Poly(ADP-ribose) polymerase-1 inhibitor modulates T regulatory and IL-17 cells in the prevention of adjuvant induced arthritis in mice model.
Rheumatoid arthritis (RA) is one of the major autoimmune diseases of global prevalence. Irrespective of much research in RA disease, no drugs with capable safety profiles are yet available. Poly(ADP-ribose) polymerase-1 (PARP-1) synthesizes and transfers ADP ribose polymers to target proteins, and regulates DNA repair and genomic integrity maintenance. PARP-1 also plays a crucial role in the progression of the inflammatory response, and its inhibition confers protection in several models of inflammatory disorders. We investigated the possible anti-arthritic effects of the PARP-1 inhibitor 5-aminoisoquinolinone (5-AIQ) in a mouse model of adjuvant induced arthritis (AIA). In this study, we examined the effects of 5-AIQ on the key mediators of arthritic inflammation, namely, edema and arthritic score, T cell subsets, regulatory T (Treg) cells, IL-17A, GITR expressing cells, NF-kB p65, IkB-α and pro and anti-inflammatory mediators mRNA expression levels. PARP-1 inhibition 5-AIQ treatment significantly attenuated the severity of AIA, reduced the arthritis scores, a substantial reduction in the levels of T cell subsets, IL-17A, NF-kB p65, GITR expressing cells, and as well as the pro-inflammatory mediators. However, 5-AIQ significantly up-regulated the number of Tregs cells, IkB-α levels and mRNA expression of anti-inflammatory mediators. Our results suggest that treatment with 5-AIQ attenuated AIA in mice might offer a promising alternative/adjunct treatment for RA.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 11451, Riyadh, Saudi Arabia. Electronic address: s_fayazahmad@yahoo.com.
Sheikh Fayaz
SF
Ahmad
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 11451, Riyadh, Saudi Arabia; Department of Cell Biology, National Research Centre, Cario, Egypt.
Khairy M A
KM
Zoheir
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 11451, Riyadh, Saudi Arabia.
Saleh A
SA
Bakheet
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 11451, Riyadh, Saudi Arabia.
Abdelkader E
AE
Ashour
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 11451, Riyadh, Saudi Arabia; Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Cairo, Egypt.
Sabry M
SM
Attia
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000517:prevention & control*; D015704:CD4 Antigens / Q000378:metabolism; D004195:Disease Models, Animal; D004487:Edema / Q000276:immunology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology*; D018655:Lymphocyte Count; D008807:Mice, Inbred BALB C; D000072000:NF-KappaB Inhibitor alpha; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D051996:Transcription Factor RelA / Q000378:metabolism
C411425:5-aminoisoquinolinone; D015704:CD4 Antigens; D004791:Enzyme Inhibitors; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050990:GATA3 Transcription Factor; D053450:Glucocorticoid-Induced TNFR-Related Protein; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D007546:Isoquinolines; C000606205:Nfkbia protein, mouse; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012333:RNA, Messenger; C106544:Tnfrsf18 protein, mouse; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D011065:Poly(ADP-ribose) Polymerases
5-Aminoisoquinolinone; Adjuvant induced arthritis; Inflammatory mediators; PARP-1 inhibitor; Regulatory T cells