title: Adrenocorticotropin hormone 1-39 promotes proliferation and differentiation of oligodendroglial progenitor cells and protects from excitotoxic and inflammation-related damage.
abstract: Oligodendroglia (OL) are highly susceptible to damage and, like neurons, are terminally differentiated. It is important to protect OL precursors (OPC) because they are reservoirs of differentiating cells capable of myelination following perinatal insult and remyelination in white matter diseases, including multiple sclerosis (MS). Patients with relapsing-remitting MS are commonly treated with high-dose corticosteroids (CS) when experiencing an exacerbation. Adrenocorticotropin hormone (ACTH), a primary component of another approved MS exacerbation treatment, is a melanocortin peptide that stimulates production of CS by the adrenals. Melanocortin receptors are also found in the central nervous system (CNS) and on immune cells. ACTH is produced within the CNS and may have CS-independent effects on glia. We found that ACTH 1-39 stimulated proliferation of OPC, and to a lesser extent astroglia (AS) and microglia (MG), in rat glial cultures. ACTH accelerated differentiation of PDGFRα(+) OPC to a later stage marked by galactolipid expression and caused greater expansion of OL myelin-like sheets compared with untreated cells. Protective effects of ACTH on OPC were assessed by treating cultures with selected toxic agents, with or without ACTH. At 200 nM, ACTH protected OPC from death induced by staurosporine, glutamate, NMDA, AMPA, kainate, quinolinic acid, H2 O2 , and slow NO release, but not against kynurenic acid or rapid NO release. These agents and ACTH were not toxic to AS or MG. Our findings indicate that ACTH 1-39 provides benefits by increasing the number of OPC, accelerating their development into mature OL, and reducing OPC death from toxic insults.
authors.affiliation: Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan; Department of Immunology and Microbiology, Wayne State University School of Medicine Detroit, Michigan.
authors.forename: Joyce A
authors.initials: JA
authors.lastname: Benjamins
authors.forename: Liljana
authors.initials: L
authors.lastname: Nedelkoska
authors.forename: Robert P
authors.initials: RP
authors.lastname: Lisak
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology; D004791:Enzyme Inhibitors / Q000633:toxicity; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D037102:Lectins / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D019311:Staurosporine / Q000633:toxicity; D013234:Stem Cells / Q000187:drug effects*; D013997:Time Factors; D059467:Transcriptome / Q000187:drug effects; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity
chemical_list: D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D005904:Glial Fibrillary Acidic Protein; D037102:Lectins; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D000324:Adrenocorticotropic Hormone; D020796:Receptor, Platelet-Derived Growth Factor alpha; D019311:Staurosporine
keywords: MC4R; corticosteroids; glutamate; melanocortin receptors; multiple sclerosis; neuroinflammation