经鼻给予人参皂苷Rb1的脑靶向性及其对大鼠脑梗死的治疗作用
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摘要
背景与目的
人参皂苷是人参、三七等中药材的主要有效成分。人参皂苷Rb1ginsenosideRbl,GRb1)是其中含量最丰富的人参皂苷单体之一。研究发现GRb1具有抗氧化、抗凋亡、调节炎症反应、促进神经递质释放等作用,对多种中枢神经系统(central nervous systerm, CNS)疾病具有治疗作用。但其分子量大、水溶性的分子结构特点以及在肠道内容易降解、有首过消除效应等药代动力学特点致使其口服等常规给药方式生物利用度低。经鼻给药具有给药方便无创、吸收迅速的特点,并且可以使药物绕过BBB直接进入脑实质,目前已成为广泛接受的脑靶向给药方式之一。
自噬(autophagy)的概念由Christian de Duve于20世纪60年代提出,是一种在进化中高度保守的,用于批量降解胞浆内容物,如长寿命蛋白及细胞器的过程。在正常生理情况下,自噬处于低水平,用于维护细胞内环境的稳定。在出现营养或生长因子缺乏、内质网应激、细胞内异常产物堆积等情况下,自噬过程被激活。自噬的调控机制和在各种生理、病理情况下的作用是近几年生命科学领域新的研究热点之一
本研究观察GRb1经鼻给药后在大鼠脑组织中的药物分布特点,评价此给药方式的脑靶向性；研究经鼻给予GRb1对大鼠实验性脑梗死模型的治疗作用,并对GRb1对脑梗死后自噬过程的可能影响进行初步探讨。
方法
建立体外神经元谷氨酸兴奋性毒性模型。选择合适浓度的谷氨酸损伤后立即分别加入GRbl 1.2、12或120μM共同作用2 h。通过MTT的方法验证GRb1对谷氨酸损伤的保护作用。
成年雄性SD大鼠分别经鼻和经静脉给予GRb1 12.5 mg/kg,在给药后5、15、30、60、120、180 min处死,留取血浆和脑组织。采用HPLC-MS/MS的方法,检测GRb1血浆和脑组织各分区(嗅球+嗅束、皮层、海马、延髓以及小脑)中的含量,采用药物靶向性指数(drug targeting index, DTI)评价经鼻GRb1的脑靶向性。
大鼠大脑中动脉栓塞(middle cerebral artery occlusion, MCAO)后立即经鼻给予3Rb1 1.25 mg/kg,12.5 mg/kg或者等体积生理盐水,在给药后24 h处死,采用TTC, Nissl、TUNEL染色以及Evans blue渗漏试验等方法观察经鼻GRbl对梗死体积、梗死后神经元变性、血脑屏障损伤的影响,确定经鼻给予GRb1的有效剂量,评价其对脑梗死超急性期和急性期的疗效。
大鼠MCAO后立即经鼻给予GRb1 12.5 mg/kg,此后每日一次,共14 d。在梗死后第1、2、3、5、7、14 d进行神经功能缺损评分(modified neurological severity score, mNSS)。在梗死后14 d处死大鼠,进行HE染色,计算梗死体积；利用激光共聚焦显微镜,观察梗死周边区FITC-dextran灌注的血管数目。评价重复经鼻给予GRb1对梗死急性期后脑组织修复的影响。
大鼠MCAO后立即经鼻给予GRb1 12.5 mgkg,在梗死后0、1.5、6、12、24h处死。采用western blot、real-time RT-PCR、透射电镜的方法,观察GRb1对大鼠脑梗死后梗死灶周边区神经细胞超微结构以及LC3、Beclin 1的表达的影响,探讨GRb1对脑梗死治疗作用的可能的新的机制。
结果
在作用时间固定的情况下,随着谷氨酸钠浓度的升高,皮层神经元活力逐渐下降。GRb1能够明显减轻5 mM谷氨酸对体外培养皮层神经元的损伤。在12μM时保护作用最大。
GRb1经鼻给药后5 min即可在血浆中检出,其血浆生物利用度为1.40%。同样,GRb1在给药后5 min在脑组织各分区内达到高峰,随后逐渐下降,但给药后60 min后在皮层、海马等区域GRb1浓度再次升高。经鼻GRb1在脑组织各分区内的DTI为7.35至23.22,表现出明显的脑靶向性。
大鼠MCAO后立即经鼻给予GRb1能够明显缩小梗死体积,在一定剂量范围内效果与剂量呈正相关。经鼻GRb1 12.5 mg/kg可以明显减轻梗死周边区神经元损伤,减少TUNEL染色阳性细胞数并减轻梗死侧皮层Evans blue渗漏。
大鼠MCAO后连续给予GRbl 14 d过程中,在1-3 d mNSS显著低于对照组,在14d仍有低于对照组的趋势；GRb1组梗死体积明显小于对照组；梗死周边区微血管数量和对照组相比无明显差异。
GRb1能调节大鼠MCAO后激活的自噬,使梗死后LC3、Beclin 1的水平较对照组先升高然后下降。
结论
本研究结果表明,GRb1在体外能够减轻谷氨酸兴奋性毒性造成的神经元损伤；GRb1经鼻给药后能迅速进入脑组织,并表现出明显的脑靶向性；经鼻GRb1能够缩小脑梗死体积、减轻神经元和微血管损伤、改善梗死后mNSS,但对梗死后梗死周边区血管再生无明显影响,提示GRb1对大鼠脑梗死治疗作用的主要机制是其神经和血管保护作用。更深入的研究发现,GRb1对梗死周边区自噬的活性具有调节作用。人参皂苷经鼻给药是一种快捷有效的CNS疾病治疗方法,具有良好的临床开发和应用前景。
Ginsenosides are the main components of ginseng and notoginseng which are widely used in Far East for thousands of years. Ginsenoside Rb1 (GRb1), one of the most abundant ginsenosides, has been proved to have anti-oxidant, anti-apoptosis, inflammation modulating and transmitters release enhancing effects. GRbl thus could benefit to many central nervous system (CNS) disorders. Due to a relatively large molecular weight of 1109.46, hydrophilic molecular structure and biotransformation in intestinal tracts, GRbl has a poor bioavailability when administrated orally. It's predicted difficult for GRbl to cross the blood-brain barrier (BBB).
Autophagy is a highly conservative process for the degradation of cellular contents, particularly organelles and long-lasting proteins. Low level autophagy is crucial for maintaining intracellular homeostasis under normal conditions. However, autophagy could be activated by deficit of nutrition and growth factors, endoplasmic reticulum (ER) stress, accumulation of abnormal products and organelle injury. The modulation and role of autophagy under pathological conditions is a hot topic in recent years.
Intranasal administration is now a widely accepted non-invasive brain targeting delivery method. In the present study, we first investigated the contribution of GRb1 in different brain regions after intranasal administration to evaluate the brain targeting effects of this delivery method. Then, the beneficial effects of intranasal GRb1 on middle cerebral artery occlusion (MCAO) in rats were evaluated. Finally, the influence of GRbl on the activity of autophagy in the border of infarction was monitored.
Methods
Different doses of glutamic acid were added to the culture of cortical neuron. The excitotoxity was tested by MTT. Then, GRbl was added to the culture right after glutamic acid. The protective effect of GRb1 was evaluated.
GRbl was delivered intranasally or intravenously at a dose of 12.5 mg/kg to male Sprague Dawley (SD) rats, respectively. Rats were scarified at 5,15,30,60,120 and 180 min after drug administration. Plasma and brain tissues, i.e. olfactory bulb+olfactory tract, cerebrum, hippocampus, medulla oblongata and cerebellum, were collected. A HPLC-MS/MS method was employed to detect the concentration of GRb1 in plasma and brain regions mentioned above. Drug targeting index (DTI) was used to evaluate the brain targeting effects.
GRb1 was administrated immediately after the onset of MCAO. Rats were decapitated 24 h later. TTC, Nissl, TUNEL staining and Evans blue test were performed to evaluate the effects of intranasal Rbl on the infarct volume, neurodegeneration and BBB breakdown after MCAO.
In order to investigate the effects of GRbl on the recovery after acute ischemic stroke, GRb1 was administrated right after the onset of MCAO at a dose of 12.5 mg/kg and once daily for 14 consecutive days. Modified neurological severity score (mNSS) was performed on day 1,2,3,5,7 and 14. Rats were scarified on day 14. HE staining was used to evaluate the infarct volume. A confocal laser microscope was used to observe the number of FITC-dextran perfused microvessels in the peri-infarction area.
The influence of GRb1 on the state of autophagy after MCAO was investigated. Rats received intranasal GRb1 right after the onset of MCAO and killed at 0,1.5,6, 12,24 h later. Western blot, real-time RT-PCR and transmission electron microscopy was used to monitor the LC3, Beclin 1 levels and ultrastructural change of neuron in the border of infarction.
Results
The viability of cortical neuron lowered as the concentration of glutamic acid raised in vitro. GRb1 could ameliorate the excitoxicity caused by 5 mM glutamic acid, with a most effective dose at 12μM.
The bioavailability (F) in plasma for intranasal GRb1 is approximately 1.40%. However, intranasal GRb1 gained rather fast plasma absorption at as early as 5 min. After i.n administration, the brain GRb1 concentration reached peak level at 5 min, followed by a decline with time. Interestingly, the concentration of GRb1 in some brain regions, such as cerebrum and hippocampus, achieved a second raise at 60 min after intranasal administration. The value of DTI ranged from 7.35 to 23.22 in different brain regions, indicating a significant brain targeting effect.
Intranasal GRbl could reduce the infarction volume significantly. GRbl at a dose of 12.5 mg/kg was more efficient than 1.25 mg/kg. Intranasal GRb1 12.5 mg/kg could ameliorate the neuronal injury and reduce the number of TUNEL positive cells in the border of infarction. The Evans blue leakage was also suppressed by intranasal GRb1.
After consecutive administration, the mNSS at day 1-3 were significant lower in the GRb1 group. HE staining indicated the infarct volume was smaller than that of the control group. But the number of microvessels in the border of the infarction in the GRb1 group was not different from that of the control group.
GRb1 could modulate the activity of autophagy after MCAO in rats. The up-regulation of LC3 and Beclin 1 were amplified at 6 h but suppressed by intranasal GRb1 later.
Conclusions
GRb1 could ameliorate the excitotoxity induced by glutamate in cortical neuron culture. Intranasal administrated GRbl could enter CNS with a relative brain targeting effect, reduce the infarct volume, ameliorate neuronal and microvascular injury and improve the neurological function. These results suggest powerful neuronal and vascular protective effects of intranasal GRb1. Moreover, GRb1 could modulate the activity of autophagy in the border of infarction. Intranasal ginsenoside would be a potential brain targeting therapy for CNS disorders.
人参皂苷是人参、三七等中药材的主要有效成分。人参皂苷Rb1ginsenosideRbl,GRb1)是其中含量最丰富的人参皂苷单体之一。研究发现GRb1具有抗氧化、抗凋亡、调节炎症反应、促进神经递质释放等作用,对多种中枢神经系统(central nervous systerm, CNS)疾病具有治疗作用。但其分子量大、水溶性的分子结构特点以及在肠道内容易降解、有首过消除效应等药代动力学特点致使其口服等常规给药方式生物利用度低。经鼻给药具有给药方便无创、吸收迅速的特点,并且可以使药物绕过BBB直接进入脑实质,目前已成为广泛接受的脑靶向给药方式之一。
自噬(autophagy)的概念由Christian de Duve于20世纪60年代提出,是一种在进化中高度保守的,用于批量降解胞浆内容物,如长寿命蛋白及细胞器的过程。在正常生理情况下,自噬处于低水平,用于维护细胞内环境的稳定。在出现营养或生长因子缺乏、内质网应激、细胞内异常产物堆积等情况下,自噬过程被激活。自噬的调控机制和在各种生理、病理情况下的作用是近几年生命科学领域新的研究热点之一
本研究观察GRb1经鼻给药后在大鼠脑组织中的药物分布特点,评价此给药方式的脑靶向性；研究经鼻给予GRb1对大鼠实验性脑梗死模型的治疗作用,并对GRb1对脑梗死后自噬过程的可能影响进行初步探讨。
方法
建立体外神经元谷氨酸兴奋性毒性模型。选择合适浓度的谷氨酸损伤后立即分别加入GRbl 1.2、12或120μM共同作用2 h。通过MTT的方法验证GRb1对谷氨酸损伤的保护作用。
成年雄性SD大鼠分别经鼻和经静脉给予GRb1 12.5 mg/kg,在给药后5、15、30、60、120、180 min处死,留取血浆和脑组织。采用HPLC-MS/MS的方法,检测GRb1血浆和脑组织各分区(嗅球+嗅束、皮层、海马、延髓以及小脑)中的含量,采用药物靶向性指数(drug targeting index, DTI)评价经鼻GRb1的脑靶向性。
大鼠大脑中动脉栓塞(middle cerebral artery occlusion, MCAO)后立即经鼻给予3Rb1 1.25 mg/kg,12.5 mg/kg或者等体积生理盐水,在给药后24 h处死,采用TTC, Nissl、TUNEL染色以及Evans blue渗漏试验等方法观察经鼻GRbl对梗死体积、梗死后神经元变性、血脑屏障损伤的影响,确定经鼻给予GRb1的有效剂量,评价其对脑梗死超急性期和急性期的疗效。
大鼠MCAO后立即经鼻给予GRb1 12.5 mg/kg,此后每日一次,共14 d。在梗死后第1、2、3、5、7、14 d进行神经功能缺损评分(modified neurological severity score, mNSS)。在梗死后14 d处死大鼠,进行HE染色,计算梗死体积；利用激光共聚焦显微镜,观察梗死周边区FITC-dextran灌注的血管数目。评价重复经鼻给予GRb1对梗死急性期后脑组织修复的影响。
大鼠MCAO后立即经鼻给予GRb1 12.5 mgkg,在梗死后0、1.5、6、12、24h处死。采用western blot、real-time RT-PCR、透射电镜的方法,观察GRb1对大鼠脑梗死后梗死灶周边区神经细胞超微结构以及LC3、Beclin 1的表达的影响,探讨GRb1对脑梗死治疗作用的可能的新的机制。
结果
在作用时间固定的情况下,随着谷氨酸钠浓度的升高,皮层神经元活力逐渐下降。GRb1能够明显减轻5 mM谷氨酸对体外培养皮层神经元的损伤。在12μM时保护作用最大。
GRb1经鼻给药后5 min即可在血浆中检出,其血浆生物利用度为1.40%。同样,GRb1在给药后5 min在脑组织各分区内达到高峰,随后逐渐下降,但给药后60 min后在皮层、海马等区域GRb1浓度再次升高。经鼻GRb1在脑组织各分区内的DTI为7.35至23.22,表现出明显的脑靶向性。
大鼠MCAO后立即经鼻给予GRb1能够明显缩小梗死体积,在一定剂量范围内效果与剂量呈正相关。经鼻GRb1 12.5 mg/kg可以明显减轻梗死周边区神经元损伤,减少TUNEL染色阳性细胞数并减轻梗死侧皮层Evans blue渗漏。
大鼠MCAO后连续给予GRbl 14 d过程中,在1-3 d mNSS显著低于对照组,在14d仍有低于对照组的趋势；GRb1组梗死体积明显小于对照组；梗死周边区微血管数量和对照组相比无明显差异。
GRb1能调节大鼠MCAO后激活的自噬,使梗死后LC3、Beclin 1的水平较对照组先升高然后下降。
结论
本研究结果表明,GRb1在体外能够减轻谷氨酸兴奋性毒性造成的神经元损伤；GRb1经鼻给药后能迅速进入脑组织,并表现出明显的脑靶向性；经鼻GRb1能够缩小脑梗死体积、减轻神经元和微血管损伤、改善梗死后mNSS,但对梗死后梗死周边区血管再生无明显影响,提示GRb1对大鼠脑梗死治疗作用的主要机制是其神经和血管保护作用。更深入的研究发现,GRb1对梗死周边区自噬的活性具有调节作用。人参皂苷经鼻给药是一种快捷有效的CNS疾病治疗方法,具有良好的临床开发和应用前景。
Ginsenosides are the main components of ginseng and notoginseng which are widely used in Far East for thousands of years. Ginsenoside Rb1 (GRb1), one of the most abundant ginsenosides, has been proved to have anti-oxidant, anti-apoptosis, inflammation modulating and transmitters release enhancing effects. GRbl thus could benefit to many central nervous system (CNS) disorders. Due to a relatively large molecular weight of 1109.46, hydrophilic molecular structure and biotransformation in intestinal tracts, GRbl has a poor bioavailability when administrated orally. It's predicted difficult for GRbl to cross the blood-brain barrier (BBB).
Autophagy is a highly conservative process for the degradation of cellular contents, particularly organelles and long-lasting proteins. Low level autophagy is crucial for maintaining intracellular homeostasis under normal conditions. However, autophagy could be activated by deficit of nutrition and growth factors, endoplasmic reticulum (ER) stress, accumulation of abnormal products and organelle injury. The modulation and role of autophagy under pathological conditions is a hot topic in recent years.
Intranasal administration is now a widely accepted non-invasive brain targeting delivery method. In the present study, we first investigated the contribution of GRb1 in different brain regions after intranasal administration to evaluate the brain targeting effects of this delivery method. Then, the beneficial effects of intranasal GRb1 on middle cerebral artery occlusion (MCAO) in rats were evaluated. Finally, the influence of GRbl on the activity of autophagy in the border of infarction was monitored.
Methods
Different doses of glutamic acid were added to the culture of cortical neuron. The excitotoxity was tested by MTT. Then, GRbl was added to the culture right after glutamic acid. The protective effect of GRb1 was evaluated.
GRbl was delivered intranasally or intravenously at a dose of 12.5 mg/kg to male Sprague Dawley (SD) rats, respectively. Rats were scarified at 5,15,30,60,120 and 180 min after drug administration. Plasma and brain tissues, i.e. olfactory bulb+olfactory tract, cerebrum, hippocampus, medulla oblongata and cerebellum, were collected. A HPLC-MS/MS method was employed to detect the concentration of GRb1 in plasma and brain regions mentioned above. Drug targeting index (DTI) was used to evaluate the brain targeting effects.
GRb1 was administrated immediately after the onset of MCAO. Rats were decapitated 24 h later. TTC, Nissl, TUNEL staining and Evans blue test were performed to evaluate the effects of intranasal Rbl on the infarct volume, neurodegeneration and BBB breakdown after MCAO.
In order to investigate the effects of GRbl on the recovery after acute ischemic stroke, GRb1 was administrated right after the onset of MCAO at a dose of 12.5 mg/kg and once daily for 14 consecutive days. Modified neurological severity score (mNSS) was performed on day 1,2,3,5,7 and 14. Rats were scarified on day 14. HE staining was used to evaluate the infarct volume. A confocal laser microscope was used to observe the number of FITC-dextran perfused microvessels in the peri-infarction area.
The influence of GRb1 on the state of autophagy after MCAO was investigated. Rats received intranasal GRb1 right after the onset of MCAO and killed at 0,1.5,6, 12,24 h later. Western blot, real-time RT-PCR and transmission electron microscopy was used to monitor the LC3, Beclin 1 levels and ultrastructural change of neuron in the border of infarction.
Results
The viability of cortical neuron lowered as the concentration of glutamic acid raised in vitro. GRb1 could ameliorate the excitoxicity caused by 5 mM glutamic acid, with a most effective dose at 12μM.
The bioavailability (F) in plasma for intranasal GRb1 is approximately 1.40%. However, intranasal GRb1 gained rather fast plasma absorption at as early as 5 min. After i.n administration, the brain GRb1 concentration reached peak level at 5 min, followed by a decline with time. Interestingly, the concentration of GRb1 in some brain regions, such as cerebrum and hippocampus, achieved a second raise at 60 min after intranasal administration. The value of DTI ranged from 7.35 to 23.22 in different brain regions, indicating a significant brain targeting effect.
Intranasal GRbl could reduce the infarction volume significantly. GRbl at a dose of 12.5 mg/kg was more efficient than 1.25 mg/kg. Intranasal GRb1 12.5 mg/kg could ameliorate the neuronal injury and reduce the number of TUNEL positive cells in the border of infarction. The Evans blue leakage was also suppressed by intranasal GRb1.
After consecutive administration, the mNSS at day 1-3 were significant lower in the GRb1 group. HE staining indicated the infarct volume was smaller than that of the control group. But the number of microvessels in the border of the infarction in the GRb1 group was not different from that of the control group.
GRb1 could modulate the activity of autophagy after MCAO in rats. The up-regulation of LC3 and Beclin 1 were amplified at 6 h but suppressed by intranasal GRb1 later.
Conclusions
GRb1 could ameliorate the excitotoxity induced by glutamate in cortical neuron culture. Intranasal administrated GRbl could enter CNS with a relative brain targeting effect, reduce the infarct volume, ameliorate neuronal and microvascular injury and improve the neurological function. These results suggest powerful neuronal and vascular protective effects of intranasal GRb1. Moreover, GRb1 could modulate the activity of autophagy in the border of infarction. Intranasal ginsenoside would be a potential brain targeting therapy for CNS disorders.
引文
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