维生素A缺乏影响胶质源性神经营养因子抑制大鼠缺氧缺血脑损伤后细胞增殖的研究
|
摘要
目的:研究体内维生素A水平缺乏通过RARα通路抑制大鼠缺氧缺血性脑损伤(HIBD)后神经细胞增殖进而影响脑组织功能恢复。方法:将74只SD大鼠随机分为假手术组(CON组)、VA正常(VAN组)及VA缺乏组(VAD组),HIBD建模按经典Rice法。Morris水迷宫评估空间记忆力,EDU细胞增殖检测VAN、VAD组HIBD后细胞增殖,更深入剖析皮质组织RA受体、神经标志物的基因水平。结果:Morris水迷宫实验提示HIBD后恢复晚期VAN组空间记忆力明显强于VAD组(P<0.05);EDU结果显示,VAN组新生细胞增殖明显强于VAD组(P<0.05);RARα是各RA受体表达的优势受体。VAN组巢蛋白(Nestin)、神经元特异性烯醇化酶(NSE)、胶质纤维酸性蛋(GFAP)及胶质源性神经营养因子(GDNF)的基因水平明显高于VAD组(P<0.05)。结论:VA缺乏抑制HIBD后脑组织功能恢复,推测是VA信号下调GDNF从而抑制NSE、Nestin及GFAP表达,进而影响细胞增殖及功能修复。
Objective:To study the effect of VA deficiency on the neural function and tissue recovery of hypoxic ischemic injury through RARα pathway to inhibit proliferation of nerve cells in rats.Method:A total of 74 SD rats were randomly divided into VAN(VA normal)、VAD(VA deficiency) and CON(control) groups. HIBD model were created for VAD and van groups according to Rice classical method. The CON group accepted shame operation only. Morris water maze was used to evaluate the neurocognitive function of the rats, EDU was used to evaluate the proliferation function of the experimental group. Furthermore,We analyzed the m RNA levels of RA receptors and neural markers in the cortex.Result:(1)Function:The Morris water maze test showed that the spatial memory of the VAN group was significantly better than that of the VAD group after HIBD(P<0.05).(2)The results of EDU showed that the proliferation of neonatal cells in group VAN was significantly stronger than that in group VAD(P<0.05).(3)RAR α was the dominant receptor for the expression of RA receptors. Furthermore, the levels of neuronal markers NSE,neural stem marker Nestin, glial cell marker GFAP and neurotrophic factor GDNF in group VAN were significantly higher than those in group VAD(P<0.05).Conclusion:The VA deficiency inhibits the recovery of nerve tissue after HIBD in vivo. The mechanism maybe that the VA signal acts on GDNF that inhibits the action of NSE, Nestin and GFAP, which finally affects the functional rehabilitation of nervous tissue.
Objective:To study the effect of VA deficiency on the neural function and tissue recovery of hypoxic ischemic injury through RARα pathway to inhibit proliferation of nerve cells in rats.Method:A total of 74 SD rats were randomly divided into VAN(VA normal)、VAD(VA deficiency) and CON(control) groups. HIBD model were created for VAD and van groups according to Rice classical method. The CON group accepted shame operation only. Morris water maze was used to evaluate the neurocognitive function of the rats, EDU was used to evaluate the proliferation function of the experimental group. Furthermore,We analyzed the m RNA levels of RA receptors and neural markers in the cortex.Result:(1)Function:The Morris water maze test showed that the spatial memory of the VAN group was significantly better than that of the VAD group after HIBD(P<0.05).(2)The results of EDU showed that the proliferation of neonatal cells in group VAN was significantly stronger than that in group VAD(P<0.05).(3)RAR α was the dominant receptor for the expression of RA receptors. Furthermore, the levels of neuronal markers NSE,neural stem marker Nestin, glial cell marker GFAP and neurotrophic factor GDNF in group VAN were significantly higher than those in group VAD(P<0.05).Conclusion:The VA deficiency inhibits the recovery of nerve tissue after HIBD in vivo. The mechanism maybe that the VA signal acts on GDNF that inhibits the action of NSE, Nestin and GFAP, which finally affects the functional rehabilitation of nervous tissue.
引文
[1]Blomhoff R,Blomhoff HK.Overview of retinoid metabolism and function[J].Developmental Neurobiology,2006,66(7):606-630.
[2]Jacobs S,Lie DC,DeCicco KL,et al.Retinoic acid is required early during adult neurogenesis in the dentate gyrus[J].Proceedings of the National Academy of Sciences of the United States of America,2006,103(10):3902-3907.
[3]Sommer,A.Vitamin A deficiency and mortality risk[J].The Lancet,1984,1(8372):347-348.
[4]Arteaga O,álvarez A.Role of antioxiaches[J].International Journal of Molecular Sciences,2017,18(2):265.
[5]Liu L,Oza S,Hogan D,et al.Global,regional,and national causes of child mortality in 2000-2013,with projections to inform post-2015 priorities:an updated systematic analysis[J].The Lancet,2015,385(9966):430-440.
[6]Haider BA,Bhutta ZA.Birth asphyxia in developing countries:current status and public health implications[J].Current Problems in Pediatric and Adolescent Health Care,2006,36(5):178-188.
[7]Low JA.Determining the contribution of asphyxia to brain damage in the neonate[J].Journal of Obstetrics and Gynaecology Research,2004,30(4):276-286.
[8]栾佐,尹国才,胡晓红,等.人神经干细胞移植治疗重度新生儿缺氧缺血性脑病一例[J].中华儿科杂志,2005,43(8):580-583.
[9]刘洋,张萱,代英等.骨髓间充质干细胞对缺氧缺血性脑损伤新生大鼠学习记忆功能的重建作用[J].中华儿科杂志.2008.46(9):648-653.
[10]Gluckman PD,Wyatt JS,Azzopardi D,et al.Selective head cooling with mild systemic hypothermia after neonatal encephalopathy:multicentre randomized trial[J].The Lancet,2005,365(9460):663-670.
[11]Maden M.Retinoic acid in the development,regeneration and maintenance of the nervous system[J].Nat Rev Neurosci.2007.8(10):755-65.
[12]Jiang W,Yu Q,Gong M,et al.Vitamin A deficiency impairs postnatal cognitive function via inhibition of neuronal calcium excitability in hippocampus[J].Journal of Neurochemistry,2012,121(6):932.
[13]J Jansen EM,Solberg L,Underhill S,et al.Transplantation of fetal neocortex ameliorates sensorimotor and locomotor deficits following neonatal ischemic-hypoxic brain injury in rats[J].Experimental Neurology,1997,147(2):487-497.
[14]Barnhart CD,Yang D.Using the Morris water maze to assess spatial learning and memory in weanling mice[J].Plos One,2015,10(4):e0124521.
[15]Ruberte E,Friederich V,et al.Retinoic acid receptors and cellular retinoid binding proteinsⅢ.Their differential transcript distribution during mouse nervous system development[J].The Development,1993,118(1):267-282.
[16]Shen H,Luo Y,Kuo CC,et al.9-Cis-retinoic acid reduces ischemic brain injury in rodents via bone morphogenetic protein[J].Journal of Neuroscience Research,2009,87(2):545-555.
[17]Cocco S,Diaz G,Stancampiano R,et al.Vitamin A deficiency produces spatial learning and memory impairment in rats[J].Neuroscience,2002,115(2):475-482.
[18]Siegenthaler JA,Ashique AM,Zarbalis K,et al.Retinoic acid from the meninges regulates cortical neuron generation[J].Cell,2009,139(3):597-609
[19]Aoto J,Nam CI,Poon MM,Ting P,Chen L.Synaptic signaling by all-trans retinoic acid in homeostatic synaptic plasticity[J].Neuron,2008,60(2):308-320.
[20]Jiang W,Wen EY,Gong M,et al.The pattern of retinoic acid receptor expression and subcellular,anatomic and functional area translocation during the postnatal development of the rat cerebral cortex and white matter[J].Brain Res,2011,1382(9):77-87.
[21]Ghribi O,Herman MM,Pramoonjago P,et al.GDNF regulates the A beta-induced endoplasmic reticulum stress response in rabbit hippocampus by inhibiting the activation of gadd 153 and the JNK and ERK kinases[J].Neurobiol Dis,2004,16(2):417-427.
[2]Jacobs S,Lie DC,DeCicco KL,et al.Retinoic acid is required early during adult neurogenesis in the dentate gyrus[J].Proceedings of the National Academy of Sciences of the United States of America,2006,103(10):3902-3907.
[3]Sommer,A.Vitamin A deficiency and mortality risk[J].The Lancet,1984,1(8372):347-348.
[4]Arteaga O,álvarez A.Role of antioxiaches[J].International Journal of Molecular Sciences,2017,18(2):265.
[5]Liu L,Oza S,Hogan D,et al.Global,regional,and national causes of child mortality in 2000-2013,with projections to inform post-2015 priorities:an updated systematic analysis[J].The Lancet,2015,385(9966):430-440.
[6]Haider BA,Bhutta ZA.Birth asphyxia in developing countries:current status and public health implications[J].Current Problems in Pediatric and Adolescent Health Care,2006,36(5):178-188.
[7]Low JA.Determining the contribution of asphyxia to brain damage in the neonate[J].Journal of Obstetrics and Gynaecology Research,2004,30(4):276-286.
[8]栾佐,尹国才,胡晓红,等.人神经干细胞移植治疗重度新生儿缺氧缺血性脑病一例[J].中华儿科杂志,2005,43(8):580-583.
[9]刘洋,张萱,代英等.骨髓间充质干细胞对缺氧缺血性脑损伤新生大鼠学习记忆功能的重建作用[J].中华儿科杂志.2008.46(9):648-653.
[10]Gluckman PD,Wyatt JS,Azzopardi D,et al.Selective head cooling with mild systemic hypothermia after neonatal encephalopathy:multicentre randomized trial[J].The Lancet,2005,365(9460):663-670.
[11]Maden M.Retinoic acid in the development,regeneration and maintenance of the nervous system[J].Nat Rev Neurosci.2007.8(10):755-65.
[12]Jiang W,Yu Q,Gong M,et al.Vitamin A deficiency impairs postnatal cognitive function via inhibition of neuronal calcium excitability in hippocampus[J].Journal of Neurochemistry,2012,121(6):932.
[13]J Jansen EM,Solberg L,Underhill S,et al.Transplantation of fetal neocortex ameliorates sensorimotor and locomotor deficits following neonatal ischemic-hypoxic brain injury in rats[J].Experimental Neurology,1997,147(2):487-497.
[14]Barnhart CD,Yang D.Using the Morris water maze to assess spatial learning and memory in weanling mice[J].Plos One,2015,10(4):e0124521.
[15]Ruberte E,Friederich V,et al.Retinoic acid receptors and cellular retinoid binding proteinsⅢ.Their differential transcript distribution during mouse nervous system development[J].The Development,1993,118(1):267-282.
[16]Shen H,Luo Y,Kuo CC,et al.9-Cis-retinoic acid reduces ischemic brain injury in rodents via bone morphogenetic protein[J].Journal of Neuroscience Research,2009,87(2):545-555.
[17]Cocco S,Diaz G,Stancampiano R,et al.Vitamin A deficiency produces spatial learning and memory impairment in rats[J].Neuroscience,2002,115(2):475-482.
[18]Siegenthaler JA,Ashique AM,Zarbalis K,et al.Retinoic acid from the meninges regulates cortical neuron generation[J].Cell,2009,139(3):597-609
[19]Aoto J,Nam CI,Poon MM,Ting P,Chen L.Synaptic signaling by all-trans retinoic acid in homeostatic synaptic plasticity[J].Neuron,2008,60(2):308-320.
[20]Jiang W,Wen EY,Gong M,et al.The pattern of retinoic acid receptor expression and subcellular,anatomic and functional area translocation during the postnatal development of the rat cerebral cortex and white matter[J].Brain Res,2011,1382(9):77-87.
[21]Ghribi O,Herman MM,Pramoonjago P,et al.GDNF regulates the A beta-induced endoplasmic reticulum stress response in rabbit hippocampus by inhibiting the activation of gadd 153 and the JNK and ERK kinases[J].Neurobiol Dis,2004,16(2):417-427.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |