体内性激素对大鼠局灶性脑缺血影响及机制的研究
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摘要
临床资料表明性别不同,中风的发生率及结局明显不同,说明性激素在中枢神经系统损伤中起一定作用。因此本研究在建立雄激素致不孕大鼠(ASR)模型的基础上,给予果纳芬(rhFSH)后应用线栓法建立大鼠大脑中动脉阻塞(MCAO)模型,探讨体内性激素的改变对局灶性脑缺血的影响及作用机制。
结果表明:ASR+MCAO组神经评分、脑梗死面积、脑水含量及缺血侧坏死的神经数目明显增加,说明MCAO可造成严重的脑损伤;通过抑制EAAT1、EAAT2、EAAT3的表达,上调mGluR4及mGluR6的表达,增加兴奋性氨基酸的神经毒性,加重脑损害;ACE、AT1及AT2的表达增高,可激活RAS系统,通过缩血管,促凋亡等加重脑损伤;CLIC4的表达增高及AKT的表达降低,可促进细胞凋亡,抑制细胞存活,加重脑损伤;PDGF-B在脑缺血过程中表达上调,是机体的一种代偿反应,有利于血管增生以及重塑。给予rhFSH后能明显降低ASR+MCAO组神经评分、脑梗死面积及脑水含量,同时使大脑缺血侧坏死的神经数目减少,说明rhFSH具有明显的脑保护作用;其机制包括:上调EAAT1、EAAT2及EAAT3的表达,同时下调mGluR4及mGluR6的表达,加强谷氨酸转运;下调ACE、AT1及AT2的表达,抑制RAS系统的激活;下调CLIC4的表达,上调AKT及PDGF-B的表达,抑制凋亡,促进细胞存活及血管增生。
结论:由雄激素增高导致体内性激素的紊乱可通过多种途径加重脑缺血造成的损害,而rhFSH具有促进雌激素分泌的作用,可拮抗体内性激素的紊乱造成的脑损伤。
There are 2.5 million new patients of cerebrovascular disease in our country each year. And 1.5 million patients die of cerebrovascular disease each year. 75% of survivor will loss of work ability. Cerebrovascular dease is the second causing death and is also the first cause of mutilation. Cerebrovascular disease brings not only heavy health burden to patients, but also heavy economic burden to patients, society and government. So it is very important to explore the mechanism of cerebrovascular disease and to search the drug.
The incidence rate and outcome of stroke is depend on the sex. Several clinical investigations have demonstrated that the incidence rate of stroke in premenopause women was lower than that in man, but incidence rate of stroke in menopause women was increasing. The clinic retrospective investigations have demonstrated that incidence rate of stroke and myocardial infarction in menopause women treated with estradiol or estradiol plus progesterone was decreasing. It is suggested that sex hormone was involved in central nerve system injury.
Aim: The androgen-induced sterile rats (ASR) model was first made, then administrated by recombinant human follitropin alfa(rhFSH). The middle cerebral artery occlusion (MCAO) model was also established after rhFSH treatment. Then the effect of sex hormone on focal ischemia in rat brain and its mechanism was explored.
Methods: The androgen-induced sterile rats model was first made, then administrated by rhFSH. The MCAO model was also established after rhFSH treatment. The rats were divided into four group: ASR+sham, ASR+ rhFSH+sham, ASR+MCAO, ASR+rhFSH+MCAO. There were 12 rats in each group. The neurological severity score were performed at o hours and 24 hours in all group according to Zea Longa, respectively. The brain ischemia area was measured by TTC stain. The cortex morphological change was measured by HE staining. The cerebral water content was measured by using dry-wet weight method. The EAAT1,EAAT2,EAAT3, mGluR4,mGluR6,AGT, ACE, AT1,AT2, CLIC4, Akt, PDGF B mRNA and protein expression in cortex were assayed by RT-PCR and Westernblot.
Results and discussion: The rat in this experiment are all ASR rat. The testosterone in the serum is higher than normal. It means that ASR is a kind of sterilized rat induced by high androgen. The androgen is higher in serum of female rat. So we can use this kind of model to explore the effect of sex hormone on body. rhFSH can promote secretion of estrogen, so it can cure the sex hormone disturbance.
The neurological severity score, brain ischemia area and cerebral water content in ASR+MCAO was higher than that of ASR+sham. It suggested that the MCAO model is successfully established. HE staining showed that the number of neuron in ischemia side of ASR+MCAO group is decreasing and the axon is disappeared. The nucleus in neuron is blurred, and nucleolus is disappeared. It suggested that the cerebral injury was induced by MCAO. rhFSH can decrease the neurological severity score, brain ischemia area and cerebral water content in ASR+MCAO group. HE staining showed the number of necrosis neuron in ischemia side of ASR+rhFSH+MCAO group is decreasing. It was implied that rhFSH has protective effect on brain ischemia in ASR rat with MCAO.
The expression of genes related to excitatory amino acids was measured. The results showed that the EAAT1, EAAT2 and EAAT3 expression in ischemia side of ASR+MCAO group were obviously lower than that of ASR+sham group. This will result in accumulation of Glu in synaptic cleft because of Glu uptake by neuron and glial cell is decreasing. The mGluR4 and mGluR6 expression in ischemia side of ASR+MCAO group were obviously higher than that of ASR+sham group. The interaction between iGluR and mGluR will enhance the toxicity of excitatory amino acid. The rhFSH can lessen the toxicity of excitatory amino acid by upregulating the expression of EAAT1,EAAT2,EA AT3 and downregulating the expression of mGluR4 and mGluR6.
The expression of genes related to renin-angiotensin system(RAS) was also measured. The results showed that the ACE, AT1 and AT2 expression in ischemia side of ASR+MCAO group were obviously higher than that of ASR+sham group, but the AGT did not change. It suggested that the brain damage was deteriorated by the activation of RAS in cortex. The activation of RAS will result in vasoconstriction, blood pressure elevation and apoptosis. The rhFSH can lessen the brain ischemia injury by downregulating of RAS.
On the other hand, the CLIC4 expression in ischemia side of ASR+MCAO group were obviously higher than that of ASR+sham group. It suggested that CLIC4 was involved in apoptosis. AKT expression in ischemia side of ASR+MCAO group were obviously lower than that of ASR+sham group. It suggested that the cell survive is inhibited. The PDGF-B expression in ischemia side of ASR+MCAO group were obviously higher than that of ASR+sham group. It suggested that upregulation of PDGF-B is a compensation for ischemia. It is helpful for vascular proliferation and remodeling.
Conclusions:
1. The androgen-induced sterile rats model was first made, then administrated by rhFSH. The MCAO model was also established after rhFSH treatment. So we can use this kind of model to explore the effect of sex hormone disturbance on brain ischemia.
2. The inhibition of excitatory amino acids transporter (EAAT) and upregulation of mGluR induced by sex hormone disturbance was involved in brain ischemia injury. The rhFSH can lessen the brain ischemia injury by upregulating of EAAT and downregulating of mGluR.
3. The activation of rennin-angiotensin system(RAS) induced by sex hormone disturbance was involved in brain ischemia injury. The rhFSH can lessen the brain ischemia injury by downregulating of RAS.
4. The upregulating of CLIC4 and downregulating of AKT induced by sex hormone disturbance was involved in brain ischemia injury. The rhFSH can lessen the brain ischemia injury by upregulating of AKT and downregulating CLIC4.
5. The upregulation of PDGF-B is a compensation for brain ischemia. It is helpful for vascular proliferation and remodeling. The rhFSH can lessen the brain ischemia injury by upregulating of PDGF-B
结果表明:ASR+MCAO组神经评分、脑梗死面积、脑水含量及缺血侧坏死的神经数目明显增加,说明MCAO可造成严重的脑损伤;通过抑制EAAT1、EAAT2、EAAT3的表达,上调mGluR4及mGluR6的表达,增加兴奋性氨基酸的神经毒性,加重脑损害;ACE、AT1及AT2的表达增高,可激活RAS系统,通过缩血管,促凋亡等加重脑损伤;CLIC4的表达增高及AKT的表达降低,可促进细胞凋亡,抑制细胞存活,加重脑损伤;PDGF-B在脑缺血过程中表达上调,是机体的一种代偿反应,有利于血管增生以及重塑。给予rhFSH后能明显降低ASR+MCAO组神经评分、脑梗死面积及脑水含量,同时使大脑缺血侧坏死的神经数目减少,说明rhFSH具有明显的脑保护作用;其机制包括:上调EAAT1、EAAT2及EAAT3的表达,同时下调mGluR4及mGluR6的表达,加强谷氨酸转运;下调ACE、AT1及AT2的表达,抑制RAS系统的激活;下调CLIC4的表达,上调AKT及PDGF-B的表达,抑制凋亡,促进细胞存活及血管增生。
结论:由雄激素增高导致体内性激素的紊乱可通过多种途径加重脑缺血造成的损害,而rhFSH具有促进雌激素分泌的作用,可拮抗体内性激素的紊乱造成的脑损伤。
There are 2.5 million new patients of cerebrovascular disease in our country each year. And 1.5 million patients die of cerebrovascular disease each year. 75% of survivor will loss of work ability. Cerebrovascular dease is the second causing death and is also the first cause of mutilation. Cerebrovascular disease brings not only heavy health burden to patients, but also heavy economic burden to patients, society and government. So it is very important to explore the mechanism of cerebrovascular disease and to search the drug.
The incidence rate and outcome of stroke is depend on the sex. Several clinical investigations have demonstrated that the incidence rate of stroke in premenopause women was lower than that in man, but incidence rate of stroke in menopause women was increasing. The clinic retrospective investigations have demonstrated that incidence rate of stroke and myocardial infarction in menopause women treated with estradiol or estradiol plus progesterone was decreasing. It is suggested that sex hormone was involved in central nerve system injury.
Aim: The androgen-induced sterile rats (ASR) model was first made, then administrated by recombinant human follitropin alfa(rhFSH). The middle cerebral artery occlusion (MCAO) model was also established after rhFSH treatment. Then the effect of sex hormone on focal ischemia in rat brain and its mechanism was explored.
Methods: The androgen-induced sterile rats model was first made, then administrated by rhFSH. The MCAO model was also established after rhFSH treatment. The rats were divided into four group: ASR+sham, ASR+ rhFSH+sham, ASR+MCAO, ASR+rhFSH+MCAO. There were 12 rats in each group. The neurological severity score were performed at o hours and 24 hours in all group according to Zea Longa, respectively. The brain ischemia area was measured by TTC stain. The cortex morphological change was measured by HE staining. The cerebral water content was measured by using dry-wet weight method. The EAAT1,EAAT2,EAAT3, mGluR4,mGluR6,AGT, ACE, AT1,AT2, CLIC4, Akt, PDGF B mRNA and protein expression in cortex were assayed by RT-PCR and Westernblot.
Results and discussion: The rat in this experiment are all ASR rat. The testosterone in the serum is higher than normal. It means that ASR is a kind of sterilized rat induced by high androgen. The androgen is higher in serum of female rat. So we can use this kind of model to explore the effect of sex hormone on body. rhFSH can promote secretion of estrogen, so it can cure the sex hormone disturbance.
The neurological severity score, brain ischemia area and cerebral water content in ASR+MCAO was higher than that of ASR+sham. It suggested that the MCAO model is successfully established. HE staining showed that the number of neuron in ischemia side of ASR+MCAO group is decreasing and the axon is disappeared. The nucleus in neuron is blurred, and nucleolus is disappeared. It suggested that the cerebral injury was induced by MCAO. rhFSH can decrease the neurological severity score, brain ischemia area and cerebral water content in ASR+MCAO group. HE staining showed the number of necrosis neuron in ischemia side of ASR+rhFSH+MCAO group is decreasing. It was implied that rhFSH has protective effect on brain ischemia in ASR rat with MCAO.
The expression of genes related to excitatory amino acids was measured. The results showed that the EAAT1, EAAT2 and EAAT3 expression in ischemia side of ASR+MCAO group were obviously lower than that of ASR+sham group. This will result in accumulation of Glu in synaptic cleft because of Glu uptake by neuron and glial cell is decreasing. The mGluR4 and mGluR6 expression in ischemia side of ASR+MCAO group were obviously higher than that of ASR+sham group. The interaction between iGluR and mGluR will enhance the toxicity of excitatory amino acid. The rhFSH can lessen the toxicity of excitatory amino acid by upregulating the expression of EAAT1,EAAT2,EA AT3 and downregulating the expression of mGluR4 and mGluR6.
The expression of genes related to renin-angiotensin system(RAS) was also measured. The results showed that the ACE, AT1 and AT2 expression in ischemia side of ASR+MCAO group were obviously higher than that of ASR+sham group, but the AGT did not change. It suggested that the brain damage was deteriorated by the activation of RAS in cortex. The activation of RAS will result in vasoconstriction, blood pressure elevation and apoptosis. The rhFSH can lessen the brain ischemia injury by downregulating of RAS.
On the other hand, the CLIC4 expression in ischemia side of ASR+MCAO group were obviously higher than that of ASR+sham group. It suggested that CLIC4 was involved in apoptosis. AKT expression in ischemia side of ASR+MCAO group were obviously lower than that of ASR+sham group. It suggested that the cell survive is inhibited. The PDGF-B expression in ischemia side of ASR+MCAO group were obviously higher than that of ASR+sham group. It suggested that upregulation of PDGF-B is a compensation for ischemia. It is helpful for vascular proliferation and remodeling.
Conclusions:
1. The androgen-induced sterile rats model was first made, then administrated by rhFSH. The MCAO model was also established after rhFSH treatment. So we can use this kind of model to explore the effect of sex hormone disturbance on brain ischemia.
2. The inhibition of excitatory amino acids transporter (EAAT) and upregulation of mGluR induced by sex hormone disturbance was involved in brain ischemia injury. The rhFSH can lessen the brain ischemia injury by upregulating of EAAT and downregulating of mGluR.
3. The activation of rennin-angiotensin system(RAS) induced by sex hormone disturbance was involved in brain ischemia injury. The rhFSH can lessen the brain ischemia injury by downregulating of RAS.
4. The upregulating of CLIC4 and downregulating of AKT induced by sex hormone disturbance was involved in brain ischemia injury. The rhFSH can lessen the brain ischemia injury by upregulating of AKT and downregulating CLIC4.
5. The upregulation of PDGF-B is a compensation for brain ischemia. It is helpful for vascular proliferation and remodeling. The rhFSH can lessen the brain ischemia injury by upregulating of PDGF-B
引文
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