CHX-3107

Phosphate ester of vitamin C and vitamin E (EPCK1), a strong antioxidant, is a water- and lipid-soluble phosphate ester of vitamin C and vitamin E. In the current study, we tested whether EPCK1 inhibits oxidative stress and prevents systemic inflammation.

Mice were randomly divided into a negative control group, a lipopolysaccharide (LPS)-induced sepsis group, and a group treated with an intraperitoneal infusion of EPCK1 (10 mg/kg) prior to or following LPS administration. In addition, RAW 264.7 cells were treated with LPS in the presence or absence of EPCK1. We examined levels of high mobility group box 1 (HMGB1) protein and inducible nitric oxide synthase (iNOS) in both in vivo and in vitro experiments, and liver histopathology in the in vivo experiment.

Liver histopathology significantly improved in the EPCK1 group compared with the LPS group. Although LPS administration increased HMGB1 and nitric oxide (NO) secretion, EPCK1 decreased the secretion of these mediators in vitro and in vivo.

Our findings suggest that EPCK1 may inhibit inflammation and potentially function as a novel anti-inflammatory therapeutic agent.

L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethy-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6yl-hydrogen phosphate] potassium salt (EPC-K1) is a novel phosphate diester derivative of ascorbic acid (vitamin C) and a-tocopherol (vitaminE),whoseantioxidantpropertieshavebeenshown to lower markers of systemic inflammation as demonstrated by Shingu et al. in a recently published article in the Journal of Surgical Research [1]. Both in vivo and in vitro experiments exhibited lower levels of high mobility group box 1 (HMGB1) and inducible nitric oxide synthase (iNOS),which are normally elevated during periods of ischemic-reperfusion injuries when mice were pretreated with EPC-K1 [1]. This result agrees with several other studies that examined the effects free radical-mediated organ damage [2e18]. Knowledge of the importance of the free radical-mediated response,which is seen in cellular death associatedwith ischemic-reperfusion injuries, dates back to the 1980s [2]. Since then, a number of studies have explored the role of free radical species in several organ systems [3e12].Detrimental effects of free radicals in skeletal muscle [3e5], myocardium [6e9], and the central nervous system (CNS) [10e12] have been well documented. In all of these tissues, the administration of EPC-K1 reduced free radical-induced injuries during periods of ischemia-reperfusion. While the precise mechanism by which EPC-K1 exerts its antiinflammatory effects remains to be elucidated, part of the answer can be attributed to the chemical structure. As a derivative of vitamins C and E, EPC-K1 possesses both a hydrophilic and hydrophobic chain, rendering it soluble in both water and lipid [13]. This dual solubility enables it to react effectively by limiting various harmful effectors, including hydroxyl, alkyl, and lipid radicals [13e16]. The ability to reduce multiple types of free radicals provides insight intohowEPC-K1 is effective in limiting systemic inflammation and injury, not just organ-specific inflammation [3e12]. Cardiac cells, for example, have a tendency to producemorehydroxyl radicals as they mainly function in oxygen-rich environments. That is in stark contrast to the CNS, which consists largely of lipids and is, therefore, easily damaged by lipid radicals and peroxidation [14]. In view of these unique characteristics, EPC-K1 showcases high potential to be an effective therapeutic agent in the context of ischemia-reperfusion injuries. Wide applicability to multiple organs offers antioxidant, antiinflammatory, and cell-protective defense against free radical-mediated cellular damage. In spite of this prospect, research on EPC-K1 peaked in the mid-1990s, with diminishing interest now shown in Western countries.