Page 51 - _NIPER-G Annual Report 2019-201

Research Area -2

Local administration of 4-Thiouridine, a novel molecule with potent anti-inflammatory
properties, protects against experimental colitis and arthritis (Collaboration with University of
Lausanne, Switzerland)
Previous studies in a rat model of Sephadex induced lung inflammation showed that 4-
Thiouridine (4SU), a thiol substituted nucleoside, was very effective in reducing edema,
leukocyte influx and TNF levels in bronchoalvelolar lavage fluid. However, little is known about
the factors and mechanisms underlying these effects. In the present study, we have used two
separate mouse models of chronic inflammation, a model of dextran sulphate sodium (DSS)
induced colitis and a model of antigen induced arthritis, to evaluate the anti-inflammatory effect
of 4-thiouridine. We have analyzed a broad spectrum of inflammatory mediators in order to
delineate the mechanisms behind a potential anti-inflammatory effect of 4SU. Colitis was
induced in C57BL/6 mice by administration of 3.5% DSS in drinking water for 5 days and the
potential anti-colitic effect of 4SU was assessed by monitoring the disease activity index (DAI),
measurement of colon length and histopathological analysis of colon tissue. We analyzed
tissue myeloperoxidase (MPO) activity, serum pro-inflammatory cytokines (IL-1β, IL-6 and
TNF), mRNA and protein expression of pro-inflammatory cytokines, COX-2, and NF-κB activity
in colitis tissue. Intracolonic administration of 4SU (5 mg/kg & 10 mg/kg.) significantly inhibited
MPO activity and reduced the levels of pro-inflammatory cytokines (IL-1β, IL-6 and TNF) as
well as COX-2. Further, NF-κB activation was also blocked by attenuating the phosphorylation
of IkB kinase (IKK α/β) in DSS-induced colitis tissues. Arthritis was induced by intra-articular
injection of mBSA in the knee of NMRI mice pre-immunized with mBSA and 4SU was
administered locally by direct injection into the knee joint. The antiarthritic potential of 4SU
was calculated by histopathological scores and histochemical analysis of joint tissue. Further,
immunohistochemistry was used to study inflammatory cell infiltration and expression of
cytokines and adhesion molecules in the synovium. Local administration of 50–100 mg/kg
4SU at the time of arthritis onset clearly prevented development of joint inflammation and
efficiently inhibited synovial expression of CD18, local cytokine production and recruitment of
leukocytes to the synovium. Taken together, our data clearly demonstrates a potent anti-
inflammatory effect of 4SU in two experimental models. In conclusion 4SU could be a new
promising candidate for therapeutic modulation of chronic inflammatory diseases like
ulcerative colitis and arthritis.

Jeengar MK, Narendra SC, Thummuri D, Magnusson M, Naidu VG, Uppugunduri S. Local
administration of 4-Thiouridine, a novel molecule with potent anti-inflammatory properties,
protects against experimental colitis and arthritis. International Immunopharmacology. 2020;
85:106598.

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