阿魏酸鈉的鎮(zhèn)靜催眠作用機制研究
發(fā)布時間：2019-05-27 03:38
【摘要】：前言失眠是常見的一種睡眠障礙性疾病,是多種軀體、精神和行為疾病所具有的常見臨床表現(xiàn)。流行病學調查資料表明,西方國家約35.2%的人有不同程度的失眠;我國失眠率也高達10%~20%。睡眠障礙可能對人體健康造成嚴重的危害,長期失眠,不僅導致抑郁,還會造成機體疲勞,導致認知功能障礙,甚至破壞免疫系統(tǒng)功能,對心臟造成損傷,干擾血糖調節(jié)、激素分泌等,甚至發(fā)展為精神抑郁。失眠的發(fā)病原因與遺傳因素、生活習慣、環(huán)境、疾病和精神心理因素有關。對其發(fā)病機制的研究表明,失眠患者5-HT、NE、GABA等中樞神經(jīng)遞質紊亂,邊緣-皮質系統(tǒng)環(huán)路異常。阿魏酸鈉是心腦血管病的常用藥物,國外研究和臨床觀察發(fā)現(xiàn)阿魏酸鈉具有鎮(zhèn)靜催眠的作用,然而,阿魏酸鈉對中樞神經(jīng)遞質5-HT、NE、GABA以及海馬神經(jīng)細胞有何影響,尚不清楚。目的本研究通過建立失眠大鼠模型,探討阿魏酸鈉對失眠大鼠的睡眠改善作用以及作用機制。材料與方法1.利用對氯苯丙氨酸(PCPA)腹腔注射制備失眠大鼠模型,觀察阿魏酸鈉對模型大鼠一般狀態(tài)、體重變化、戊巴比妥鈉致大鼠睡眠時間的影響,并對大鼠GABA、5-HT、NE、IL-1β含量及GABAARa1 m RNA表達量進行測定,同時觀察大鼠腦組織病理學變化;2.阿魏酸鈉改善睡眠作用與5-羥色胺能神經(jīng)系統(tǒng)相關性的實驗研究。觀察阿魏酸鈉對大鼠前額葉皮質區(qū)、下丘腦部位和海馬組織5-HT水平的影響;觀察阿魏酸鈉分別聯(lián)合5-HT合成的前體物質5-HTP和5-HT合成酶的抑制劑PCPA后對大鼠睡眠潛伏期和睡眠持續(xù)時間的影響;Elisa法測定阿魏酸鈉對大鼠中樞不同腦區(qū)5-HT合成的限速酶色氨酸羥化酶(TPH)和代謝產(chǎn)物5-HIAA的含量的影響;應用RT-PCR技術考察阿魏酸鈉對大鼠下丘腦5-HT轉運體編碼基因Slc6a4和5-HT1A受體編碼基因5-HTR1A表達的影響;3.阿魏酸鈉對模型大鼠GABA水平影響的機制研究。利用對氯苯丙氨酸(PCPA)腹腔注射制備失眠大鼠模型,分離各組大鼠腦干、下丘腦、額葉皮質和海馬組織,Elisa法測定大鼠腦干、下丘腦、額葉皮質和海馬組織GABA水平,HPLC法測定Glu水平,Western Blot法測定GAD、GS水平;4.阿魏酸鈉對大鼠海馬神經(jīng)細胞的影響及作用機制研究。疊氮鈉誘導大鼠海馬神經(jīng)細胞制備線粒體損傷海馬神經(jīng)細胞模型,MTT法考察阿魏酸鈉對線粒體損傷海馬神經(jīng)細胞的保護作用。采用腹腔注射對氯苯丙氨酸(PCPA)法制備睡眠剝奪大鼠模型,TUNEL染色法觀察阿魏酸鈉對大鼠海馬神經(jīng)細胞凋亡的影響,采用透射電子顯微鏡觀察阿魏酸鈉對線粒體結構影響,測定阿魏酸鈉對線粒體ATP酶活力的影響,RT-PCR法檢測各組大鼠海馬組織Bcl-2和Bax的m RNA和蛋白表達水平,探討阿魏酸鈉對海馬神經(jīng)細胞的作用機制。結果1.阿魏酸鈉對PCPA失眠模型大鼠一般狀態(tài),睡眠質量及睡眠相關的神經(jīng)遞質均有較好的調節(jié)作用。阿魏酸鈉可有效改善模型大鼠的一般狀態(tài),縮短睡眠潛伏期、延長睡眠時間、提高GABA、5-HT、IL-1β水平及GABA m RNA相對表達量,同時可有效降低NE水平;2.阿魏酸鈉改善睡眠作用與5-羥色胺能神經(jīng)系統(tǒng)相關性的實驗研究。阿魏酸鈉可明顯提高大鼠前額葉皮質區(qū)、下丘腦部位和海馬組織5-HT和TPH濃度(P0.05)。阿魏酸鈉組與5-HTP聯(lián)合應用試驗中,阿魏酸鈉組以及5-HTP組大鼠睡眠潛伏期均有縮短的趨勢,在睡眠持續(xù)時間上均有延長的趨勢,但差異與空白對照組均無統(tǒng)計學意義(P0.05),當阿魏酸鈉和5-HTP聯(lián)合應用時,大鼠的睡眠潛伏期和睡眠持續(xù)時間與空白組比較差異均具有統(tǒng)計學意義(P0.05)。阿魏酸鈉和PACA聯(lián)合應用試驗中,阿魏酸鈉組大鼠睡眠潛伏期明顯縮短(P0.05),PCPA組潛伏期明顯長于阿魏酸鈉組和空白對照組(P0.05),睡眠持續(xù)時間實驗結果表明,與空白組比較,阿魏酸鈉組可以顯著延長大鼠睡眠時間(P0.05),PCPA組睡眠持續(xù)時間明顯縮短(P0.05),聯(lián)合組與空白組比較差異無統(tǒng)計學意義(P0.05)。阿魏酸鈉組大鼠海馬區(qū)、下丘腦部位以及前額葉皮質區(qū)5-HIAA的濃度較空白組均顯著升高(P0.05),海馬組織與下丘腦5-HIAA/5-HT比值與空白組相比差異具有統(tǒng)計學意義(P0.05)。前額葉皮質區(qū)5-HIAA/5-HT比值與空白組相比差異無統(tǒng)計學意義(P0.05)。阿魏酸鈉組大鼠下丘腦部位Slc6a4表達明顯降低,5-HTR1A表達顯著升高;3.與對照組比較,模型組大鼠不同腦區(qū)GABA、GAD水平均顯著降低,Glu、GS水平均顯著升高,阿魏酸鈉各劑量組均可提高模型大鼠不同腦區(qū)GABA、GAD水平,降低不同腦區(qū)Glu水平,降低下丘腦、額葉皮質和海馬組織GS水平,對大鼠腦干GS調節(jié)效果不明顯;4.MTT法考察阿魏酸鈉對線粒體損傷海馬神經(jīng)細胞的保護作用研究結果顯示,線粒體損傷大鼠海馬神經(jīng)細胞存活率較正常對照組顯著下降(P0.05),阿魏酸鈉組海馬神經(jīng)細胞存活率高于模型組(P0.05)。TUNEL染色法結果顯示阿魏酸鈉可降低睡眠剝奪模型大鼠海馬神經(jīng)細胞凋亡率,RT-PCR結果顯示阿魏酸鈉可以促進Bcl-2 m RNA和蛋白表達,抑制Bax m RNA和蛋白表達,抑制海馬神經(jīng)細胞凋亡。結論1.阿魏酸鈉對PCPA失眠模型大鼠一般狀態(tài),睡眠質量均有較好的調節(jié)作用;該作用可能是通過增加GABA水平,抑制神經(jīng)元興奮,提高5-HT,減低NE水平,降低NE水平來抑制NE的維持覺醒功能來實現(xiàn)。2.阿魏酸鈉可通過協(xié)同5-HT前體物質5-HTP、拮抗腦內5-HT合成酶抑制劑PCPA、提高5-HT能神經(jīng)系統(tǒng)的興奮性、抑制5-HT轉運體表達、增強5-HT受體表達等機制發(fā)揮改善睡眠的作用;3.阿魏酸鈉對大鼠GABA水平影響可能是通過影響腦組織各部位中GAD及GS的表達水平,抑制或促進GABA與Glu之間的相互轉化,改變Glu/GABA比值平衡實現(xiàn)的;4.阿魏酸鈉可以抑制睡眠剝奪引起的海馬神經(jīng)細胞凋亡,從而改善睡眠,其作用機制與促進Bcl-2 m RNA和蛋白表達,抑制Bax m RNA和蛋白表達有關。
[Abstract]:Insomnia is a common type of sleep disorder, which is a common clinical manifestation of various body, mental and behavioral diseases. According to the epidemiological survey, about 35.2% of Western countries have different levels of insomnia, and the rate of insomnia in China is also as high as 10% ~ 20%. The sleep disorder may cause serious harm to human health, long-term insomnia, not only cause depression, but also cause body fatigue, cause cognitive dysfunction, even destroy the function of the immune system, cause damage to the heart, interfere with blood glucose regulation, hormone secretion, etc., And even developed into mental depression. The causes of insomnia are related to the genetic factors, the living habits, the environment, the disease and the mental and psychological factors. The study of its pathogenesis indicated that 5-HT, NE, GABA and other central neurotransmitters, such as 5-HT, NE, GABA and other central neurotransmitters, were abnormal in the edge-cortex system. Sodium ferulate is a common drug for cardiovascular and cerebrovascular diseases. It is found that sodium ferulate has a sedative and hypnotic effect in foreign research and clinical observation. However, the effect of sodium ferulate on the 5-HT, NE, GABA and hippocampal neurons of the central neurotransmitters is not clear. Objective To study the effect and mechanism of sodium ferulate on the sleep improvement of insomnia rats by establishing a model of insomnia rats. Materials and Methods 1. The effect of sodium ferulate on the sleep time of rats induced by sodium pentobarbital was observed by intraperitoneal injection of p-chlorophenylalanine (PCPA), and the content of GABA,5-HT, NE, IL-1 and the expression of GABAAR1 m were measured. The pathological changes of the brain tissue of the rats were also observed. Experimental study of the relationship between the effect of sodium ferulate on the sleep and the nervous system of 5-hydroxytryptamine. The effects of sodium ferulate on the levels of 5-HT in the prefrontal cortex, the hypothalamus and the hippocampus of the rats were observed, and the effects of sodium ferulate on the sleep latency and sleep duration of the rats were observed with 5-HT-synthesized precursor materials 5-HTP and 5-HT synthetase inhibitor PCPA, respectively. The effects of sodium ferulate on the content of 5-HT (5-HT) and 5-HT1A receptor-encoding gene (5-HT1A) in the hypothalamus of rats were determined by Elisa method. The effect of sodium ferulate on the expression of 5-HT1A receptor-encoding gene, Sc6a4 and 5-HT1A, was investigated by RT-PCR. The mechanism of the effect of sodium ferulate on the level of GABA in the model rats. The rat brain stem, the hypothalamus, the frontal cortex and the hippocampus of the rat brain stem, the hypothalamus, the frontal cortex and the hippocampus were isolated by intraperitoneal injection of p-chlorophenylalanine (PCPA). The levels of GABA in the brain stem, the hypothalamus, the frontal cortex and the hippocampus of the rats were determined by the Elisa method. GS level;4. The effect of sodium ferulate on the rat hippocampal neurons and its mechanism of action. The effects of sodium ferulate on the protective effects of sodium ferulate on the nerve cells of the hippocampus were studied by means of MTT method. The effect of sodium ferulate on the apoptosis of the rat's hippocampal neurons was studied by means of intraperitoneal injection of p-phenylalanine (PCPA), and the effect of sodium ferulate on the structure of the mitochondria was observed by a transmission electron microscope. The effect of sodium ferulate on the activity of the mitochondrial ATP enzyme was determined. The mRNA and protein expression levels of Bcl-2 and Bax in the hippocampus of each group were detected by RT-PCR, and the mechanism of the action of sodium ferulate on the nerve cells in the hippocampus was discussed. Results 1. Sodium ferulate has a good effect on the general status, sleep quality and sleep-related neurotransmitters in the model of PCPA insomnia. Sodium ferulate can effectively improve the normal state of the model rat, shorten the sleep period, prolong the sleep time, improve the relative expression of the GABA,5-HT, IL-1, and the GABA m RNA, and can effectively reduce the NE level; Experimental study of the relationship between the effect of sodium ferulate on the sleep and the nervous system of 5-hydroxytryptamine. Sodium ferulate significantly increased the concentration of 5-HT and TPH in the prefrontal cortex, the hypothalamus and the hippocampus of the rats (P0.05). During the combined application of sodium ferulate and 5-HTP, the sleep latency of the sodium ferulate group and the 5-HTP group had a tendency to be shortened, but there was no significant difference in the duration of the sleep (P0.05). When the sodium ferulate and the 5-HTP were used in combination, The sleep latency and sleep duration of the rats were significantly different from those in the blank group (P0.05). In the combined application of sodium ferulate and PACA, the sleep latency of the sodium ferulate group was significantly shorter than that of the sodium ferulate group (P0.05). The latency of the PCPA group was significantly longer than that of the sodium ferulate group and the blank control group (P0.05). The experimental results of the sleep duration showed that compared with the blank group, The group of sodium ferulate could significantly prolong the sleep time of the rats (P0.05). The sleep duration of the PCPA group was significantly shortened (P0.05), and the difference between the combined group and the blank group was not statistically significant (P0.05). The concentration of 5-HIAA in the hippocampus, the hypothalamus and the prefrontal cortex of the sodium ferulate group was significantly higher than that in the blank group (P0.05). The ratio of the 5-HIAA/5-HT in the hippocampus and the hypothalamus was statistically significant (P0.05). The 5-HIAA/5-HT ratio in the prefrontal cortex was not statistically significant (P0.05). The expression of Sc6a4 in the hypothalamus of the sodium ferulate group was significantly decreased, and the expression of 5-HTR1A was significantly increased. Compared with the control group, the levels of GABA and GAD in different brain regions of the model group were significantly decreased, and the levels of Glu and GS increased significantly, and the levels of GABA and GAD in different brain regions of the model rats can be improved by the dosage groups of sodium ferulate, and the levels of Glu and GAD in different brain regions can be reduced, and the hypothalamus can be reduced. The results of the study of the protective effect of sodium ferulate on the nerve cells in the hippocampus of the rats with mitochondrial injury showed that the survival rate of the neurons in the hippocampus of the rats with the mitochondrial injury was significantly lower than that in the normal control group (P0.05). The results of the TUNEL staining showed that the sodium ferulate could decrease the apoptosis rate of the hippocampal neurons in the sleep deprivation model. The results of RT-PCR showed that the sodium ferulate could promote the expression of Bcl-2 mRNA and protein, and inhibit the expression of Bax mRNA and protein. And the apoptosis of the hippocampal neurons is inhibited. Conclusion 1. The effect of sodium ferulate on the general status and the quality of sleep in the model of PCPA insomnia may be achieved by increasing the level of GABA, inhibiting the excitation of neurons, increasing the 5-HT, reducing the NE level, and decreasing the NE level to inhibit the maintenance of NE. Sodium ferulate can play an important role in improving sleep by combining 5-HT precursor substance 5-HTP, antagonizing the 5-HT synthetase inhibitor PCPA in the brain, increasing the excitability of the 5-HT energy nervous system, inhibiting the expression of 5-HT transporter, and enhancing the expression of 5-HT receptor. The effect of sodium ferulate on the level of GABA in rats may be by influencing the expression level of GAD and GS in various parts of the brain tissue, inhibiting or promoting the mutual transformation between GABA and Glu, and changing the balance of Glu/ GABA ratio; Sodium ferulate can inhibit the apoptosis of the hippocampal neurons caused by sleep deprivation, so as to improve the sleep, and the mechanism of action is related to the promotion of the expression of Bcl-2 mRNA and protein and the inhibition of the expression of Bax mRNA and protein.
【學位授予單位】：鄭州大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R740
本文編號：2485881
[Abstract]:Insomnia is a common type of sleep disorder, which is a common clinical manifestation of various body, mental and behavioral diseases. According to the epidemiological survey, about 35.2% of Western countries have different levels of insomnia, and the rate of insomnia in China is also as high as 10% ~ 20%. The sleep disorder may cause serious harm to human health, long-term insomnia, not only cause depression, but also cause body fatigue, cause cognitive dysfunction, even destroy the function of the immune system, cause damage to the heart, interfere with blood glucose regulation, hormone secretion, etc., And even developed into mental depression. The causes of insomnia are related to the genetic factors, the living habits, the environment, the disease and the mental and psychological factors. The study of its pathogenesis indicated that 5-HT, NE, GABA and other central neurotransmitters, such as 5-HT, NE, GABA and other central neurotransmitters, were abnormal in the edge-cortex system. Sodium ferulate is a common drug for cardiovascular and cerebrovascular diseases. It is found that sodium ferulate has a sedative and hypnotic effect in foreign research and clinical observation. However, the effect of sodium ferulate on the 5-HT, NE, GABA and hippocampal neurons of the central neurotransmitters is not clear. Objective To study the effect and mechanism of sodium ferulate on the sleep improvement of insomnia rats by establishing a model of insomnia rats. Materials and Methods 1. The effect of sodium ferulate on the sleep time of rats induced by sodium pentobarbital was observed by intraperitoneal injection of p-chlorophenylalanine (PCPA), and the content of GABA,5-HT, NE, IL-1 and the expression of GABAAR1 m were measured. The pathological changes of the brain tissue of the rats were also observed. Experimental study of the relationship between the effect of sodium ferulate on the sleep and the nervous system of 5-hydroxytryptamine. The effects of sodium ferulate on the levels of 5-HT in the prefrontal cortex, the hypothalamus and the hippocampus of the rats were observed, and the effects of sodium ferulate on the sleep latency and sleep duration of the rats were observed with 5-HT-synthesized precursor materials 5-HTP and 5-HT synthetase inhibitor PCPA, respectively. The effects of sodium ferulate on the content of 5-HT (5-HT) and 5-HT1A receptor-encoding gene (5-HT1A) in the hypothalamus of rats were determined by Elisa method. The effect of sodium ferulate on the expression of 5-HT1A receptor-encoding gene, Sc6a4 and 5-HT1A, was investigated by RT-PCR. The mechanism of the effect of sodium ferulate on the level of GABA in the model rats. The rat brain stem, the hypothalamus, the frontal cortex and the hippocampus of the rat brain stem, the hypothalamus, the frontal cortex and the hippocampus were isolated by intraperitoneal injection of p-chlorophenylalanine (PCPA). The levels of GABA in the brain stem, the hypothalamus, the frontal cortex and the hippocampus of the rats were determined by the Elisa method. GS level;4. The effect of sodium ferulate on the rat hippocampal neurons and its mechanism of action. The effects of sodium ferulate on the protective effects of sodium ferulate on the nerve cells of the hippocampus were studied by means of MTT method. The effect of sodium ferulate on the apoptosis of the rat's hippocampal neurons was studied by means of intraperitoneal injection of p-phenylalanine (PCPA), and the effect of sodium ferulate on the structure of the mitochondria was observed by a transmission electron microscope. The effect of sodium ferulate on the activity of the mitochondrial ATP enzyme was determined. The mRNA and protein expression levels of Bcl-2 and Bax in the hippocampus of each group were detected by RT-PCR, and the mechanism of the action of sodium ferulate on the nerve cells in the hippocampus was discussed. Results 1. Sodium ferulate has a good effect on the general status, sleep quality and sleep-related neurotransmitters in the model of PCPA insomnia. Sodium ferulate can effectively improve the normal state of the model rat, shorten the sleep period, prolong the sleep time, improve the relative expression of the GABA,5-HT, IL-1, and the GABA m RNA, and can effectively reduce the NE level; Experimental study of the relationship between the effect of sodium ferulate on the sleep and the nervous system of 5-hydroxytryptamine. Sodium ferulate significantly increased the concentration of 5-HT and TPH in the prefrontal cortex, the hypothalamus and the hippocampus of the rats (P0.05). During the combined application of sodium ferulate and 5-HTP, the sleep latency of the sodium ferulate group and the 5-HTP group had a tendency to be shortened, but there was no significant difference in the duration of the sleep (P0.05). When the sodium ferulate and the 5-HTP were used in combination, The sleep latency and sleep duration of the rats were significantly different from those in the blank group (P0.05). In the combined application of sodium ferulate and PACA, the sleep latency of the sodium ferulate group was significantly shorter than that of the sodium ferulate group (P0.05). The latency of the PCPA group was significantly longer than that of the sodium ferulate group and the blank control group (P0.05). The experimental results of the sleep duration showed that compared with the blank group, The group of sodium ferulate could significantly prolong the sleep time of the rats (P0.05). The sleep duration of the PCPA group was significantly shortened (P0.05), and the difference between the combined group and the blank group was not statistically significant (P0.05). The concentration of 5-HIAA in the hippocampus, the hypothalamus and the prefrontal cortex of the sodium ferulate group was significantly higher than that in the blank group (P0.05). The ratio of the 5-HIAA/5-HT in the hippocampus and the hypothalamus was statistically significant (P0.05). The 5-HIAA/5-HT ratio in the prefrontal cortex was not statistically significant (P0.05). The expression of Sc6a4 in the hypothalamus of the sodium ferulate group was significantly decreased, and the expression of 5-HTR1A was significantly increased. Compared with the control group, the levels of GABA and GAD in different brain regions of the model group were significantly decreased, and the levels of Glu and GS increased significantly, and the levels of GABA and GAD in different brain regions of the model rats can be improved by the dosage groups of sodium ferulate, and the levels of Glu and GAD in different brain regions can be reduced, and the hypothalamus can be reduced. The results of the study of the protective effect of sodium ferulate on the nerve cells in the hippocampus of the rats with mitochondrial injury showed that the survival rate of the neurons in the hippocampus of the rats with the mitochondrial injury was significantly lower than that in the normal control group (P0.05). The results of the TUNEL staining showed that the sodium ferulate could decrease the apoptosis rate of the hippocampal neurons in the sleep deprivation model. The results of RT-PCR showed that the sodium ferulate could promote the expression of Bcl-2 mRNA and protein, and inhibit the expression of Bax mRNA and protein. And the apoptosis of the hippocampal neurons is inhibited. Conclusion 1. The effect of sodium ferulate on the general status and the quality of sleep in the model of PCPA insomnia may be achieved by increasing the level of GABA, inhibiting the excitation of neurons, increasing the 5-HT, reducing the NE level, and decreasing the NE level to inhibit the maintenance of NE. Sodium ferulate can play an important role in improving sleep by combining 5-HT precursor substance 5-HTP, antagonizing the 5-HT synthetase inhibitor PCPA in the brain, increasing the excitability of the 5-HT energy nervous system, inhibiting the expression of 5-HT transporter, and enhancing the expression of 5-HT receptor. The effect of sodium ferulate on the level of GABA in rats may be by influencing the expression level of GAD and GS in various parts of the brain tissue, inhibiting or promoting the mutual transformation between GABA and Glu, and changing the balance of Glu/ GABA ratio; Sodium ferulate can inhibit the apoptosis of the hippocampal neurons caused by sleep deprivation, so as to improve the sleep, and the mechanism of action is related to the promotion of the expression of Bcl-2 mRNA and protein and the inhibition of the expression of Bax mRNA and protein.
【學位授予單位】：鄭州大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R740
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