Panax ginseng is a slow-growing perennial plant.Panax ginseng extract has numerous biological activities,including antitumor,anti-inflammatory and antistress activities.Panax ginseng extract also has a cognition-enhan...Panax ginseng is a slow-growing perennial plant.Panax ginseng extract has numerous biological activities,including antitumor,anti-inflammatory and antistress activities.Panax ginseng extract also has a cognition-enhancing effect in rats with alcohol-induced memory impairment.In this study,we partially occluded the bilateral carotid arteries in the rat to induce chronic cerebral hypoperfusion,a wellknown model of vascular dementia.The rats were then intragastrically administered 50 or 100 mg/kg Panax ginseng extract.Morris water maze and balance beam tests were used to evaluate memory deficits and motor function,respectively.Protein quantity was used to evaluate cholinergic neurons.Immunofluorescence staining was used to assess the number of glial fibrillary acidic protein-positive cells.Western blot assay was used to evaluate protein levels of vascular endothelial growth factor,basic fibroblast growth factor,Bcl-2 and Bax.Treatment with Panax ginseng extract for 8 weeks significantly improved behavioral function and increased neuronal density and VEGF and b FGF protein expression in the hippocampal CA3 area.Furthermore,Panax ginseng extract reduced the number of glial fibrillary acidic protein-immunoreactive cells,and it decreased apoptosis by upregulating Bcl-2 and downregulating Bax protein expression.The effect of Panax ginseng extract was dose-dependent and similar to that of nimodipine,a commonly used drug for the treatment of vascular dementia.These findings suggest that Panax ginseng extract is neuroprotective against vascular dementia induced by chronic cerebral hypoperfusion,and therefore might have therapeutic potential for preventing and treating the disease.展开更多
Xiao-Xu-Ming decoction has been widely used to treat stroke and sequelae of stroke. We have previously shown that the active fractions of Xiao-Xu-Ming decoction attenuate cerebral ischemic injury. However, the global ...Xiao-Xu-Ming decoction has been widely used to treat stroke and sequelae of stroke. We have previously shown that the active fractions of Xiao-Xu-Ming decoction attenuate cerebral ischemic injury. However, the global protein profile and signaling conduction pathways regulated by Xiao-Xu-Ming decoction are still unclear. This study established a two-vessel occlusion rat model by bilateral common carotid artery occlusion. Rats were intragastrically administered 50 or 150 mg/kg Xiao-Xu-Ming decoction for 4 consecutive weeks. Learning and memory abilities were measured with Morris water maze. Motor ability was detected with prehensile test. Coordination ability was examined using the inclined screen test. Neuronal plasticity was observed by immunofluorescent staining. Differentially expressed proteins of rat hippocampus were analyzed by label-free quantitative proteomics. Real time-polymerase chain reaction and western blot assay were used to identify the changes in proteins. Results showed that Xiao-Xu-Ming decoction dramatically alleviated learning and memory deficits, and motor and coordination dysfunction, and increased the expression of microtubule-associated protein 2. Xiao-Xu-Ming decoction extract remarkably decreased 13 upregulated proteins and increased 39 downregulated proteins. The regulated proteins were mainly involved in oxidation reduction process, intracellular signaling cascade process, and protein catabolic process. The signaling pathways were mainly involved in ubiquitin mediated proteolysis and the phosphatidylinositol signaling system. Furthermore, there was an interaction among Rab2 a, Ptpn1, Ppm1 e, Cdk18, Gorasp2, Eps15, Capza2, Syngap1 and Mt-nd1. Protein analyses confirmed the changes in expression of MTND1. The current findings provide new insights into the molecular mechanisms of Xiao-Xu-Ming decoction extract's effects on chronic cerebral hypoperfusion.展开更多
The present study established a rat model of vascular dementia induced by chronic cerebral hypoperfusion through permanent ligation of bilateral common carotid arteries.At 60 days after modeling,escape latency and swi...The present study established a rat model of vascular dementia induced by chronic cerebral hypoperfusion through permanent ligation of bilateral common carotid arteries.At 60 days after modeling,escape latency and swimming path length during hidden-platform acquisition training in Morris water maze significantly increased in the model group.In addition,the number of accurate crossings over the original platform significantly decreased,hippocampal CA1 synaptophysin and growth-associated protein 43 expression significantly decreased,cAMP response element-binding protein expression remained unchanged,and phosphorylated cAMP response element-binding protein expression significantly decreased.Results suggested that abnormal expression of hippocampal synaptic structural protein and cAMP response element-binding protein phosphorylation played a role in cognitive impairment following chronic cerebral hypoperfusion.展开更多
3′-Daidzein sulfonate sodium（DSS） is a new synthetic water-soluble compound derived from daidzein,a soya isoflavone that plays regulatory roles in neurobiology.In this study,we hypothesized that the regulatory role...3′-Daidzein sulfonate sodium（DSS） is a new synthetic water-soluble compound derived from daidzein,a soya isoflavone that plays regulatory roles in neurobiology.In this study,we hypothesized that the regulatory role of DSS in neurobiology exhibits therapeutic effects on hippocampal damage and memory impairment.To validate this hypothesis,we established rat models of chronic cerebral hypoperfusion（CCH） by the permanent occlusion of the common carotid arteries using the two-vessel occlusion method.Three weeks after modeling,rat models were intragastrically administered 0.1,0.2,and 0.4 mg/kg DSS,once a day,for 5 successive weeks.The Morris water maze test was performed to investigate CCH-induced learning and memory deficits.TUNEL assay was used to analyze apoptosis in the hippocampal CA1,CA3 regions and dentate gyrus.Hematoxylin-eosin staining was performed to observe the morphology of neurons in the hippocampal CA1,CA3 regions and dentate gyrus.Western blot analysis was performed to investigate the phosphorylation of PKA,ERK1/2 and CREB in the hippocampal PKA/ERK1/2/CREB signaling pathway.Results showed that DSS treatment greatly improved the learning and memory deficits of rats with CCH,reduced apoptosis of neurons in the hippocampal CA1,CA3 regions and dentate gyrus,and increased the phosphorylation of PKA,ERK1/2,and CREB in the hippocampus.These findings suggest that DSS protects against CCH-induced memory impairment and hippocampal damage possibly through activating the PKA/ERK1/2/CREB signaling pathway.展开更多
BACKGROUND： Chronic cerebral hypoxia and ischemia have been shown to be related to occurrence of sporadic Alzheimer＇s disease, and β- and y-secretase play an important role in the generation of β-amyloid protein. ...BACKGROUND： Chronic cerebral hypoxia and ischemia have been shown to be related to occurrence of sporadic Alzheimer＇s disease, and β- and y-secretase play an important role in the generation of β-amyloid protein. Early clinical symptoms in Alzheimer＇s disease patients include learning and memory deficits. OBJECTIVE： To measure learning and memory, as well as β- and β-secretase activities in the hippocampus of a cerebral ischemia/hypoxia rat model with chronic cerebral hypoperfusion. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Department of Pathology, Capital Medical University from March to December, 2008. MATERIALS： β- and y-secretase activity kits were purchased from R ＆ D Systems, USA. METHODS： Male Sprague Dawiey rats, aged 23 weeks, were randomly assigned to model （n = 56） and sham-surgery （n = 46） groups. Cerebral hypoperfusion rat models were established by bilateral common carotid occlusion. MAIN OUTCOME MEASURES： Morris water maze was used to test changes in escape latency and path length, and β- and y-secretase activities were measured on days 10, 30, 90, and 180 following surgery. RESULTS： Progressive cognitive impairment resulted from 30 days of chronic cerebral hypoperfusion, which lasted for 180 days after cerebral hypoperfusion. β-secretase activity was increased at 10 days after hypoperfusion, which continued until 180 days, with a 14.25% increase compared to the sham-surgery group; y-secretase activity was increased by 10.5%. CONCLUSION： Chronic cerebral hypoperfusion results in impaired spatial memory and upregulated β- and y-secretase activities, which could play an important role in β-amyloid production.展开更多
Ohjectire To examine the hypothesis of normal perjusion pressure breakthrough (NPPB). Methods A modified Spetzler carotid -jugular (CJ) fistula model was created to imitate NPPB. In 9 male adult Sprague- Dawley rats, ...Ohjectire To examine the hypothesis of normal perjusion pressure breakthrough (NPPB). Methods A modified Spetzler carotid -jugular (CJ) fistula model was created to imitate NPPB. In 9 male adult Sprague- Dawley rats, the ipsilateral vertebral artery and bilateral external carotid arteries were occluded. The period of hypoperfusion CJ fistula was extended to 14 weeks, as a modofcation of Spetzler model. The histological change were examtned under transmission electron microscope 14 weeks after creation of the listula. Results Ischemic histological changes such as increased pinocytosis, increased lucency of the basal lamina, and frank necrosis of the cerebral capillary were found in rats of CJ fistula group. Conclusion The findings in this study suggest that blood - braln barrier (BBB) was impaired by chronic hypoperfusion. The impaired BBB mny be one of the important causes of the NPPB phenomenon.展开更多
Aim To investigate whether tluoxetine, a selective serotonin reuptake inhibitor（ SSRI） , could amelio- rate cognitive impairments induced by chronic cerebral hypopeffusion in rats and to clarify the underlying mecha...Aim To investigate whether tluoxetine, a selective serotonin reuptake inhibitor（ SSRI） , could amelio- rate cognitive impairments induced by chronic cerebral hypopeffusion in rats and to clarify the underlying mecha- nisms of its efficacy. Methods Rats were subjected to permanent bilateral occlusion of the common carotid arteries （two-vessel occlusion, 2VO）. Two weeks later, rats were treated with 30 mg · kg^-1 fluoxetine （intragastric injec- tion, i. g. ） for 6 weeks. Cognitive function was evaluated by Morris water maze （MWM） and novel objects recog- nition （NOR） test. Long-term potentiation （LTP） was used to address the underlying synaptic mechanisms. West- ern blot was used to quantify the protein levels. Results Fluoxetine treatment significantly improved the cognitive 2VO impairments caused by 2VO, accompanied with a reversion of 2VO-induced inhibitory of LTP. Furthermore, caused an up-regulation of hyperpolarization-activated cyclic nueleotide-gated channel 2 （HCN2） surface expres- sions in the hippocampal CA1 area and fluoxetine also effectively recovered the up-regulation of HCN2 surface ex- pressions. Conclusion Fluoxetine can ameliorate cognitive impairments induced by chronic cerebral hypopeffusion and a possible mechanism may via down-regulating HCN2 surface expression in the Hippocampal CA1 area.展开更多
Objective：To observe the therapeutic effect of Yangxue Qingnao Granule（养血清脑颗粒, YXQNG） on cognitive impairment induced by chronic cerebral hypoperfusion and to investigate its impact on oxidative stress,apopto...Objective：To observe the therapeutic effect of Yangxue Qingnao Granule（养血清脑颗粒, YXQNG） on cognitive impairment induced by chronic cerebral hypoperfusion and to investigate its impact on oxidative stress,apoptosis,and the cholinergic system.Methods：Adult male Wistar rats were subjected to chronic cerebral hypoperfusion by permanent occlusion of bilateral common carotid arteries（2-VO）.Thirty rats were randomly assigned to one of the five treatment groups in a 1：1：1：1：1 ratio：sham operation plus normal saline treatment,2-VO plus normal saline treatment,2-VO plus YXQNG at a dose of 2 g·kg（-1）·d^（-1） or 4 g·kg（-1）·d^（-1）, or 2-VO plus rivastigmine 2 mgkg^（-1）·d^（-1）.The Morris water maze test was used to assess the spatial memory retrieval.Apoptosis,total antioxide capacity（T-AOC）,acetylcholine esterase（AchE） and choline acetyl transferase（ChAT） activities in the hippocampus and the cortex were investigated.Results：In the chronic cerebral hypoperfusion model,the 2-VO plus saline treatment resulted in impaired special learning as shown by the significantly prolonged escape latency and shorter swim time in the first quadrant as compared to the sham operation.The impairment was associated with apoptosis and significant decreases in T-AOC,AchE and ChAT activities in the hippocampus and the cortex.Treatment with YXQNG at either 2 g·kg（-1）·d^（-1） or 4 g·kg（-1）·d^（-1） dose,or rivastigmine resulted in significantly shorter escape latencies and longer swim time in the first quadrant.YXQNG at both doses,but not rivastigmine,had significant reduction in apoptosis,and significant increases in T-AOC and ChAT activity in both the hippocampus and the cortex.Unlike rivastigmine,neither dose of YXQNG showed significant reduction in AchE activity.Conclusions：YXQNG ameliorated cognitive impairment induced by chronic cerebral hypoperfusion.The protective effect may be mediated through its regulation of apoptosis and activities of T-AOC and ChAT in the hippocampus and cortex of the rats in the chronic cerebral hypoperfusion model,a mechanism that is different from rivastigmine.展开更多
The glymphatic system plays a pivotal role in maintaining cerebral homeostasis.Chronic cerebral hypoperfusion,arising from small vessel disease or carotid stenosis,results in cerebrometabolic disturbances ultimately m...The glymphatic system plays a pivotal role in maintaining cerebral homeostasis.Chronic cerebral hypoperfusion,arising from small vessel disease or carotid stenosis,results in cerebrometabolic disturbances ultimately manifesting in white matter injury and cognitive dysfunction.However,whether the glymphatic system serves as a potential therapeutic target for white matter injury and cognitive decline during hypoperfusion remains unknown.Here,we established a mouse model of chronic cerebral hypoperfusion via bilateral common carotid artery stenosis.We found that the hypoperfusion model was associated with significant white matter injury and initial cognitive impairment in conjunction with impaired glym・phatic system function.The glymphatic dysfunction was associated with altered cerebral perfusion and loss of aquaporin 4 polarization.Treatment of digoxin rescued changes in glymphatic transport,white matter structure,and cognitive function.Suppression of glymphatic functions by treatment with the AQP4 inhibitor TGN-020 abolished this protective effect of digoxin from hypoperfusion injury.Our research yields new insight into the relationship between hemodynamics,glymphatic transport,white matter injury,and cognitive changes after chronic cerebral hypoperfusion.展开更多
Cognitive impairment caused by chronic cerebral hypoperfusion(CCH)is associated with white matter injury(WMI),possibly through the alteration of autophagy.Here,the autophagy—lysosomal pathway(ALP)dysfunction in white...Cognitive impairment caused by chronic cerebral hypoperfusion(CCH)is associated with white matter injury(WMI),possibly through the alteration of autophagy.Here,the autophagy—lysosomal pathway(ALP)dysfunction in white matter(WM)and its relationship with cognitive impairment were investigated in rats subjected to two vessel occlusion(2VO).The results showed that cognitive impairment occurred by the 28th day after 2VO.Injury and autophagy activation of mature oligodendrocytes and neuronal axons sequentially occurred in WM by the 3rd day.By the 14th day,abnormal accumulation of autophagy substrate,lysosomal dysfunction,and the activation of mechanistic target of rapamycin(MTOR)pathway were observed in WM,paralleled with mature oligodendrocyte death.This indicates autophagy activation was followed by ALP dysfunction caused by autophagy inhibition or lysosomal dysfunction.To target the ALP dysfunction,enhanced autophagy by systemic rapamycin treatment or overexpression of Beclin1(BECN1)in oligodendrocytes reduced mature oligodendrocyte death,and subsequently alleviated the WMI and cognitive impairment after CCH.These results reveal that early autophagy activation was followed by ALP dysfunction in WM after 2VO,which was associated with the aggravation of WMI and cognitive impairment.This study highlights that alleviating ALP dysfunction by enhancing oligodendrocyte autophagy has benefits for cognitive recovery after CCH.展开更多
目的探讨山奈酚(kaempferol,KAE)对慢性脑缺血大鼠的作用及其机制。方法采用双侧颈总动脉永久性结扎(bilateral common carotid arteries occlusion,2VO)建立大鼠慢性脑缺血动物模型;Morris水迷宫、抓握实验检测大鼠行为学;尼氏染色及H...目的探讨山奈酚(kaempferol,KAE)对慢性脑缺血大鼠的作用及其机制。方法采用双侧颈总动脉永久性结扎(bilateral common carotid arteries occlusion,2VO)建立大鼠慢性脑缺血动物模型;Morris水迷宫、抓握实验检测大鼠行为学;尼氏染色及HE染色观察脑组织病理改变;比色法检测MDA含量和SOD活性;Western blot检测脑组织DJ-1蛋白表达水平。结果与2-VO模型组比较,KAE明显改善慢性脑缺血诱导的学习记忆障碍和抓握能力损伤。此外,KAE明显减轻2VO大鼠脑组织病理损伤,增高脑组织中SOD活性,提高海马和皮层中抗氧化蛋白DJ-1的表达水平。结论KAE明显改善慢性脑缺血诱导的大鼠认知功能障碍、四肢平衡能力障碍及病理损伤,其机制可能与提高体内抗氧化系统有关。展开更多
基金supported by the National Natural Science Foundation of China,No.81660243the Joint Foundation of Department of Science and Technology of Guizhou Province of China,No.LG[2012]028the Science and Technology Department of Guizhou Province of China,No.qian SY[2015]3041
文摘Panax ginseng is a slow-growing perennial plant.Panax ginseng extract has numerous biological activities,including antitumor,anti-inflammatory and antistress activities.Panax ginseng extract also has a cognition-enhancing effect in rats with alcohol-induced memory impairment.In this study,we partially occluded the bilateral carotid arteries in the rat to induce chronic cerebral hypoperfusion,a wellknown model of vascular dementia.The rats were then intragastrically administered 50 or 100 mg/kg Panax ginseng extract.Morris water maze and balance beam tests were used to evaluate memory deficits and motor function,respectively.Protein quantity was used to evaluate cholinergic neurons.Immunofluorescence staining was used to assess the number of glial fibrillary acidic protein-positive cells.Western blot assay was used to evaluate protein levels of vascular endothelial growth factor,basic fibroblast growth factor,Bcl-2 and Bax.Treatment with Panax ginseng extract for 8 weeks significantly improved behavioral function and increased neuronal density and VEGF and b FGF protein expression in the hippocampal CA3 area.Furthermore,Panax ginseng extract reduced the number of glial fibrillary acidic protein-immunoreactive cells,and it decreased apoptosis by upregulating Bcl-2 and downregulating Bax protein expression.The effect of Panax ginseng extract was dose-dependent and similar to that of nimodipine,a commonly used drug for the treatment of vascular dementia.These findings suggest that Panax ginseng extract is neuroprotective against vascular dementia induced by chronic cerebral hypoperfusion,and therefore might have therapeutic potential for preventing and treating the disease.
基金supported in part by the National Natural Science Foundation of China,No.81473383(to YHW)the Significant New-Drugs Creation of Science and Technology Major Projects in China,No.2018ZX09711001-003-019(to YHW)the Innovation Fund for Graduate of Beijing Union Medical College of China,No.2017-1007-02(to XC)
文摘Xiao-Xu-Ming decoction has been widely used to treat stroke and sequelae of stroke. We have previously shown that the active fractions of Xiao-Xu-Ming decoction attenuate cerebral ischemic injury. However, the global protein profile and signaling conduction pathways regulated by Xiao-Xu-Ming decoction are still unclear. This study established a two-vessel occlusion rat model by bilateral common carotid artery occlusion. Rats were intragastrically administered 50 or 150 mg/kg Xiao-Xu-Ming decoction for 4 consecutive weeks. Learning and memory abilities were measured with Morris water maze. Motor ability was detected with prehensile test. Coordination ability was examined using the inclined screen test. Neuronal plasticity was observed by immunofluorescent staining. Differentially expressed proteins of rat hippocampus were analyzed by label-free quantitative proteomics. Real time-polymerase chain reaction and western blot assay were used to identify the changes in proteins. Results showed that Xiao-Xu-Ming decoction dramatically alleviated learning and memory deficits, and motor and coordination dysfunction, and increased the expression of microtubule-associated protein 2. Xiao-Xu-Ming decoction extract remarkably decreased 13 upregulated proteins and increased 39 downregulated proteins. The regulated proteins were mainly involved in oxidation reduction process, intracellular signaling cascade process, and protein catabolic process. The signaling pathways were mainly involved in ubiquitin mediated proteolysis and the phosphatidylinositol signaling system. Furthermore, there was an interaction among Rab2 a, Ptpn1, Ppm1 e, Cdk18, Gorasp2, Eps15, Capza2, Syngap1 and Mt-nd1. Protein analyses confirmed the changes in expression of MTND1. The current findings provide new insights into the molecular mechanisms of Xiao-Xu-Ming decoction extract's effects on chronic cerebral hypoperfusion.
基金supported by the National Natural Science Foundation of China,No.30973782the National Natural Science Foundation for the Youth,No.81001693+1 种基金the Natural Science Foundation of Beijing,No.7102014,7122018the Science and Technology Foundation for Chinese Medicine in Beijing,No.JJ2008-042
文摘The present study established a rat model of vascular dementia induced by chronic cerebral hypoperfusion through permanent ligation of bilateral common carotid arteries.At 60 days after modeling,escape latency and swimming path length during hidden-platform acquisition training in Morris water maze significantly increased in the model group.In addition,the number of accurate crossings over the original platform significantly decreased,hippocampal CA1 synaptophysin and growth-associated protein 43 expression significantly decreased,cAMP response element-binding protein expression remained unchanged,and phosphorylated cAMP response element-binding protein expression significantly decreased.Results suggested that abnormal expression of hippocampal synaptic structural protein and cAMP response element-binding protein phosphorylation played a role in cognitive impairment following chronic cerebral hypoperfusion.
基金supported by the National Natural Science Foundation of China,No.81560583the Natural Science Foundation of Jiangxi Province of China,No.20142BAB205021
文摘3′-Daidzein sulfonate sodium（DSS） is a new synthetic water-soluble compound derived from daidzein,a soya isoflavone that plays regulatory roles in neurobiology.In this study,we hypothesized that the regulatory role of DSS in neurobiology exhibits therapeutic effects on hippocampal damage and memory impairment.To validate this hypothesis,we established rat models of chronic cerebral hypoperfusion（CCH） by the permanent occlusion of the common carotid arteries using the two-vessel occlusion method.Three weeks after modeling,rat models were intragastrically administered 0.1,0.2,and 0.4 mg/kg DSS,once a day,for 5 successive weeks.The Morris water maze test was performed to investigate CCH-induced learning and memory deficits.TUNEL assay was used to analyze apoptosis in the hippocampal CA1,CA3 regions and dentate gyrus.Hematoxylin-eosin staining was performed to observe the morphology of neurons in the hippocampal CA1,CA3 regions and dentate gyrus.Western blot analysis was performed to investigate the phosphorylation of PKA,ERK1/2 and CREB in the hippocampal PKA/ERK1/2/CREB signaling pathway.Results showed that DSS treatment greatly improved the learning and memory deficits of rats with CCH,reduced apoptosis of neurons in the hippocampal CA1,CA3 regions and dentate gyrus,and increased the phosphorylation of PKA,ERK1/2,and CREB in the hippocampus.These findings suggest that DSS protects against CCH-induced memory impairment and hippocampal damage possibly through activating the PKA/ERK1/2/CREB signaling pathway.
基金the Natural Science Foundation of Bei-jing, No. 7073088
文摘BACKGROUND： Chronic cerebral hypoxia and ischemia have been shown to be related to occurrence of sporadic Alzheimer＇s disease, and β- and y-secretase play an important role in the generation of β-amyloid protein. Early clinical symptoms in Alzheimer＇s disease patients include learning and memory deficits. OBJECTIVE： To measure learning and memory, as well as β- and β-secretase activities in the hippocampus of a cerebral ischemia/hypoxia rat model with chronic cerebral hypoperfusion. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Department of Pathology, Capital Medical University from March to December, 2008. MATERIALS： β- and y-secretase activity kits were purchased from R ＆ D Systems, USA. METHODS： Male Sprague Dawiey rats, aged 23 weeks, were randomly assigned to model （n = 56） and sham-surgery （n = 46） groups. Cerebral hypoperfusion rat models were established by bilateral common carotid occlusion. MAIN OUTCOME MEASURES： Morris water maze was used to test changes in escape latency and path length, and β- and y-secretase activities were measured on days 10, 30, 90, and 180 following surgery. RESULTS： Progressive cognitive impairment resulted from 30 days of chronic cerebral hypoperfusion, which lasted for 180 days after cerebral hypoperfusion. β-secretase activity was increased at 10 days after hypoperfusion, which continued until 180 days, with a 14.25% increase compared to the sham-surgery group; y-secretase activity was increased by 10.5%. CONCLUSION： Chronic cerebral hypoperfusion results in impaired spatial memory and upregulated β- and y-secretase activities, which could play an important role in β-amyloid production.
文摘Ohjectire To examine the hypothesis of normal perjusion pressure breakthrough (NPPB). Methods A modified Spetzler carotid -jugular (CJ) fistula model was created to imitate NPPB. In 9 male adult Sprague- Dawley rats, the ipsilateral vertebral artery and bilateral external carotid arteries were occluded. The period of hypoperfusion CJ fistula was extended to 14 weeks, as a modofcation of Spetzler model. The histological change were examtned under transmission electron microscope 14 weeks after creation of the listula. Results Ischemic histological changes such as increased pinocytosis, increased lucency of the basal lamina, and frank necrosis of the cerebral capillary were found in rats of CJ fistula group. Conclusion The findings in this study suggest that blood - braln barrier (BBB) was impaired by chronic hypoperfusion. The impaired BBB mny be one of the important causes of the NPPB phenomenon.
文摘Aim To investigate whether tluoxetine, a selective serotonin reuptake inhibitor（ SSRI） , could amelio- rate cognitive impairments induced by chronic cerebral hypopeffusion in rats and to clarify the underlying mecha- nisms of its efficacy. Methods Rats were subjected to permanent bilateral occlusion of the common carotid arteries （two-vessel occlusion, 2VO）. Two weeks later, rats were treated with 30 mg · kg^-1 fluoxetine （intragastric injec- tion, i. g. ） for 6 weeks. Cognitive function was evaluated by Morris water maze （MWM） and novel objects recog- nition （NOR） test. Long-term potentiation （LTP） was used to address the underlying synaptic mechanisms. West- ern blot was used to quantify the protein levels. Results Fluoxetine treatment significantly improved the cognitive 2VO impairments caused by 2VO, accompanied with a reversion of 2VO-induced inhibitory of LTP. Furthermore, caused an up-regulation of hyperpolarization-activated cyclic nueleotide-gated channel 2 （HCN2） surface expres- sions in the hippocampal CA1 area and fluoxetine also effectively recovered the up-regulation of HCN2 surface ex- pressions. Conclusion Fluoxetine can ameliorate cognitive impairments induced by chronic cerebral hypopeffusion and a possible mechanism may via down-regulating HCN2 surface expression in the Hippocampal CA1 area.
文摘Objective：To observe the therapeutic effect of Yangxue Qingnao Granule（养血清脑颗粒, YXQNG） on cognitive impairment induced by chronic cerebral hypoperfusion and to investigate its impact on oxidative stress,apoptosis,and the cholinergic system.Methods：Adult male Wistar rats were subjected to chronic cerebral hypoperfusion by permanent occlusion of bilateral common carotid arteries（2-VO）.Thirty rats were randomly assigned to one of the five treatment groups in a 1：1：1：1：1 ratio：sham operation plus normal saline treatment,2-VO plus normal saline treatment,2-VO plus YXQNG at a dose of 2 g·kg（-1）·d^（-1） or 4 g·kg（-1）·d^（-1）, or 2-VO plus rivastigmine 2 mgkg^（-1）·d^（-1）.The Morris water maze test was used to assess the spatial memory retrieval.Apoptosis,total antioxide capacity（T-AOC）,acetylcholine esterase（AchE） and choline acetyl transferase（ChAT） activities in the hippocampus and the cortex were investigated.Results：In the chronic cerebral hypoperfusion model,the 2-VO plus saline treatment resulted in impaired special learning as shown by the significantly prolonged escape latency and shorter swim time in the first quadrant as compared to the sham operation.The impairment was associated with apoptosis and significant decreases in T-AOC,AchE and ChAT activities in the hippocampus and the cortex.Treatment with YXQNG at either 2 g·kg（-1）·d^（-1） or 4 g·kg（-1）·d^（-1） dose,or rivastigmine resulted in significantly shorter escape latencies and longer swim time in the first quadrant.YXQNG at both doses,but not rivastigmine,had significant reduction in apoptosis,and significant increases in T-AOC and ChAT activity in both the hippocampus and the cortex.Unlike rivastigmine,neither dose of YXQNG showed significant reduction in AchE activity.Conclusions：YXQNG ameliorated cognitive impairment induced by chronic cerebral hypoperfusion.The protective effect may be mediated through its regulation of apoptosis and activities of T-AOC and ChAT in the hippocampus and cortex of the rats in the chronic cerebral hypoperfusion model,a mechanism that is different from rivastigmine.
基金supported by Grants from the National Natural Science Foundation of China(81873749 and 81801072)。
文摘The glymphatic system plays a pivotal role in maintaining cerebral homeostasis.Chronic cerebral hypoperfusion,arising from small vessel disease or carotid stenosis,results in cerebrometabolic disturbances ultimately manifesting in white matter injury and cognitive dysfunction.However,whether the glymphatic system serves as a potential therapeutic target for white matter injury and cognitive decline during hypoperfusion remains unknown.Here,we established a mouse model of chronic cerebral hypoperfusion via bilateral common carotid artery stenosis.We found that the hypoperfusion model was associated with significant white matter injury and initial cognitive impairment in conjunction with impaired glym・phatic system function.The glymphatic dysfunction was associated with altered cerebral perfusion and loss of aquaporin 4 polarization.Treatment of digoxin rescued changes in glymphatic transport,white matter structure,and cognitive function.Suppression of glymphatic functions by treatment with the AQP4 inhibitor TGN-020 abolished this protective effect of digoxin from hypoperfusion injury.Our research yields new insight into the relationship between hemodynamics,glymphatic transport,white matter injury,and cognitive changes after chronic cerebral hypoperfusion.
基金the Natural Science Foundation of Liaoning Province(LJKQZ2021031,2022-MS-246,China)to Yueyang Liu。
文摘Cognitive impairment caused by chronic cerebral hypoperfusion(CCH)is associated with white matter injury(WMI),possibly through the alteration of autophagy.Here,the autophagy—lysosomal pathway(ALP)dysfunction in white matter(WM)and its relationship with cognitive impairment were investigated in rats subjected to two vessel occlusion(2VO).The results showed that cognitive impairment occurred by the 28th day after 2VO.Injury and autophagy activation of mature oligodendrocytes and neuronal axons sequentially occurred in WM by the 3rd day.By the 14th day,abnormal accumulation of autophagy substrate,lysosomal dysfunction,and the activation of mechanistic target of rapamycin(MTOR)pathway were observed in WM,paralleled with mature oligodendrocyte death.This indicates autophagy activation was followed by ALP dysfunction caused by autophagy inhibition or lysosomal dysfunction.To target the ALP dysfunction,enhanced autophagy by systemic rapamycin treatment or overexpression of Beclin1(BECN1)in oligodendrocytes reduced mature oligodendrocyte death,and subsequently alleviated the WMI and cognitive impairment after CCH.These results reveal that early autophagy activation was followed by ALP dysfunction in WM after 2VO,which was associated with the aggravation of WMI and cognitive impairment.This study highlights that alleviating ALP dysfunction by enhancing oligodendrocyte autophagy has benefits for cognitive recovery after CCH.
