On-site mortality in crush syndrome remains high due to lack of effective drugs based on definite diagnosis. Anisodamine (Ani) is widely used in China for treatment of shock, and activation of α7 nicotinic acetylcholine receptor (α7nAChR) mediates such antishock effect. The present work was designed to test whether activation of α7nAChR with Ani decreased mortality in crush syndrome shortly after decompression. Sprague-Dawley rats and C57BL/6 mice with crush syndrome were injected with Ani (20 mg/kg and 28 mg/kg respectively, i.p.) 30 min before decompression. Survival time, serum potassium, insulin, and glucose levels were observed shortly after decompression. Involvement of α7nAChR was verified with methyllycaconitine (selective α7nAChR antagonist) and PNU282987 (selective α7nAChR agonist), or in α7nAChR knockout mice. Effect of Ani was also appraised in C2C12 myotubes. Ani reduced mortality and serum potassium and enhanced insulin sensitivity shortly after decompression in animals with crush syndrome, and PNU282987 exerted similar effects. Such effects were counteracted by methyllycaconitine or in α7nAChR knockout mice. Mortality and serum potassium in rats with hyperkalemia were also reduced by Ani. Phosphorylation of Na/K-ATPase was enhanced by Ani in C2C12 myotubes. Inhibition of tyrosine kinase on insulin receptor, phosphoinositide 3-kinase, mammalian target of rapamycin, signal transducer and activator of transcription 3, and Na/K-ATPase counteracted the effect of Ani on extracellular potassium. These findings demonstrated that activation of α7nAChR could decrease on-site mortality in crush syndrome, at least in part based on the decline of serum potassium through insulin signaling-Na/K-ATPase pathway.
Sodium sulfide, a H2 S donor, presents protective effect on acute cerebral ischemia, and might be a promising therapeutic drug.
Hyperkalemia is a major cause of on-site death in crush syndrome (CS), which is more severe and common in male victims. Anisodamine is a belladonna alkaloid and widely used in China for treatment of shock through activation of α7 nicotinic acetylcholine receptor (α7nAChR). The present work was designed to study the protective effect of anisodamine in CS and the possible role of estradiol involved. Male and ovariectomized female CS mice exhibited lower serum estradiol and insulin sensitivity, and higher potassium compared to the relative female controls at 6 h after decompression. There was no gender difference in on-site mortality in CS mice within 24 h after decompression. Serum estradiol increased with similar values in CS mice of both gender compared to that in normal mice. Anisodamine decreased serum potassium and increased serum estradiol and insulin sensitivity in CS mice, and methyllycaconitine, selective antagonist of α7nAChR, counteracted such effects of anisodamine. Treatment with anisodamine or estradiol increased serum estradiol and insulin sensitivity, decreased serum potassium and on-site mortality, and eliminated the difference in these parameters between CS mice received ovariectomy or its sham operation. Anisodamine could also increase blood pressure in CS rats within 3.5 h after decompression, which could also be attenuated by methyllycaconitine, without influences on heart rate. These results suggest that activation of α7nAChR with anisodamine could decrease serum potassium and on-site mortality in CS through estradiol-induced enhancement of insulin sensitivity.
Depression is a common mental disorder with relatively high lifetime prevalence and substantial disability, especially in women [1][2][3]. Clinical manifestations of depression include loss of interest or pleasure, disturbed sleep or appetite, poor concentration, etc., worst of which is suicide. To solve such an important global public health issue, it is essential to establish ideal animal models for study and treatment of depression. Cynomolgus monkeys have been proved to be advantageous for modeling human depression through mother-infant separation [4] and social subordination stress [5].Behavioral tests have been performed in animals to test severity of depression and successfulness of modeling, for example, forced swim test and tail suspension test for rodents [6,7] and sucrose intake test for nonhuman primates [8]. In this study, we attempted to establish several behavioral criteria that can be easily measured to distinguish depression in cynomolgus monkeys.After a fourteen-month observation in groups, six socially subordinate female cynomolgus monkeys and six socially dominant counterparts were chosen as depressed models and alert controls, respectively, based on their social status hierarchy (Figure 1). The subordinate and dominant monkeys came from six and four groups, respectively, and each group consisted of 14-26 monkeys. The monkeys were 6-10 years of age and housed alone in adjacent cages separated with transparent plexiglass. All the monkeys were provided by Suzhou Xishan Zhongke Lab Animal Ltd (Suzhou, China) and received humane care.In this study, body weight, food consumption, preference for sucrose water, attempts for apple, and time of depressed posture were measured. Data are expressed as mean AE SEM and analyzed with unpaired t-test. P < 0.05 was considered statistically significant. The body weight of depressed monkeys was significantly lower than that of nondepressed monkeys (3.03 AE 0.07 vs. 3.57 AE 0.13 kg, P < 0.01; Figure 2A). Food consumption relative to body weight was calculated as the mean of 3-day measurements. Our results showed that depressed monkeys ate more food than the nondepressed (40.76 AE 2.76 vs. 18.25 AE 0.86 g/kg, P < 0.01; Figure 2B). The monkeys were deprived of water for 23 h and obliged to drink from two bottles containing pure water at the 24th h. After a 3-day adaptation, pure water was changed to 1.5% sucrose water in one bottle and then consumption of both kinds of water was recorded for 3 days. Preference of sucrose water was calculated as the percentage of sucrose water intake to total water intake. Depressed monkeys exhibited less preference for sucrose as compared to nondepressed monkeys (51.5 AE 12.6% vs. 81.0 AE 2.9%, P < 0.05; Figure 2C).Apples were given to monkeys in the cages for 3 days and then put out of the cages. Distance between the wall of the cage and the apple was a bit longer than the length of the monkey ' s arm. Monkeys could stretch their arms through the meshes of the cage wall. Times of reaching for apple were counted for 15 min on 3 day...
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