| Background and Objectives:In many countries including China, stroke is the third leading cause of death only preceded by heart disease and total cancer. According to recent estimates published by the World Health Organization, about 15 million people per year fall victim to stroke worldwidely, of whom 5 million die and another 5 million are left permanently disabled. Many stroke survivors become dependent, and require lifelong assistance. Therefore, prevention is the only possible way to curb the stroke pandemicly. Blood pressure level is one of the most consistent and powerful predictor of stroke, so blood pressure control is an important way to reduce the morbidity. However, blood pressure level is not the unique determinant for stroke. Here we propose other important determinants for stroke.Calorie restriction (CR) is the only experimental manipulation that is known to extend the lifespan of a number of organisms including yeast, worms, flies, rodents and perhaps non-human primates. In addition, CR has been shown to reduce the incidence of age-related disorders (for example, diabetes, cancer and cardiovascular disorders) in mammals. The mechanisms through which this occurs have been unclear. CR induces metabolic changes, improves insulin sensitivity and alters neuroendocrine function in animals. In addition to its effects on metabolism, CR can have profound effects on brain function. For example, CR can protect neurons against degeneration in animal models of Huntington's disease, Alzheimer's disease, Parkinson's disease and stroke.ABR is one of the most important mechanisms in the regulation of cardiovascular activities. Since the end of 1980s, the pathological importance of ABR function has attracted the attention of many investigators. Baroreflex function, expressed as baroreflex sensitivity (BRS), was found as an important determinant of cardiac death after acute myocardial infarction. There is also established evidence of abnormal BRS in animal models of stroke and patients with chronic cerebrovascular disease. Indeed, it was found that BRS was impaired after acute stroke. Post-stroke patients with impaired BRS had a poor prognosis. We have proved that BRS can be as a new predictor for stroke incident. And CR can protect neurons against degeneration in animal models of stroke. However, to our knowledge, there is no more report about the mechanisms how BRS works in this process. So the first aim of this study was to investigate the relationship of ABR, CR, and Stroke.It had been reported that acetylcholine inhibits the production of pro-inflammatory cytokines from endotoxin-stimulated macrophages through a mechanism dependent on the a7 nicotinic acetylcholine receptor subunit in 2000. Because acetylcholine is the principal vagus neurotransmitter, the central nervous system also regulates proinflammatory cytokine production through the efferent vagus nerve, termed the "cholinergic anti-inflammatory pathway". It had been reported that activation of this mechanism via vagus nerve stimulation can control the production of pro-inflammatory cytokines in experimental models of systemic inflammation, including lethal endotoxemia, hemorrhagic shock, and ischemia-reperfusion injury. Thus, the "cholinergic anti-inflammatory pathway" can directly modulate the systemic response to pathogenic invasion. In this process, we know that vagus nerve plays an important role in the regulation of various signals central neruron system sent out. So investigation of the relationship of ABR and vagal function makes it easy to find the effects of cholinergic pathway on the protection of stroke. Shytle et al. report for the first time that cultured microglial cells express alpha7nAChR subunit as determined, and their findings suggest the existence of a brain cholinergic pathway that regulates microglial activation through alpha7 nicotinic receptors. Negative regulation of microglia activation may also represent additional mechanism underlying nicotine's reported neuroprotective properties.Many reports have shown the effect of caloric restriction (CR) on pretection of stroke, and this effect is related to the function of ABR. How dose ABR produce a marked effect on it? Though preliminary, we investigate the regulations of cholinergic pathway on the protection of stroke caused by the impaired BRS. It will develop a new way to find the effective factors involved in the pretection and treatment of stroke.Main Methods and Results:Male SHR-SP, at the age of 12 weeks, were fed ad libitum (AL) or CR diet (80%, 60%, 40%of AL). We subjected the animals to middle cerebral artery (MCA) occlusion, and the infarct area and hemisphere areas of each section (both sides) were traced and quantified by an image analysis system. We found the ratio of the infarct area and hemisphere areas was significantly different in the four groups. SHR-SP fed CR diet (60% of AL) showed the best protective effect of CR. Sinoaortic denervation (SAD) was performed to destroy the peripheral baroreflex arc in SHR-SP, and after a month, they were fed ad libitum (AL) or CR diet (60% of AL). The infarct area was traced and quantified. The ratio of the infarct area and hemisphere areas was decreased in both of the CR group, while sinoaortic denervation group decreased less than the sham-operated group. The survival time and stroke incidence were observed and was expressed by Kaplan-Meier survival curves. The effects of caloric restriction to the prevention of stroke were weekened by sinoaortic denervation. Sinoaortic denervation (SAD) rats were given Atropine to observe the different reaction to the stimulation. After the injection of Atropine, the decrease of heart period in sham-operated group is more obviously than sinoaortic denervation group. Also we detected the discharge of the nucleus ambiguous of the two groups. The level of the discharge of the nucleus ambiguous in sinoaortic denervation group was lower than that of sham-operated group. The group with low discharge level has the liability to the development of stroke. We used Western blotting to detect the protein expression ofα7 and AchT. The protein expression of a7 and AchT in brain was obviously decreased in sinoaortic denervation rats. Levels of interleukin (IL)-1βand IL-6 in serum were detected by ELISA. The levels of interleukin (IL)-1βand IL-6 were higher in sinoaortic denervation rats than that in sham-operated rats. After the injection of Carbachol to the lateral cerebral ventricle, we observed the influence of Carbachol to the treatment of stroke. The ratio of the infarct area and hemisphere areas was significantly decreased by the injection of Carbachol. Carbachol dose-independently inhibited the H2O2-induced apoptosis of Bend. 3 detected by flow cytometry. It also inhibited the H2O2-induced apoptosis of neuron cells observed by fluorescence microscope. Western blotting was used to measure the protein expression of SIRT1. Carbachol dose-independently increased the protein expression of SIRT1. Knock-down of SIRT1 was attained by siRNA.Conclusion:In conclusion, the present study provides evidence that caloric restriction is a new and important predictor for stroke death in hypertension rats. Restoration of ABR function is a new target for the prevention of stroke. ABR functional impairment decreases the prevention of stroke by CR. The cholinegic pathway is involved in the protective mechanisms of stoke, and this function is mediated by ABR. The regulation of cholinegic pathway maybe have two aspects: one is due to the increase of ectogenic inflammatory transmitter, and the other is for the improvement of the apoptosis of vascular endothelial cells and neuron cells in the brain. Furthermore, we find this improvement is mediated by the protein expression of SIRT1. |
PDF Full Text Request