Astrocyte ablation induced by La-aminoadipate (L-AAA) potentiates remyelination in a cuprizone demyelinating mouse model

• Published in: Metabolic brain disease 2019-04, Vol.34 (2), p.593-603
• Main Authors: Madadi, Soheila, Pasbakhsh, Parichehr, Tahmasebi, Fatemeh, Mortezaee, Keywan, Khanehzad, Maryam, Boroujeni, Fatemeh Beigi, Noorzehi, Golaleh, Kashani, Iraj Ragerdi
• Format: Article
• Language: English
• Subjects: Ablation; Animals; Astrocytes; Astrocytes - drug effects; Astrocytes - metabolism; Biochemistry; Biomarkers; Biomedical and Life Sciences; Biomedicine; Brain - drug effects; Brain - metabolism; Cell differentiation; Cells (biology); Central nervous system; Chemokines; Corpus callosum; Cuprizone; Cuprizone - pharmacology; CXCL10 protein; CXCL12 protein; Demyelinating diseases; Demyelinating Diseases - chemically induced; Demyelinating Diseases - pathology; Demyelination; Disease Models, Animal; Fibers; Gene expression; Glial fibrillary acidic protein; Glial stem cells; Gliosis; Immunofluorescence; Male; Medical materials; Metabolic Diseases; Mice; Mice, Inbred C57BL; Microglia; Microglia - metabolism; Multiple sclerosis; Myelin; Myelination; Neurology; Neurosciences; Olig2 protein; Oligodendroglia - metabolism; Oncology; Original Article; Peptides; Pharmacology; Progenitor cells; Proteins; Remyelination - drug effects; Transmission electron microscopy; Tubes
• ISSN: 0885-7490; 1573-7365
• DOI: 10.1007/s11011-019-0385-9

Chronic demyelination in the central nervous system (CNS) is accompanied by an increase in the number of reactive astrocytes and astrogliosis. There are controversial issues regarding astrocytes and their roles in demyelinating diseases in particular for multiple sclerosis (MS). We aimed to evaluate possible roles for pharmacologic astrocyte ablation strategy using La-aminoadipate (L-AAA) on remyelination in a cuprizone model of demyelination. Male C57BL/6 mice were fed with 0.2% cuprizone for 12 weeks followed by 2-week administration of L-AAA through a cannula inserted 1 mm above the corpus callosum. Rotarod test showed a significant decrease in the range of motor coordination deficits after ablation of astrocytes in mice receiving cuprizone. Results of Luxol fast blue (LFB) and transmission electron microscopy (TEM) for evaluation of myelin content within the corpus callosum revealed a noticeable rise in the percentage of myelinated areas and in the number of myelinated fibers after L-AAA administration in the animals. Astrocyte ablation reduced protein expressions for GFAP (an astrocyte marker) and Iba-1 (a microglial marker), but increased expression of Olig2 (an oligodendrocyte marker) assessed by immunofluorescence. Finally, expression of genes related to recruitment of microglia (astrocyte chemokines CXCL10 and CXCL12) and suppression of oligodendrocyte progenitor cell (OPC) differentiation (astrocyte peptides ET-1 and EDNRB ) showed a considerable decrease after administration of L-AAA (for all p