Acetyl-α-boswellic acid and Acetyl-β-boswellic acid protects against caerulein-induced pancreatitis via down-regulating MAPKs in mice

Highlights

• Cytokine levels in RAW264.7 cells stimulated with lipopolysaccharide were reduced.

• It can alleviate cyanobacterial-induced pancreatic edema and inflammatory cell infiltration in a mouse model of pancreatitis.

• The levels of mitogen-activated protein kinase (MAPK) family phosphorylated protein levels in pancreas were down-regulated.

Abstract

This study is to investigate the protective effect of Acetyl-α-boswellic acid and Acetyl-β-boswellic mixture(α/β-ABA), which is the active ingredients isolated from Frankincense, on actue pancreatitis and its mechanism. Our experimental results showed that 2 μM α/β-ABA reduced production of NO, TNF-α, IL-6, IL-10 and IL-1β in RAW264.7 cells that were stimulated with lipopolysaccharide (LPS) which indicates its anti-inflammatory role. In pancreatitis model induced by caerulein, intra-gastrical administration of 100 mg/kg α/β-ABA relieved inflammatory cells infiltration significantly and attenuated the serum elevation of amylase TNF-α and IL-6 remarkably in mice. Furthermore, α/β-ABA down-regulated mitogen-activated protein kinase (MAPK) family phosphorylated proteins in pancreas, including phosphorylated p38, ERK1/2 and JNK, to reduce the serum inflammatory factors. Finally, α/β-ABA alleviated the pancreatic edema and inflammatory cell infiltration in pancreatitis mice model. This study suggests that α/β-ABA may be targeted for drug development against pancreatitis via modulating MAPKs pathway.

Introduction

Acute pancreatitis (AP) is a common acute abdomen that caused by autodigestion of pancreas. The pathological changes include pancreatic edema, hemorrhage and necrosis while it manifested as abdominal pain, vomiting, fever as well as elevated serum urease and amylase in clinic. Recently, epidemiological studies revealed that the incidence of pancreatitis increases each year [1], and the total mortality rate reaches 5% to 10% now [2]. Severe acute pancreatitis (SAP) accounts for 15%–20% of acute pancreatitis [3], which usually complicates with systemic inflammatory response or, acute respiratory distress syndrome or acute renal insufficiency and liver function damage. Uncontrolled SAP could lead to multiple organ failure [4], [5] with mortality as high as 36% to 50%. Although recent progressions in pathogenesis and treatment of AP, its incidence still increase and the mortality remains high [2], [6], [7]. AP remains a major threat to human health due to its high morbidity, mortality and treatment limitations. The pathogenesis of AP is complex and not fully understood, however inflammation theory is now considered to be one of the main culprits in its pathogenesis, and a large number of inflammatory factors are associated with the pathological process of pancreatitis [8].

Frankincense, an aromatic resin used in incense and perfumes from Boswellia carteri, is also used to treat a variety of inflammatory diseases in traditional medicine. The main components of frankincense include various boswellic acids, volatile oils, terpenes, arabinose and so on.

Previous studies showed that Boswellia extracted and its triterpenoids boswellic acid compounds include Acetyl-α-boswellic acid (α-ABA), Acetyl-β-boswellic acid (β-ABA) (Fig. 1), 11-keto-β-boswellic acid (KBA) and 3-O-acetyl-11-keto-β-boswellic acid (AKBA) have anti-inflammatory activity against a variety of acute and chronic inflammatory models [9], [10]. Up to now, most studies on active compounds of Frankincense are regarding to AKBA and KBA. However, oral administration of boswellic acid resulted in several times higher C_max values of α-ABA and β-ABA in plasma than those of KBA and AKBA [11], and the concentration of α-ABA and β-ABA in mice brain were also higher than those of KBA and AKBA [12]. Therefore, this study was to investigate whether the mixture of α-ABA and β-ABA (α/β-ABA) pose anti-inflammatory effect against LPS-activated proinflammatory cytokines and caerulein-induced acute pancreatitis in RAW 264.7 macrophages.