| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Septic shock with fever and even death is induced as one of the biological responses, which are triggered by LPS (lipopolysaccharide, endotoxin), a highly conserved outer membrane compound of gram-negative bacteria. Murine and human macrophages exhibit a particularly vigorous response to endotoxin, which induces production of a variety of inflammatory modulators such as nitric oxide (NO), reactive oxygen species (ROS), several cytokines (IL-1β, TNF-α, IL-6, INF-γ), and prostaglandins.
Zinc (Zn) is an essential trace element in all-living systems. It has four coordinating bonds and plays a structural role in many proteins and enzymes. It has been also reported to exhibit insulinomimetic activity in both in vitro and in vivo experiments. In the development of insulinomimetic agents, synthetic low-molecular weight Zn complexes such as bis(maltolato)zinc(II), Zn(mal)_2, and its derivatives exhibited more promise in insulinomimetic activity than ionic zinc species. While, Zn is known to exhi
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bit antioxidative effects and inhibit LPS-induced NO and ROS production. Then, Zn has extensive pharmacological activity and may protect the body against the LPS-induced septic shock with suppressing inflammatory stimulation.
In the present study, we examined the suppressive effect of zinc-maltolate derivatives as a potential liver-protecting agent on the LPS-induced in vitro hepatotoxicity in isolated rat primary hepatocytes and in vivo endotoxin shock in rats, which is a model of human septicemia. The results indicated that the survival rate of rats, who were intraperitoneally (ip) administered with LPS (30 mg/kg) and ip pre- or post-treated with Zn(mal)_2 injection at a dose of 10 mg Zn/kg, was almost 100% or approximately 70% within 96 hours after LPS injection, respectively. While, the survival rates was decreased in both cases at lower and higher doses of 5 and 20 mg Zn/kg. In addition, pharmacokinetic analysis suggested that Zn complexes with S_2O_2 coordination mode may exhibit more potent anti-septic activity than zinc-maltolate derivatives after oral administration, mainly due to the higher bioavailability from the gastrointestine and distribution to organs of Zn(S_2O_2) complexes. Less
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