Effects of melatonin on experimental endotoxic shock

• Main Authors: Chiao, Chin-Wei, 喬晉瑋
• Other Authors: Wu, Chin-Chen
• Format: Others
• Language: zh-TW
• Published: 1999
• Online Access: http://ndltd.ncl.edu.tw/handle/71158413124069733118

碩士 === 國防醫學院 === 藥理學研究所 === 87 === Sepsis or septic shock is a dilemma for the physicians whose patients' lives are in danger. Septic shock, resulting from bacterial infection, is caused by the proliferation of either Gram (+) or Gram (-) organisms; however, Gram (-) sepsis is predominant. Septic shock involves a cascade of events that evolve over time, beginning with the proliferation of the invading organisms, followed by the release of "intrinsic regulators" from the infected host. These factors include cytokines, platelet-activating factor, etc. They could further cause the overproduction of nitric oxide (NO?) which leads to vasodilatation and hypotension. NO? is one of free radicals which can be scavenged by some antioxidants which could prevent the deleterious effects induced by septic shock. This study aimed to examine the effects of melatonin, an endogenous antioxidant, on murine with endotoxic shock. Our preliminary results demonstrated that melatonin 1 and 3 mg/kg increased 6h-survival rate and improved the circulatory failure induced by endotoxin (E. coli lipopolysaccharide, LPS, 5 mg/kg). Thus, these doses were chosen in this study. After rats treated with LPS, two phases of hypotension and a sustained increase of heart rate were observed. The delayed hypotension was attenuated by pretreatment of LPS-rats with melatonin, but it further enhanced the tachycardia induced by LPS. If melatonin was administered at 2h after LPS, only the lower dose (1 mg/kg) of melatonin improved the delayed hypotension, and neither exerted any effects on the tachycardia. LPS also caused the vascular hyporeactivity to norepinephrine (NE, 1 mg/kg). This vascular hyporeactivity was prevented by pretreatment with melatonin. Only low dose (1 mg/kg) of melatonin had therapeutic effect when it was given at 2 h after LPS. Endotoxin significantly increased the formation of superoxide anion (O2?-) and this could be prevented by pretreatment with melatonin. When melatonin was given at 2 h after LPS, it also inhibited the overproduction of O2?-. However, the post-treatment is not as effective as the pre-treatment. Endotoxemia with 6h was associated with an overproduction of NO? in the plasma and an expression of inducible NO synthase (iNOS) in the liver. The plasma NO? level was not affected by melatonin either given before or after LPS, but melatonin did inhibit the expression of iNOS. The injection of LPS resulted in bell-shape changes in the plasma levels of tumor necrosis factor-a (TNF-a) which reached a peak at 2h after LPS injection and subsequently decreased slowly. Pretreatment with melatonin significantly decreased the TNF-a level in the plasma while the post-treatment had a mildly inhibitory effect. LPS caused biphasic changes of blood glucose (i.e. hyperglycemia followed by hypoglycemia). Pre-treatment, but not post-treatment, with melatonin stabilized the changes of blood glucose of LPS-rats. In addition, melatonin improved the 72h-survival rate in mice with endotoxemia and the histological examination of liver and lung tissues from these mice showed that melatonin possessed protective effects on these tissues. In conclusion, melatonin exerted beneficial effects on animals with endotoxic shock. The protection of melatonin on septic shock may mainly be attributed to the scavenging effect on O2?- and possibly related to the coupling with melatonin receptors which needs to be clarified.