title: Polymerase I pathway inhibitor ameliorates experimental autoimmune encephalomyelitis.
abstract: Applying high throughput gene expression microarrays we identified that the suppression of polymerase 1 (POL1) pathway is associated with benign course of multiple sclerosis (MS). This finding supports the rationale for direct targeting of the POL1 transcription machinery as an innovative strategy to suppress MS. To evaluate the effects of a specific polymerase I inhibitor (POL1-I) on experimental autoimmune encephalomyelitis (EAE), we immunized female C57BL/6J mice (8 weeks) with MOG35-55/CFA. A new POL1-I was administered at a daily dose of 12.5mg/kg body weight by oral gavage either from the day of immunization until disease onset (EAE score 1.0, immunization model), at disease onset (EAE score=1.0) for the following 14 days (treatment model), or by alternate daily dose of 25.0mg/kg body weight, by oral gavage from the day of immunization for the following 25 days (combined model). POL1-I remarkably suppressed EAE in the immunization model; while in the Vehicle group the onset of EAE occurred on day 10.0±0.4 with maximal clinical score of 3.2±0.2, in the POL1-I treated mice onset was significantly delayed and occurred on day 16.9±1.1 (p=0.001), and maximal disease score 2.0±0.1 was reduced (p=0.004). In the treatment model POL1-I treatment significantly reduced disease activity; maximal score was 2.0±0.5 while in the Vehicle group it reached a mean maximal score of 3.9±0.1, (p=0.0008). In the combined model, POL1-I treatment completely inhibited disease activity. The effect of POL1-I treatment was modulated through decreased expression of POL1 pathway key-related genes LRPPRC, pre-RNA, POLR1D and RRN3 together with activation of P53 dependent apoptosis of CD4+ splenocytes. Our findings demonstrate that POL1 pathway inhibition delayed and suppressed the development of EAE and ameliorated the disease in mice with persistent clinical signs.
authors.affiliation: Multiple Sclerosis Center, Neurogenomics Laboratory, Sheba Medical Center, Tel-Hashomer, Israel; Sackler School of Medicine, Tel-Aviv University, Israel. Electronic address: Anat.Achiron@sheba.health.gov.il.
authors.forename: Anat
authors.initials: A
authors.lastname: Achiron
authors.forename: Roi
authors.initials: R
authors.lastname: Mashiach
authors.forename: Rina
authors.initials: R
authors.lastname: Zilkha-Falb
authors.forename: Michael M
authors.initials: MM
authors.lastname: Meijler
authors.forename: Michael
authors.initials: M
authors.lastname: Gurevich
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000627:therapeutic use*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000201:enzymology* / Q000276:immunology; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009287:Naphthyridines / Q000627:therapeutic use*; D009434:Neural Pathways / Q000276:immunology; D012318:RNA Polymerase I / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D052160:Benzothiazoles; C557717:CX 5461; D009287:Naphthyridines; D012318:RNA Polymerase I
keywords: Apoptosis; Experimental autoimmune encephalomyelitis; Multiple sclerosis; Polymerase 1 inhibitor; Polymerase 1 pathway