Therapeutic effects of α-iso-cubebenol, a natural compound isolated from the Schisandra chinensis fruit, against sepsis

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Abstract

α-Iso-cubebenol, a natural compound isolated from the Schisandra chinensis fruit, strongly enhances survival rate in cecal ligation and puncture (CLP) challenge-induced sepsis. Mechanistically, α-iso-cubebenol markedly reduces viable bacteria in the peritoneal fluid and peripheral blood, by increasing production of superoxide anion. α-Iso-cubebenol also significantly attenuates widespread immune cell apoptosis in a mouse CLP sepsis model, and inhibits the production of proinflammatory cytokines including interleukin-1β (IL-1β) and IL-6 in CLP mice and lipopolysaccharide-stimulated splenocytes. Taken together, the results indicate that α-iso-cubebenol can reverse the progression of septic shock by triggering multiple protective downstream signaling pathways to enhance microbial killing and maintain organ function and leukocyte survival.

Highlights

► α-Iso-cubebenol showed therapeutic effect against experimental sepsis. ► α-Iso-cubebenol enhanced the bactericidal effects of phagocytic cells. ► α-Iso-cubebenol reduced immune cell apoptosis. ► α-Iso-cubebenol significantly reduced the production of IL-1β in sepsis model. ► The finding suggests a novel therapeutic approach to treat polymicrobial sepsis.

Introduction

Sepsis, a systemic inflammatory response, is caused by viable bacteria or bacterial products such as lipopolysaccharide (LPS) [1]. More than 750,000 patients develop sepsis annually in the United States, and the incidence rate is gradually increasing [2]. The number of hospitalizations with sepsis in the US increased from 300,000 to around 800,000 from 2000 to 2007 [3]. Although the mortality rate of sepsis decreased somewhat from 2000 to 2007, sepsis remains the major cause of death in intensive care units, and the overall mortality associated with sepsis ranges from 30% to 70% [2]. Only 2% of hospitalizations are for sepsis, yet it makes up 17% of in-hospital deaths in the US [4]. Sepsis-induced lethality is accompanied by the failure of an appropriate immune response against invading pathogens [5], [6]. The inability of the innate immune system to respond during early sepsis (i.e., the first 6 h) results in increased mortality. Excessive lymphocyte apoptosis can occur during sepsis, which results in the clinical signs of multi-organ failure [7], [8]. Since sepsis is caused by viable bacteria or bacterial products, the levels of proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin (IL)-1β are substantially increased during sepsis [9], [10], [11]. Thus, an effective treatment for sepsis should control bacteria, prevent production of inflammatory cytokines, and block widespread leukocyte apoptosis.

We previously isolated a novel natural compound, α-iso-cubebenol, from the Schisandra chinensis fruit and demonstrated that the compound inhibits inducible nitric oxide synthase and cyclooxygenase-2 expression in lipopolysaccharide (LPS)-stimulated macrophages [12]. Subsequently, α-iso-cubebenol has been reported to induce heme oxygenase-1 expression and have anti-inflammatory activity in Porphyromonas gingivalis LPS-stimulated macrophages [13]. In this study we investigated the in vivo efficacy of α-iso-cubebenol in a preclinical mouse model of sepsis. We also examined the mechanisms of septic protection by this novel natural compound.

Section snippets

Purification of α-iso-cubebenol

α-Iso-cubebenol (CAS registry number: 1219105-52-8) was purified from the dried fruit of S. chinensis as described previously [12]. The fruit of S. chinensis (Turcz.) Baill was collected in September 2005 from Moonkyong, Korea. A voucher specimen (Accession No. SC-PDRL-1) has been deposited in the Herbarium of Pusan National University. The plant was identified by one of the authors (Y. Choi). The dried fruit of S. chinensis (2.5 kg) ground to a fine powder and then successively extracted at

α-Iso-cubebenol administration protects against sepsis-induced mortality

We first investigated whether α-iso-cubebenol, its chemical structure was shown in Fig. 1A, has anti-septic activity against polymicrobial sepsis using a CLP sepsis model. α-Iso-cubebenol administration strongly protected against mortality induced by CLP in a dose-dependent manner (Fig. 1B). Survival was strongly enhanced, reaching 80% when 15 mg/kg of α-iso-cubebenol was injected 2 h post-CLP and additionally three times at 12 h intervals (Fig. 1B). Inflammation of vital organs such as lung is

Discussion

With improvements in hospital care and increased awareness of deadly diseases, mortality rates from sepsis have decreased in recent years [3], [4]. However, 1 in 1200 Americans die of severe sepsis annually [3], [4]. Even though 17% of in-hospital deaths in the US are caused by sepsis, drugs that combat sepsis without antibiotics are not clinically available. Xigris, which had been approved by the US FDA as a therapeutic agent against sepsis, was withdrawn from the market. Thus, researchers are

Acknowledgments

This research was supported by Ministry for Food, Agriculture, Forestry and Fisheries, Republic of Korea (311054031HD120) and by National Research Foundation of Korea (NRF) Grants funded by the Korean government (MEST) (Nos. 2009 0093198, 35B-2011-1-E00012).

We thank Dr. Brian A. Zabel of Palo Alto Institute for Research and Education for helpful discussion.

SL, YC, and YB have pending patent applications. The other authors have no financial conflicts of interest.

References (21)

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