Orally administered sodium 4‑phenylbutyrate suppresses the development of dextran sulfate sodium‑induced colitis in mice

Abstract

Abstract. Sodium 4-phenylbutyrate (PBA) exerts therapeutic effects in a wide range of pathologies. A previous study by the present authors revealed that intraperitoneal administration of PBA suppresses the onset of dextran sulfate sodium (DSS)-induced colitis in mice. In the present study, the effects of orally administered PBA are investigated, as this route of administration is more clinically relevant. The therapeutic efficacy of PBA (10 mg/12 h) in mice with experimental colitis was assessed based on the disease activity index, production of inflammatory cytokines, colon length and histopathological investigations. The results of the present study demonstrated a significantly higher survival rate in the PBA-treated group compared with the PBA-untreated (DSS control) group (P=0.0156). PBA treatment improved pathological indices of experimental colitis (P<0.05). Furthermore, the oral administration of PBA significantly inhibited the DSS-induced shortening of the colon (P<0.05) and overproduction of interleukin (IL)-1β and IL-6 (both P<0.05) as measured in colonic lavage fluids. A marked attenuation of the DSS-induced overproduction of tumor necrosis factor was also observed. For histopathological analysis, a marked decrease in mature goblet cells and increase in enlarged nuclei of the absorptive cells was observed in colon lesions of DSS control mice as compared with normal untreated mice. However, in the PBA-treated mice, no such lesions were observed and the mucosa resembled that of DSS-untreated mice. The results of the present study, combined with those results of a previous study, suggest that oral and intraperitoneal administration of PBA have similar preventative effects on DSS-induced colitis, achieved by suppressing its pathogenesis.

A Colon-Targeted Prodrug, 4-Phenylbutyric Acid-Glutamic Acid Conjugate, Ameliorates 2,4-Dinitrobenzenesulfonic Acid-Induced Colitis in Rats

“…Moreover, oral PBA-GA administration decreased the elevated levels of the ER stress marker proteins in the inflamed colons to their normal levels. These findings may explain why such high doses of 4-PBA (500–1000 mg/kg) are needed to show efficacy in murine colitis [ 29 , 31 ], given that the elimination half-life is very short owing to rapid metabolism, although the oral administration of 5000 mg of 4-PBA affords concentrations of 1.18–1.32 mM 4-PBA in blood in humans [ 45 ]. Oral PBA-GA administration not only provides higher 4-PBA concentrations at the inflamed site but also avoids such rapid metabolism, thereby maintaining active therapeutic concentrations in the inflamed site for longer periods, even at much lower doses.…”

“…4-phenylbutyric acid (4-PBA), an FDA-approved drug for the treatment of urea cycle disorders, is a representative chemical chaperone. Owing to its safety and effectiveness against ER stress [ 28 ], the anti-colitic activity of 4-PBA has been investigated [ 29 , 30 , 31 ]. Consistent with the therapeutic hypothesis, 4-PBA reduces ER stress in the inflamed large intestine and shows considerable anti-colitic effects in animal models.…”

Experimental Trypanosoma cruzi Infection Induces Pain in Mice Dependent on Early Spinal Cord Glial Cells and NFκB Activation and Cytokine Production

“…Samples were then centrifuged for separation of plasma, and the resultant supernatant was separated for the tests. TNF-α and IL-1β levels were determined through an enzyme-linked immunosorbent assay (ELISA) test using paired antibodies following the manufacturer’s instructions (eBioscience Inc.; Thermo Fisher Scientific, Waltham, MA, USA) ( 36 ). In summary, 96-well plates were first coated overnight in a refrigerator mixed with an immunoaffinity-purified polyclonal sheep antibody specifically for each cytokine.…”

A Colon-Targeted Prodrug, 4-Phenylbutyric Acid-Glutamic Acid Conjugate, Ameliorates 2,4-Dinitrobenzenesulfonic Acid-Induced Colitis in Rats

“…Because of its safety and effectiveness against ER stress [28], the anti-colitic activity of 4-PBA was investigated [29][30][31]. Consistent with the therapeutic hypothesis, 4-PBA reduces ER stress in the inflamed large intestine and shows considerable anti-colitic effects in animal models.…”