UTL-5g Lowers Elevated Blood Levels of TNF-a and TGF-β and Increases Survival Rates in Animals Treated with LPS/D-(+)-galactosamine

¹ Institute of Materia Medica & Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Chongqing, China

² New Phiaring Bio-medical Science Co., Ltd, Chengdu, China

³ 21^st Century Therapeutics, Ferndale, Michigan, USA

⁴ Henry Ford Health System, Detroit, Michigan, USA

*Corresponding author:

Jiajiu Shaw

21^st Century Therapeutics, Inc.

Ferndale, Michigan

USA

Phone 1-248-545-0595

E-mail: jiajiuhaw@gmail.com

Abstract

N-(2,4-dichlorophenyl)-5-methyl-1,2-oxazole-3-carboxamide (UTL-5g) is a small-molecule chemoprotector against cisplatin and radioprotector against radiation. To further investigate its protective effects, we evaluated whether UTL-5g protects mice in a septic shock animal model. The two metabolites of UTL-5g, 5-methylisoxazole-3-carboxylic acid (Isox) and 2,4-dichloroaniline (DCA) were also evaluated side-by-side with UTL-5g. First, mice were pretreated with UTL-5g, Isox, and DCA before the i.p. injection of lipopolysaccharide (LPS)/D-(+)-galactosamine hydrochloride (D-Gal), respectively. Oral administration of both UTL-5g and Isox increased mouse survival while DCA did not, indicating that Isox is an active metabolite of UTL-5g while DCA is not. In the second study, mice were pretreated with UTL-5g or Isox individually by i.p. injection each at 30 mg/kg before LPS/D-Gal injection. The survival rates for both UTL-5g and Isox were better than those found for oral administration. In the third study, the same molar dose of UTL-5g and Isox by i.p. injection was used respectively and the results showed that UTL-5g had a better protective effect than Isox. In the fourth study, a protocol similar to the third study was used but blood samples were collected from the orbital plexus two hr after LPS/D-gal treatment. The results showed that UTL-5g lowered blood levels of both TNF-a and TGF-b elevated by LPS/D-gal. In summary, pretreatment of UTL-5g protected mice treated with LPS/D-Gal and the protection was related to the lowering of TNF-a and TGF-b levels elevated by LPS/D-Gal. In addition, UTL-5g appeared to be both an active drug and a prodrug wherein Isox is the active metabolite.

Keywords: UTL-5g, sepsis animal model, LPS/D-Gal, survival, TNF-a, TGF-β.

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