title: The immunomodulator glatiramer acetate augments the expression of neurotrophic factors in brains of experimental autoimmune encephalomyelitis mice.
abstract: Neurotrophins (NTs) such as BDNF, NT-3, and NT-4 are important modulators of neuronal function and survival. Their expression in the CNS after various insults is thus of major therapeutic consequence. Glatiramer acetate [(GA) Copaxone], an approved drug for the treatment of multiple sclerosis, has been shown to induce Th2/3 cells that accumulate in the CNS, expressing in situ antiinflammatory cytokines and BDNF. In the present study, we investigated whether s.c. injections of GA, applied at various stages of experimental autoimmune encephalomyelitis, affect the expression of NTs, particularly BDNF, in the brain. In untreated experimental autoimmune encephalomyelitis mice, the expression of NTs was elevated shortly after disease appearance but subsequently declined below that of naive mice. In contrast, GA treatment led to sustained augmentation in the expression of BDNF, NT-3, and NT-4 in various brain regions as demonstrated by histological analysis of immunostained brain sections. GA treatment, even when started 45 days after disease induction, restored the impaired level of NTs to that of healthy mice. BDNF elevation after GA treatment was demonstrated on both protein and mRNA levels. Prominent staining was manifested not only by infiltrating GA-induced T cells, but also by CNS resident cells (neurons and astrocytes), indicative of a bystander therapeutic effect. Of importance, in GA-treated mice, intense BDNF expression was manifested by neuronal progenitors that migrated into lesions in injured regions. These results indicate that the immunomodulator GA exerts not only an antiinflammatory effect, but also enhances neuroprotection and regeneration of neural elements in the diseased brain.
authors.affiliation: Departments of Immunology and Veterinary Resources, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Rina
authors.initials: R
authors.lastname: Aharoni
authors.forename: Raya
authors.initials: R
authors.lastname: Eilam
authors.forename: Hagit
authors.initials: H
authors.lastname: Domev
authors.forename: Galya
authors.initials: G
authors.lastname: Labunskay
authors.forename: Michael
authors.initials: M
authors.lastname: Sela
authors.forename: Ruth
authors.initials: R
authors.lastname: Arnon
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002470:Cell Survival; D002490:Central Nervous System / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005260:Female; D000068717:Glatiramer Acetate; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology*; D017403:In Situ Hybridization; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000737:chemistry; D063308:Myelin-Oligodendrocyte Glycoprotein; D009414:Nerve Growth Factors / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D020933:Neurotrophin 3 / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D011108:Polymers / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D019208:Brain-Derived Neurotrophic Factor; D007166:Immunosuppressive Agents; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D020933:Neurotrophin 3; D010455:Peptides; D011108:Polymers; D000068717:Glatiramer Acetate; C073922:neurotrophin 4