外源性褪黑素对豚鼠形觉剥夺性近视中褪黑素受体、iNOS、c-fos表达的影响
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摘要
近视是一种常见的屈光不正,并有引发病理性改变的风险。包括人在内的大多数动物出生时是处于远视状态的,在生长过程中逐渐形成正视。这个过程是需要依赖视觉的。如果此过程中缺乏早期的视觉经历,则很可能会导致眼球的发育异常,最终导致近视的形成。形觉剥夺性近视(form deprivation myopia, FDM)是指用人为的方法比如缝合眼睑、戴弥散镜片或半透明眼罩来改变实验动物的视觉经历,造成实验动物屈光度及眼轴长度发生改变从而引起近视的一种实验方法。Wiesel于1977年用缝合恒河猴眼睑的方法首次成功诱导出形觉剥夺性近视,此后近视动物模型建立的方法在不断的发展与完善。已有的研究表明,形觉剥夺性近视是一种涉及多种介质与因子改变的复杂的过程。新近的研究将重点越来越聚焦于视网膜上各种神经介质的功能和变化,这些神经介质中,褪黑素(melatonin, MLT)逐渐受到人们的关注。
褪黑素是一种神经内分泌激素,化学名为N-乙酰-5-甲氧色胺,由5-羟色胺转化而来。因发现进入蛙黑色素细胞后会使蛙全身的肽色变浅而得名。在生理状况下,人及其它哺乳动物、鸟类体内褪黑素主要来源于松果体。但有些松果体外组织也能合成少量,例如视网膜、肠、副泪腺等。松果体内分泌褪黑素呈24小时规律性波动,表现为夜间分泌增加而白天分泌减少,其分泌节律由交叉上核团(SCN)根据昼夜节律来控制。
褪黑素在动物体内发挥各种生理作用需要通过褪黑素受体的介导来完成。二十世纪末召开了国际药理学联合会会议,在此次会议上MLT受体被分为3种亚型,分别为MT1、MT2、MT3;人眼部视网膜及其外大部分眼部组织中存在MT1、MT2。MLT不仅具有清除氢氧自由基的能力,而且可以抑制体内一氧化氮(NO)过度生成,对损伤和炎症有保护作用。c-fos是一种原癌基因,属于即刻-早期基因类。本实验在建立豚鼠形觉剥夺性近视模型的同时,给予不同剂量外源性MLT干预。观察各组眼屈光度、眼轴长度、及视网膜MT1、iNOS及c-fos的变化,推测外源性MLT在FDM形成中的作用。
材料与方法
选用出生后7天的雄性健康花色豚鼠40只,复方托品酰胺眼液滴眼后检影验光,排除先天性近视及其它眼疾。用半透明眼罩遮盖豚鼠右眼,左眼为对照眼,建立FDM模型。将40只豚鼠随机分为4组,每组10只。A组为对照组,经腹腔注射生理盐水5 ml·kg-1,B、C、D组分别经腹腔注射外源性MLT5 mg·kg-1、10 mg-kg-1、20 mg·kg-1,隔日一次,连续注射8周。实验进行8周后,用A超测量豚鼠双眼眼轴长度,用检影验光法检测双眼屈光度数,用免疫组织化学染色法检测豚鼠双眼视网膜上褪黑素受体MT1、诱导型一氧化氮合酶(iNOS)和c-fos的表达水平。采集相应的视网膜切片图像,用Image-Pro Plus 6.0图像分析软件进行分析,用平均光密度值来表示以上指标的表达强度。
所有的实验数据用x±s表示,数据的统计学分析采用SPSS 17.0统计软件包,首先进行方差齐性检验,然后再行单因素方差分析及LSD-t检验,以α=0.05作为检验水准。P<0.05为差异有统计学意义。
结果
1.A组遮盖眼屈光度数、眼轴长度、视网膜中iNOS、MT1、c-fos平均光密度值表达分别为：(-7.86±0.26)D、(8.51±0.16)mm、(0.4836±0.0247)、(0.3179±0.0344)、(0.2282±0.0246),与对照眼相比遮盖眼近视屈光度增加,眼轴增长,视网膜中iNOS免疫活性增加而MT1、c-fos活性降低(P<0.05)。FDM模型建立成功。
2.不同剂量MLT作用于FDM,随外源性MLT剂量的增加,与A组相比,以上指标变化被明显抑制甚至逆转：C组和D组FDM眼的屈光度数、眼轴长度、视网膜中iNOS、MT1、c-fos平均光密度值表达分别为：(-4.30±0.59)和(-3.41±0.88)D、(8.04±0.24)和(7.43±0.39)mm、(0.3733±0.0427)和(0.3079±0.1261)、(0.3743±0.0447)和(0.4055±0.0919)、(0.3713±0.0786)和(0.4458±0.0974)。C组和D组与A组比较有显著性差异(P<0.05),差异有统计学意义；但B组与A组之间的差异无显著性(P>0.05)。
结论
1.8周后遮盖眼近视屈光度数增加,眼轴延长,成功建立FDM模型。
2.豚鼠遮盖眼视网膜中iNOS表达明显增多,MT1、c-fos表达明显减少,提示iNOS、MT1及c-fos可能参与了近视的形成。
3.外源性MLT能抑制甚至逆转FDM中屈光度、眼轴长度、iNOS、MT1、c-fos免疫活性。
4.外源性MLT高剂量组上述检测结果的抑制趋势较低剂量组明显。据此可推测外源性MLT对FDM的形成有抑制作用。
Myopia is a common refractive error, and posing a risk of pathological changes. Most animals including humans are born with hyperopia. In the growth process formed emmetropia gradually. This process relies on vision. If this process lack of early visual experience, are eventually leading to myopia. Form deprivation myopia (FDM) is employing methods, such as suturing the eyelids, wearing translucent goggles dispersion lenses or to change the visual experience delete, changes in refraction and axial length of the experimental animals, then myopia happened. Since Wiesel built up form deprivation myopia successfully by sewing the eyelids of rhesus monkey in 1977 for the first time, the method to establish animal models of myopia in constant development and improvement. Previous studies showed that form deprivation myopia is a complex process of change that involved in variety of media and factors. Recent studies more and more focus on the function and changes of neurotransmitter in retinal. In these neurotransmitters, people gradually pay attention to the melatonin (MLT).
Melatonin is a neuroendocrine hormone, the chemical known as N-acetyl -5-methoxy tryptamine, and it transformed from 5-hydroxytryptamine. Melatonin enter the frog melanoma cells can make the frog's skin color lighter, so called melatonin. In physiological conditions, the melatonin of human and other mammals and birds mainly from the pineal. But some other organizations can also synthesize a small amount of melatonin, such as the retina, intestine, vice lacrimal gland and so on. Pineal melatonin secretion was regular fluctuations in 24-hour, it means secretion increases during the night and reduce during the day. Circadian rhythms control the secretion rhythm by the suprachiasmatic nucleus rhythm (SCN).
Melatonin receptors play a role mainly through melatonin receptors. At the end of the twentieth century, the International Union of Pharmacology meeting was held, in this meeting MLT receptors were divided into 3 subtypes, namely MT1, MT2, MT3; Human retina and most of the eye tissues have MT1, MT2. MLT not only has the ability to remove hydroxyl radicals, but also can inhibit the body nitric oxide (NO) over-production, protect of injury and inflammation. C-fos is a proto-oncogene, belong to the immediate-early gene class. In this study, we establish the guinea pig model of form deprivation myopia and inject different doses of exogenous MLT, and observe every group guinea pig's refractive error, axial length, and retinal MT1, iNOS and c-fos changes. Speculat the formation of exogenous MLT's role in the FDM.
Material and Methods
To forty seven-days-old healthy male multicolor guinea pigs. Defore the cycloplegic retinoscopy guinea pigs to exclude congenital myopia and other eye diseases. Covering guinea pig's right eye with semi-transparent goggle to establish FDM model, the left eye as the control eye. The 40 guinea pigs were randomly divided into 4 groups of 10 each. Group A:The control group, by intraperitoneal injection of saline 5 ml·kg-1; B, C, D groups were treated with intraperitoneal injection of exogenous MLT 5 mg·kg-1、10 mg·kg-1、20 mg·kg-1, every other day, continuous infusion for 8 weeks. After 8 weeks of the experiment, the axial length was measured with A-mode ultrasound, the eyes refractive state was determined by streak retinoscopy, melatonin receptor MT1、iNOS and c-fos were analysed with immunohistochemistry. Imaging the retinal slice acquisition, analyze the protein expression by Image-Pro Plus 6.0 image analysis software, expressed of these indicators'intensity with the average optical density.
All experimental data are denoted by x±s, using the SPSS 17.0 statistical package for data statistical analysis. First we test homogeneity of variance, then compar with univariate analysis of variance and LSD-t test, andα= 0.05 as the test standard. P<0.05 was considered statistically significant.
Results
1. In the FDM eyes of group A,the diopter、axial length、iNOS、MT1 and c-fos were (-7.86±0.26) D、(8.51±0.16) mm、(0.4836±0.0247)、(0.3179±0.0344) and(0.2282±0.0246). Covered eye compared with the control eyes increased myopia, axial length growth, the immune activity of iNOS in the retina increased MT1, c-fos activity decreased (P<0.05).The FDM model was successfully established.
2. Intra-peritoneal injection of different doses MLT, as compared with group A, these indexes were significantly inhibited or even reversed changes with doses of exogenous melatonin increased. In the FDM eyes of group C and D, the diopter、axial length、iNOS、MT1 and c-fos were (-4.30±0.59)and(-3.41±0.88)D、(8.04±0.24) and (7.43±0.39) mm、(0.3733±0.0427) and (0.3079±0.1261)、(0.3743±0.0447) and (0.4055±0.0919)、(0.3713±0.0786) and (0.4458±0.0974) respectively;Group C and Group D covered with the control group A have significant difference (P<0.05), the difference was statistically significant. Covered with group B and group A, the difference was not significant (P> 0.05).
Conclusion
1. Myopia of covered eye was increased and axial length was growthed after 8 weeks, the guinea pigs form deprivation myopia model has been successfully established.
2. INOS expression in the retina of guinea pigs covered eye increased significantly, MT1, c-fos expression was significantly reduced, suggesting that iNOS, MT1 and c-fos may be involved in the formation of myopia.
3. Exogenous melatonin can inhibit or even reverse the changes of refractive error, axial length and immunoreactivity of iNOS, MT1, c-fos in the FDM.
4. The high dose melatonin groups were more significant than the low dose group. Inferred on the basis, the exogenous melatonin may inhibited the formation of FDA.
褪黑素是一种神经内分泌激素,化学名为N-乙酰-5-甲氧色胺,由5-羟色胺转化而来。因发现进入蛙黑色素细胞后会使蛙全身的肽色变浅而得名。在生理状况下,人及其它哺乳动物、鸟类体内褪黑素主要来源于松果体。但有些松果体外组织也能合成少量,例如视网膜、肠、副泪腺等。松果体内分泌褪黑素呈24小时规律性波动,表现为夜间分泌增加而白天分泌减少,其分泌节律由交叉上核团(SCN)根据昼夜节律来控制。
褪黑素在动物体内发挥各种生理作用需要通过褪黑素受体的介导来完成。二十世纪末召开了国际药理学联合会会议,在此次会议上MLT受体被分为3种亚型,分别为MT1、MT2、MT3;人眼部视网膜及其外大部分眼部组织中存在MT1、MT2。MLT不仅具有清除氢氧自由基的能力,而且可以抑制体内一氧化氮(NO)过度生成,对损伤和炎症有保护作用。c-fos是一种原癌基因,属于即刻-早期基因类。本实验在建立豚鼠形觉剥夺性近视模型的同时,给予不同剂量外源性MLT干预。观察各组眼屈光度、眼轴长度、及视网膜MT1、iNOS及c-fos的变化,推测外源性MLT在FDM形成中的作用。
材料与方法
选用出生后7天的雄性健康花色豚鼠40只,复方托品酰胺眼液滴眼后检影验光,排除先天性近视及其它眼疾。用半透明眼罩遮盖豚鼠右眼,左眼为对照眼,建立FDM模型。将40只豚鼠随机分为4组,每组10只。A组为对照组,经腹腔注射生理盐水5 ml·kg-1,B、C、D组分别经腹腔注射外源性MLT5 mg·kg-1、10 mg-kg-1、20 mg·kg-1,隔日一次,连续注射8周。实验进行8周后,用A超测量豚鼠双眼眼轴长度,用检影验光法检测双眼屈光度数,用免疫组织化学染色法检测豚鼠双眼视网膜上褪黑素受体MT1、诱导型一氧化氮合酶(iNOS)和c-fos的表达水平。采集相应的视网膜切片图像,用Image-Pro Plus 6.0图像分析软件进行分析,用平均光密度值来表示以上指标的表达强度。
所有的实验数据用x±s表示,数据的统计学分析采用SPSS 17.0统计软件包,首先进行方差齐性检验,然后再行单因素方差分析及LSD-t检验,以α=0.05作为检验水准。P<0.05为差异有统计学意义。
结果
1.A组遮盖眼屈光度数、眼轴长度、视网膜中iNOS、MT1、c-fos平均光密度值表达分别为：(-7.86±0.26)D、(8.51±0.16)mm、(0.4836±0.0247)、(0.3179±0.0344)、(0.2282±0.0246),与对照眼相比遮盖眼近视屈光度增加,眼轴增长,视网膜中iNOS免疫活性增加而MT1、c-fos活性降低(P<0.05)。FDM模型建立成功。
2.不同剂量MLT作用于FDM,随外源性MLT剂量的增加,与A组相比,以上指标变化被明显抑制甚至逆转：C组和D组FDM眼的屈光度数、眼轴长度、视网膜中iNOS、MT1、c-fos平均光密度值表达分别为：(-4.30±0.59)和(-3.41±0.88)D、(8.04±0.24)和(7.43±0.39)mm、(0.3733±0.0427)和(0.3079±0.1261)、(0.3743±0.0447)和(0.4055±0.0919)、(0.3713±0.0786)和(0.4458±0.0974)。C组和D组与A组比较有显著性差异(P<0.05),差异有统计学意义；但B组与A组之间的差异无显著性(P>0.05)。
结论
1.8周后遮盖眼近视屈光度数增加,眼轴延长,成功建立FDM模型。
2.豚鼠遮盖眼视网膜中iNOS表达明显增多,MT1、c-fos表达明显减少,提示iNOS、MT1及c-fos可能参与了近视的形成。
3.外源性MLT能抑制甚至逆转FDM中屈光度、眼轴长度、iNOS、MT1、c-fos免疫活性。
4.外源性MLT高剂量组上述检测结果的抑制趋势较低剂量组明显。据此可推测外源性MLT对FDM的形成有抑制作用。
Myopia is a common refractive error, and posing a risk of pathological changes. Most animals including humans are born with hyperopia. In the growth process formed emmetropia gradually. This process relies on vision. If this process lack of early visual experience, are eventually leading to myopia. Form deprivation myopia (FDM) is employing methods, such as suturing the eyelids, wearing translucent goggles dispersion lenses or to change the visual experience delete, changes in refraction and axial length of the experimental animals, then myopia happened. Since Wiesel built up form deprivation myopia successfully by sewing the eyelids of rhesus monkey in 1977 for the first time, the method to establish animal models of myopia in constant development and improvement. Previous studies showed that form deprivation myopia is a complex process of change that involved in variety of media and factors. Recent studies more and more focus on the function and changes of neurotransmitter in retinal. In these neurotransmitters, people gradually pay attention to the melatonin (MLT).
Melatonin is a neuroendocrine hormone, the chemical known as N-acetyl -5-methoxy tryptamine, and it transformed from 5-hydroxytryptamine. Melatonin enter the frog melanoma cells can make the frog's skin color lighter, so called melatonin. In physiological conditions, the melatonin of human and other mammals and birds mainly from the pineal. But some other organizations can also synthesize a small amount of melatonin, such as the retina, intestine, vice lacrimal gland and so on. Pineal melatonin secretion was regular fluctuations in 24-hour, it means secretion increases during the night and reduce during the day. Circadian rhythms control the secretion rhythm by the suprachiasmatic nucleus rhythm (SCN).
Melatonin receptors play a role mainly through melatonin receptors. At the end of the twentieth century, the International Union of Pharmacology meeting was held, in this meeting MLT receptors were divided into 3 subtypes, namely MT1, MT2, MT3; Human retina and most of the eye tissues have MT1, MT2. MLT not only has the ability to remove hydroxyl radicals, but also can inhibit the body nitric oxide (NO) over-production, protect of injury and inflammation. C-fos is a proto-oncogene, belong to the immediate-early gene class. In this study, we establish the guinea pig model of form deprivation myopia and inject different doses of exogenous MLT, and observe every group guinea pig's refractive error, axial length, and retinal MT1, iNOS and c-fos changes. Speculat the formation of exogenous MLT's role in the FDM.
Material and Methods
To forty seven-days-old healthy male multicolor guinea pigs. Defore the cycloplegic retinoscopy guinea pigs to exclude congenital myopia and other eye diseases. Covering guinea pig's right eye with semi-transparent goggle to establish FDM model, the left eye as the control eye. The 40 guinea pigs were randomly divided into 4 groups of 10 each. Group A:The control group, by intraperitoneal injection of saline 5 ml·kg-1; B, C, D groups were treated with intraperitoneal injection of exogenous MLT 5 mg·kg-1、10 mg·kg-1、20 mg·kg-1, every other day, continuous infusion for 8 weeks. After 8 weeks of the experiment, the axial length was measured with A-mode ultrasound, the eyes refractive state was determined by streak retinoscopy, melatonin receptor MT1、iNOS and c-fos were analysed with immunohistochemistry. Imaging the retinal slice acquisition, analyze the protein expression by Image-Pro Plus 6.0 image analysis software, expressed of these indicators'intensity with the average optical density.
All experimental data are denoted by x±s, using the SPSS 17.0 statistical package for data statistical analysis. First we test homogeneity of variance, then compar with univariate analysis of variance and LSD-t test, andα= 0.05 as the test standard. P<0.05 was considered statistically significant.
Results
1. In the FDM eyes of group A,the diopter、axial length、iNOS、MT1 and c-fos were (-7.86±0.26) D、(8.51±0.16) mm、(0.4836±0.0247)、(0.3179±0.0344) and(0.2282±0.0246). Covered eye compared with the control eyes increased myopia, axial length growth, the immune activity of iNOS in the retina increased MT1, c-fos activity decreased (P<0.05).The FDM model was successfully established.
2. Intra-peritoneal injection of different doses MLT, as compared with group A, these indexes were significantly inhibited or even reversed changes with doses of exogenous melatonin increased. In the FDM eyes of group C and D, the diopter、axial length、iNOS、MT1 and c-fos were (-4.30±0.59)and(-3.41±0.88)D、(8.04±0.24) and (7.43±0.39) mm、(0.3733±0.0427) and (0.3079±0.1261)、(0.3743±0.0447) and (0.4055±0.0919)、(0.3713±0.0786) and (0.4458±0.0974) respectively;Group C and Group D covered with the control group A have significant difference (P<0.05), the difference was statistically significant. Covered with group B and group A, the difference was not significant (P> 0.05).
Conclusion
1. Myopia of covered eye was increased and axial length was growthed after 8 weeks, the guinea pigs form deprivation myopia model has been successfully established.
2. INOS expression in the retina of guinea pigs covered eye increased significantly, MT1, c-fos expression was significantly reduced, suggesting that iNOS, MT1 and c-fos may be involved in the formation of myopia.
3. Exogenous melatonin can inhibit or even reverse the changes of refractive error, axial length and immunoreactivity of iNOS, MT1, c-fos in the FDM.
4. The high dose melatonin groups were more significant than the low dose group. Inferred on the basis, the exogenous melatonin may inhibited the formation of FDA.
引文
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