Gastroparesis Lab Report

Introduction Reactive oxygen species (ROS) include super oxide ion (O2-), hydrogen peroxide (H2O2) and hydroxyl radical (HO- ) are the causative agents to produce oxidative stress. ROS are produced by two independent pathways: mainly the mitochondrial oxidative metabolism and cellular responses to bacterial invasion, xenobiotic and cytokines. To counteract the formation of ROS, a number of antioxidant proteins have been described. These proteins are superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase, and ferritin heavy chain etc. Oxidative stress has been implicated to both the onset and progression of type I and type II diabetes ( ). The consequence of ROS production is associated with the development of
insulin resistance, loss of β-cell, and impaired glucose tolerance ( ). At the cellular level ROS causes the damage of lipids, proteins and DNA. The cellular toxicity of ROS is mediated by cumulative effects of five independent signaling pathways: glycation of proteins, polyol pathway flux, activation of protein kinase C, over reactivity of hexosamine pathway and activation of the serine threonine family of kinases such as p38 MAPK and c-jun N-terminal kinases (JNK) [ ]. Impaired gastrointestinal motility is one of the major complications of diabetes.
Diabetic gastroparesis involves enteric nerve, Interstitial Cells of Cajal (ICC), and smooth muscle dysfunction which results in delayed gastric emptying. It occurs in both Type I and Type II diabetic patients: 20-55% in type I or insulin-dependent patients; and up to 30% in type II non-insulin dependent. The pathophysiological mechanisms responsible for diabetic gastroparesis remain unclear. The results derived from diabetic animal models suggest that gastroparesis is a multi-factorial disease. Given that both acute and chronic hyperglycemia can frequently impair GI motility [1, 2], many factors, including ROS , may play pivotal role in the development of diabetic gastroparesis. In support of our hypothesis, it was demonstrated the activation of p38 MAPK a direct modulator of ROS production is associated with development of delayed gastric emptying. The blockade of p38 MAPK pathway using SB203580, a specific inhibitor ameliorates delayed gastric emptying in diabetic rats, at least in part, by inhibiting the production inflammatory cytokines ( ). This is an interesting observation raised the question whether production of ROS and downstream signaling pathways are involved in impaired gastric
motility.
We hypothesize that ROS might be critical for the development and progression of gastric motility dysfunction in diabetic individuals.
Therefore, to further elucidate mechanisms underlying the development of gastroparesis in male rats using an established male rat model of gastroparesis model ( ). One of the important down steam signaling pathway of ROS is the activation of serine threonine kinase pathways p38 MAPK and JNK pathways. Oxidative medication and/or inactivation of MAP kinase phosphatase-1 (MKP-1) is the plausible mechanism for the activation of these pathways ( ). Our data demonstrate the following: (a) production of ROS in both diabetic and diabetic gastroparesis rats; (b) activation of both p38 MAPK and JNK pathways in diabetic gastroparesis rats and (c) degradation of MKP-1 might be the possible mechanism of activation of these pathways. Our findings shed light upon the role of ROS in the sequel of gastroparesis, and may help identify novel therapeutic targets for the treatment and/or prevention of gastroparesis in
men.