Preventive Effects of Ethyl Pyruvate on Endotoxin-Induced Uveitis in Rats

Ethyl pyruvate (EP) is a membrane-permeant aliphatic ester derived from the endogenous metabolite pyruvic acid (Fig. 1). Exogenous EP has the potential to augment intracellular pyruvate levels, which enable the cells to protect themselves from reactive oxygen species (ROS)-mediated damage.1–3 However, several studies have shown that EP as an intact ester also has direct pharmacologic effects, which have been recently reviewed by Kao and Fink.4 The pharmacologic effects of EP are quite diverse, and include downregulation of the secretion of proinflammatory cytokines, enhanced antitumor immunity, amelioration of redox-mediated damage to cells and tissues, inhibition or promotion of apoptosis based on the circumstances, and support of cellular adenosine triphosphate synthesis. Recently, a number of studies have shown that EP is a robust and potent anti-inflammatory agent in pathologic conditions, such as hemorrhagic shock, sepsis, systemic inflammation, colitis, pancreatitis, and pulmonary fibrosis.5–13 These reports indicate that the anti-inflammatory effects of EP are caused by downregulation of the proinflammatory transcription factor nuclear factor kappa B (NF-κB) and the expression of NF-κB–dependent proinflammatory marker proteins, such as TNF-α, IL-6, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS).5,6 In addition, a few studies indicate its potential in preventing sugar and oxidative stress–induced cataract formation and toxicity to some of the ocular tissues.14–16 Although the role of EP in various inflammatory conditions has been examined, its potential anti-inflammatory role in the prevention of ocular inflammation has never been explored. Figure 1. Structure of ethyl pyruvate. Inflammation has been implicated in pathogenic mechanisms in various vision-threatening ocular diseases, such as uveitis,17 diabetic retinopathy,18 and AMD.19 Among all ocular inflammatory diseases, uveitis is considered as a potent, blindness causing intraocular condition.20,21 So far, the etiology of the uveitis is yet to be understood. Nevertheless, autoimmune disorders, infections, exposure to toxins, and many other unknown factors are believed to cause uveitis.17 A potential common pharmacologic strategy against uveitis is likely to contain suppression and regulation of intraocular inflammation. Various chemical mediators play key roles in ocular inflammation, particularly uveitis. The key inflammatory molecules include cytokines IL-622 and TNF-α,23 the arachidonic acid cascade enzyme COX-224 and its major metabolite prostaglandin E2,25 monocyte chemotactic protein (MCP)-1,26 angiotensin II type 1 receptor,27,28 intracellular signaling pathways Janus kinase and signal transducer and activator of transcription (JAK/STAT)22,27 and IκB/NF-κB,29 and intercellular adhesion molecule (ICAM)-1.30 A number of antioxidants that can prevent the NF-κB–dependent expression of inflammatory cytokines have been shown to have potent antiocular inflammatory actions.31 Antioxidants like benfotiamine, guggulsterone, curcumin, lutein, and reservatrol have been shown to prevent endotoxin-induced uveitis (EIU) in experimental animals.31 EP has now well established as an antioxidant with potent anti-inflammatory agent in various nonocular conditions. However, the efficacy of EP in ocular inflammatory pathologic conditions such as uveitis is not known. We investigated the efficacy of EP in preventing ocular inflammation in rats. Our results indicate that supplementation of EP prevents lipopolysaccharide (LPS)-induced ocular inflammation leading to uveitis in rats.