| 1BackgroundSleep disorders are a group of syndromes characterized by disturbance in the patient’s amount, quality and time of sleep, or in behaviors or physiological conditions associated with sleep. Nowadays, pronounced attention focus on sleep disorders, the silent epidemics, for elevated living burden, progressive aging problem, that lead to a great hazard to beings. A sleep questionnaire survey in2002in China showed the morbidity of sleep disorder reached as high as42.7%. The most important symptoms of sleep disorders are insomnia and sleepiness during waking hours, especially insomnia. It covers a number of different patterns of sleep disturbance. These patterns include inability to fall asleep at bedtime, repeated awakening during the night, and/or incapability to go back to sleep once awakened. The morbidity of insomnia varies from survey (10.2%-37.8%). In general, it is predominant in female and is associated with the increasing age.Sleep disorders are classified based on what the causes. Primary sleep disorders are distinguished from those that are not caused by other mental disorders, prescription medications, substance abuse, or medical conditions. The two major categories of primary sleep disorders are the dyssomnias and parasomnias. In addition to the primary sleep disorders, there are three categories of sleep disorders that are caused by or related to substance use or other physical or mental disorders. Here, we are about to talk about sleep disorders due to medical conditions such as brain disease, viral encephalitis, and hypo-or hyperthyroidism that may develop sleep disorders. Sleep disorders have also been associated with chronic neurological conditions like Parkinson’s disease or Huntington’s disease. Indeed, insomnia usually is the primary care of patients, especially the ones older than45, with chronic cerebral ischemia which is in terms of the poor cerebral circulation most caused by arteriosclerosis or cervical syndrome. Still, it remains unclear about the epidemic study on the relationship between sleep disorder and cerebral ischemia. Moreover, in our preliminary experiments, we confirmed that the chronic cerebral ischemia rats were more sensitive and maintaining at high level of arousal under the sustained stress, they could stand on the platform longer and fewer times fell into the water during the sleep deprivation.Brain ischemia, also known as cerebral ischemia, is a condition in which there is insufficient blood flow to the brain to meet metabolic demand. This leads to poor oxygen supply or cerebral hypoxia and thus to the death of brain tissue or cerebral infarction/ischemic stroke. Ischemia results in alterations in brain metabolism, reduction in metabolic rates, and energy crisis. Symptoms of brain ischemia can include unconsciousness, blindness, problems with coordination, and weakness in the body.In basic theories of Chinese medicine, Chronic cerebral ischemia is characterized by dizzying, headache, insomnia as well as forgettery in Chinese traditional medicine which suggests improve cerebral blood perfusion may attenuate sleep disorders. Brain ischemia links to a bunch of diseases. Patients with sickle cell anemia, compressed blood vessels, ventricular tachycardia, plaque buildup in the arteries, blood clots, extremely low blood pressure, or congenital heart defects have a higher predisposition to brain ischemia in comparison with healthy counterparts. For various causes of the diseases, lacking in effective treatment to chronic cerebral ischemia become more and more intractable, let alone brain ischemia combined sleeps disorder. In contrast, traditional medicine for its multi-targets characteristics may bring bonus to patients with brain ischemia.Wulongdan, an experience prescription of Prof. Zang Kuntang, shows potent effects in treating cerebral ischemia diseases like Cerebral infarction, cerebral embolism, transient ischemic attack, stroke sequelae and recovery, cerebral arteriosclerosis, cerebral atrophy, high blood pressure dizziness, headache, cervical spondylosis (vertebral-basilar artery insufficiency), head injury or surgery complications and so on. It has been well elucidated that Wulongdan reveals several pharmacological effects in curing brain ischemia via different pathways. However, little is known about whether is functional to brain ischemia-related sleeps disorder.2Purpose and significanceRecently, increasing more evidence show that sleep disorders are associated with chronic cerebral ischemia. Logically, it comes to be a new parameter of recovery for patients with chronic cerebral ischemia. Hence, we pick clock genes and neurotransmitters that were bound up with sleep-wake cycle aim to explore:1. the association of cerebral ischemia and sleep disorder,2. the targets of Wulongdan, a widely used medicine curing cerebral ischemia, are functioning in cerebral ischemia related sleep disorder.3Methods3.1Effects of Wulongdan on pineal clock Genes Expression in rats with chronic cerebral ischemiaMale Sprague-Dawley rats were randomly divided into3groups: sham group, chronic cerebral ischemia group, treatment group, with5in each group. The rats were fed a week for adaption. Chronic cerebral ischemia model of SD rats were established by permanent ligation of the bilateral carotid arteries while the sham group underwent the same surgical procedure without ligation of any carotid arteries. Daily basis corresponding treatments with Wulongdan were given after three weeks of the operation. All animals were weighed pre and post operation. Clock、Perl were measured by real-time quantitative RT-PCR analysis.3.2Effects of Wulongdan on four Amino Acid Contents in rats with chronic cerebral ischemiaIn conjunction with the rats fed with "wulongdan" for3weeks, the control rats were fed with vehicle. The contents of Asp、Glu、Gly and GABA in both hippocampus and brainstem were analyzed using HPLC. Chromatographic condition: chromatographic column Hypersil ODS(4.0mm×125mm,5μm); mobile phase(A):10mmol·L-1Na2HPO4PH7.2PB, mobile phase (B): PB+carbinol+acetonitrile (50+35+15); the flow rate was1.0mL·min-1. Detection wavelength: excitation wavelength340nm, emission wavelength450run; Column temperature was40℃.3.3Statistic analysisSPSS13.0was used to analyze the data. All data were indicated by mean±standard deviation(X±s), P<0.05, with statistical difference.4Results4.1Effects of Wulongdan on weight of rats with chronic cerebral ischemiaThe data showed that: there was no difference among groups before surgery while display a marked difference between sham group and cerebral ischemia group one week after surgery (P=0.015). In addition, after the drug was given for3weeks, the weight of treatment group increased to as much as model rats(P=0.013).4.2Effects of Wulongdan on pineal clock Genes Expression in rats with chronic cerebral ischemiaThe expression of Clock mRNA (P<0.01)、Perl mRNA (P<0.05) in sham group displayed significantly higher than operation group, however, no change in Bmall mRNA compared to the chronic cerebral ischemia group(P>0.05); Interestingly, contrast to decreased Bmall gene (compare with sham group, P<0.05), the amount of clock mRNA in treatment group showed robustly increased (P<0.01), while there was no apparent change of Perl mRNA between chronic cerebral ischemia group and treatment group.4.3Effects of Wulongdan on four Amino Acid Contents in rats with chronic cerebral ischemiaGlu in operation group is higher than sham group(P<0.05) and treatment group(P<0.05) but no difference between sham group and operation group on the contents of Asp、Gly、GAB A. In the hippocampus of rat, as well as in the brainstem, Gly was obviously different among three groups, compare to operation group, the sham group (P<0.01) and treatment group (P<0.05) were increased. The rats in operation group showed an increase in the radio of (Asp+Glu)/(Gly+GABA) in both brain regions compare to the rats in sham group(P<0.01) and treatment group (P<0.05), furthermore, ratio of Glu/GABA in hippocampus had statistical differences among groups(P<0.05,vs model group) rather than in brainstem.5Conclusion5.1Chronic cerebral ischemia influences the clock genes expression on pineal in ratsThe Clocks Perl were less expressed in rats with chronic cerebral ischemia, These findings suggest that the disorder of biological clock system is associated with chronic cerebral ischemia. 5.2Chronic cerebral ischemia change the contents of amino acid neurotransmitters in ratsThe Results Suggested That the model of chronic cerebral ischemia can increase the contents of excitatory amino acid while decrease the inhibitory amino acid.5.3Wulongdan may be used to treat insomnia through the regulation of clock genes and neurotransmitters Amino Acid in rats with chronic cerebral ischemiaExperiment suggests that Wulongdan can improve the low expression of clock mRNA in rats with chronic cerebral ischemia. In addition, compare to sham group, expression of Bmall in treatment group is at low level, which is similar to ketamine. So we consider that Wulongdan may has a certain hypnotic effect. Meanwhile, Wulongdan can regulate the ratio of the excitatory amino acid in to the inhibitory amino acid and make the neurotransmitters Amino Acid Rebalancing. |
PDF Full Text Request