| Summary: | 博士 === 國立臺灣大學 === 藥理學研究所 === 94 === Blockades of cytokine and oxygen free radicals release are considered to be beneficial in reducing multiple organ injury and increase the survival rate in sepsis/septic shock, so we discussed in the two parts about aporphine alkaloid agents – thaliporphine and N-allylsecoboldine, which were obtained from Chinese herb. Also, we attempted to elucidate the protective effects and the probably contributive mechanisms.
Part One: Thaliporphine increases survival rate and attenuates multiple organ injury in lipopolysaccharide-induced endotoxemia.
Thaliporphine, a phenolic aporphine alkaloid obtained from Chinese herbs and possessing antioxidant and alpha1 adrenoceptor antagonistic activity, has protective effects in endotoxemic rats. Rats injected with endotoxin (E. coli lipopolysaccharide, LPS) developed severe hypotension and tachycardia as well as vascular hyporeactivity to norepinephrine. Pretreatment of LPS-treated rats with thaliporphine attenuated the delayed hypotension significantly whilst only a higher dose (1 mg/kg) of thaliporphine decreased LPS-induced tachycardia. LPS significantly increased nitric oxide (NO•) and superoxide anion (O2•-) levels, a response that was reduced by pretreatment with 1 mg/kg thaliporphine. Endotoxemia for 240 min resulted in a bell-shaped time course for the change of serum tumor necrosis factor-alpha (TNF-alpha) level with a peak at 60 min. Pretreatment of LPS-treated rats with 1 mg/kg thaliporphine significantly reduced the serum TNF-alpha level at 60 min. In addition, LPS caused a biphasic change in blood glucose and thaliporphine attenuated the late-phase decrease in blood glucose. Endotoxemia induced multiple organ injury in the liver, kidney and heart, as indicated by increases of aspartate aminotransferase (GOT), alanine aminotransferase (GPT), creatinine (CRE), lactate dehydrogenase (LDH) and creatine phosphate kinase muscle-brain (CKMB) levels in serum. These increases of biochemical markers and inflammatory cell infiltration into injured tissues were reduced significantly by treatment with thaliporphine. In addition, thaliporphine increased the survival rate of LPS treated mice dose-dependently. In conclusion, our results suggest that thaliporphine could be a novel agent for attenuating endotoxin-induced circulatory failure and multiple organ injury and may increase the survival rate. These beneficial effects of thaliporphine may be attributed to the suppression of TNF-alpha, NO• and O2•- production.
Part Two: N-Allylsecoboldine as a novel agent prevents acute renal failure resulted from endotoxemia.
N-Allylsecoboldine is a secoaporphine derivative with antioxidant and alpha1-adrenoceptor blocking activities. Pretreatment of LPS-treated rats with N-allylsecoboldine significantly attenuated the late-phase hypotension, hypoglycemia and incremental plasma tumor necrosis factor (TNF)-alpha. Overproduction of plasma nitrate in endotoxemia was not changed but the continuous decrease of urinary nitrate appeared to be partially ameliorated by N-allylsecoboldine. However, N-allylsecoboldine inhibited the inducible nitric oxide synthase (iNOS) protein expression in the renal cortex of endotoxemic rats. N-Allylsecoboldine also improved the endotoxemia-induced organ injury as demonstrated from the conspicuous recovery of marker enzymes in the LPS-treated rats. Endotoxemia was associated with renal dysfunctions as indicated by decreases in renal blood flow, urinary potassium excretion, and renal nitrate clearance. However, pretreatment with N-allylsecoboldine showed significant alleviation of these renal dysfunctions. In addition, a lower dose of N-allylsecoboldine ameliorated the mortality of LPS-treated mice. This study demonstrates N-allylsecoboldine''s ability to avail against acute renal failure and increase survival rate during endotoxemia. These beneficial effects may be attributed to the inhibition of iNOS expression, TNF-alpha production, and free radical scavenging activities. However, the role of alpha1-adrenoceptor antagonism for N-allylsecoboldine in sepsis remains unclear.
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