Antioxidative phytoceuticals to ameliorate pancreatitis in animal models: an answer from nature

Abstract

Despite enthusiastic efforts directed at elucidating critical underlying mechanisms towards the identification of novel therapeutic targets for severe acute pancreatitis (SAP), the disease remains without a specific therapy to be executed within the first hours to days after onset of symptoms. Although earlier management for SAP should aim to either treat organ failure or reduce infectious complications, the current standard of care for the general management of AP in the first hours to days after onset of symptoms include intravenous fluid replacement, nutritional changes, and the use of analgesics with a close monitoring of vital signs. Furthermore, repeated evaluation of severity is very important, as the condition is particularly unstable in the early stages. In cases where biliary pancreatitis is accompanied by acute cholangitis or in cases where biliary stasis is suspected, an early endoscopic retrograde cholangiopancreatography is recommended. However, practice guidelines regarding the treatment of pancreatitis are suboptimal. In chronic pancreatitis, conservative management strategies include lifestyle modifications and dietary changes followed by analgesics and pancreatic enzyme supplementation. Recently, attention has been focused on phytoceuticals or antioxidants as agents that could surpass the limitations associated with currently available therapies. Because oxidative stress has been shown to play an important role in the pathogenesis of pancreatitis, antioxidants alone or combined with conventional therapy may improve oxidative-stress-induced organ damage. Interest in phytoceuticals stems from their potential use as simple, accurate tools for pancreatitis prognostication that could replace older and more tedious methods. Therefore, the use of antioxidative nutrition or phytoceuticals may represent a new direction for clinical research in pancreatitis. In this review article, recent advances in the understanding of the pathogenesis of pancreatitis are discussed and the paradigm shift underway to develop phytoceuticals and antioxidants to treat it is introduced. Despite the promise of studies evaluating the effects of antioxidants/phytoceuticals in pancreatitis, translation to the clinic has thus far been disappointing. However, it is expected that continued research will provide solid evidence to justify the use of antioxidative phytoceuticals in the treatment of pancreatitis.

Keywords: Acute pancreatitis; Antioxidants; Chronic pancreatitis; Phytoceuticals; Severe acute pancreatitis.

Figure 1

Animal models for pancreatitis. A: Cerulein-induced edematous pancreatitis. Caerulein-induced pancreatitis is a valuable experimental model for studying altered intracellular transport, compartmentation of lysosomal, and digestive enzymes, resulting in edematous pancreatitis. The formation of enlarged secretory vacuoles containing lysosomal and digestive enzymes is paralleled by the activation of lysosomes and degradation of cellular organelles in autophagosomes. On the level of secretory and autophagic vacuoles, activation of serine proteases occurs, which in addition to increasing lysosomal enzyme activities can represent the initial stage for acinar cell destruction and the development of pancreatitis; B: L-arginine-induced necrotizing pancreatitis. Parenchymal hemorrhage and widespread acinar cell necrotic changes were noted with L-arginine; C: Pancreatic duct ligation-induced pancreatitis. Morphologic examination of the pancreas showed massive interstitial edema, apoptosis, and necrosis of acinar cells with infiltration of neutrophil granulocytes and monocytes 0.75 d after pancreatic duct ligation. Two weeks later after periodontal ligament, the destructed parenchyma with fat replacement as well as some fibrotic changes were seen.

Figure 2

Animal model of choline-deficient, ethionine-supplemented diet-induced necrotizing pancreatitis. A: Choline-deficient, ethionine-supplemented (CDE) diet-induced necrotizing pancreatitis. Massive destruction of pancreatic parenchyma with focal necrotic foci was seen; B: Systemic inflammatory response syndrome hepatic necrosis and pneumonitis was seen; C: Chronic fibrosing pancreatitis was noted 2 mo after CDE diet administration.

Figure 3

Therapeutic and preventive effect of antioxidative phytoceuticals, Artemisia extract and Korean red ginseng against pancreatitis. A: Therapeutic effect of Artemisia extracts against cerulean or L-arginine-induced pancreatitis and chronic fibrosing pancreatitis; B: Korean red ginseng to ameliorate hydrogen sulfide (H₂S)-induced pancreatitis. NF-κB: Nuclear factor kappa B; PDL: Periodontal ligament; CSE: Cystathionine γ-lyase.