorial anti-inflammatory, neuroprotective effect of GA is in the induction of reactive T cells that release immunomodulatory cytokines and neurotrophic factors at the injury site. These GA-induced cytokines and growth factors may have a direct effect on axon function. Building on previous findings that suggest a neuroprotective effect of GA, we assessed the therapeutic effects of GA on brain and spinal cord pathology and functional correlates using the chronic experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Therapeutic regimens were utilized based on promising prophylactic efficacy. More specifically, C57BL/6 mice were treated with 2 mg/mouse/day GA for 8 days beginning at various time points after EAE post-induction day 15, yielding a thorough, clinically relevant assessment of GA efficacy within the context of severe progressive disease. Therapeutic treatment with GA significantly decreased clinical scores and improved rotorod motor performance in EAE mice. These functional improvements were supported by an increase in myelinated axons and fewer amyloid precursor protein-positive axons in the spinal cords of GA-treated EAE mice. Furthermore, therapeutic GA decreased microglia/macrophage and T cell infiltrates and increased oligodendrocyte numbers in both the spinal cord and corpus callosum of EAE mice. Finally, GA improved callosal axon conduction and nodal protein organization in EAE. Our results demonstrate that therapeutic GA treatment has significant beneficial effects in a chronic mouse model of MS, in which its positive effects on both myelinated and non-myelinated axons results in improved axon function.
authors.affiliation: Department of Neurology, UCLA School of Medicine, Los Angeles, California.
authors.forename: Spencer
authors.initials: S
authors.lastname: Moore
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Khalaj
authors.forename: Rhusheet
authors.initials: R
authors.lastname: Patel
authors.forename: JaeHee
authors.initials: J
authors.lastname: Yoon
authors.forename: Daniel
authors.initials: D
authors.lastname: Ichwan
authors.forename: Liat
authors.initials: L
authors.lastname: Hayardeny
authors.forename: Seema K
authors.initials: SK
authors.lastname: Tiwari-Woodruff
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000150:complications*; D000068717:Glatiramer Acetate; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009069:Movement Disorders / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D004676:Myelin Basic Protein / Q000378:metabolism; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009431:Neural Conduction / Q000187:drug effects*; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000473:pathology; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000473:pathology; D013997:Time Factors
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000068717:Glatiramer Acetate; D007166:Immunosuppressive Agents; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D010455:Peptides; C499047:Mbp protein, mouse; C512773:Olig2 protein, mouse; C047516:Plp1 protein, mouse
keywords: axon conduction; demyelination; experimental autoimmune encephalomyelitis (EAE); glatiramer acetate; inflammation; motor deficit; multiple sclerosis (MS); neural repair; neurodegeneration; rotarod; therapeutics