Cerebral ischemia/reperfusion injury impairs learning and memory in patients.Studies have shown that synaptic function is involved in the formation and development of memory,and that DNA methylation plays a key role i...Cerebral ischemia/reperfusion injury impairs learning and memory in patients.Studies have shown that synaptic function is involved in the formation and development of memory,and that DNA methylation plays a key role in the regulation of learning and memory.To investigate the role of DNA hypomethylation in cerebral ischemia/reperfusion injury,in this study,we established a rat model of cerebral ischemia/reperfusion injury by occlusion of the middle cerebral artery and then treated the rats with intraperitoneal 5-aza-2′-deoxycytidine,an inhibitor of DNA methylation.Our results showed that 5-aza-2′-deoxycytidine markedly improved the neurological function,and cognitive,social and spatial memory abilities,and dose-dependently increased the synaptic density and the expression of SYP and SHANK2 proteins in the hippocampus in a dose-dependent manner in rats with cerebral ischemia/reperfusion injury.The effects of 5-aza-2′-deoxycytidine were closely related to its reduction of genomic DNA methylation and DNA methylation at specific sites of the Syp and Shank2 genes in rats with cerebral ischemia/reperfusion injury.These findings suggest that inhibition of DNA methylation by 5-aza-2′-deoxycytidine promotes the recovery of learning and memory impairment in a rat model of cerebral ischemia/reperfusion injury.These results provide theoretical evidence for stroke treatment using epigenetic methods.展开更多
BACKGROUND: Calcitonin gene-related peptide (CGRP) and nerve growth actor (NGF) cam improve spatial learning and memory abilities of rats with cerebral ischemia/reperfusion; however, the effect of combination of them ...BACKGROUND: Calcitonin gene-related peptide (CGRP) and nerve growth actor (NGF) cam improve spatial learning and memory abilities of rats with cerebral ischemia/reperfusion; however, the effect of combination of them on relieving learning and memory injury following cerebral ischemia/reperfusion should be further studied. OBJECTIVE: To study the effects of exogenous CGRP and NGF on learning and memory abilities of rats with focal cerebral ischemia/reperfusion. DESIGN: Randomized controlled animal study. SETTING: Department of Neurosurgery, the Second Hospital of Xiamen; Department of Neurosurgery, the Second Affiliated Hospital of China Medical University; Department of Neurobiology, Basic Medical College of China Medical University. MATERIALS: A total of 30 healthy male SD rats, aged 8 weeks, of clean grade, weighing 250-300 g, were provided by Experimental Animal Department of China Medical University. All rats were randomly divided into sham-operation group, ischemia/reperfusion group and treatment group with 10 in each group. The main reagents were detailed as the follows: 100 g/L chloral hydrate, 0.5 mL CGRP (2 mg/L, Sigma Company, USA), and NGF (1× 106 U/L, 0.5 mL, Siweite Company, Dalian). METHODS: The experiment was carried out in the Department of Neurobiology, Basic Medical College of China Medical University from February to July 2005. Rat models of middle cerebral artery occlusion were established by method of occlusion, 2 hours after that rats were anesthetized and the thread was slightly drawn out for 10 mm under direct staring to perform reperfusion. Rats in the ischemia/reperfusion group received intraperitoneal injection of 1 mL saline via the abdomen at two hours later, while rats in the treatment group at 2 hours later received intraperitoneal injection of 2 mg/L CGRP (0.5 mL) and 1×106 U/L NGF (0.5 mL) once a day for 10 successive days. First administration was accomplished within 15 minutes after ischemia/reperfusion. Rats in the sham-operation group were separated of the vessels without occlusion or administration. The neural function was evaluated with Zea Longa 5-grade scale. Animals with the score of one, two and three points received Morris water-maze test to measure searching time on platform (omitting platform-escaping latency). Meanwhile, leaning and memory abilities of animals were reflected through testing times of passing through platform per minute. MAIN OUTCOME MEASURES: Experimental results of omitting platform-escaping latency and spatial probe. RESULTS: Three and two rats in the ischemia/reperfusion group and treatment group respectively were not in accordance with the criteria in the process, and the rest were involved in the final analysis. ① Comparisons of platform-escaping latency during Morris water-maze test in all the three groups: Ten days after modeling, the platform-escaping latency in the ischemia/reperfusion group was obviously longer than that in sham-operation group (P < 0.01), and was significantly shorter than that in the treatment group (P < 0.01). ② Comparisons of times of passing through platform in all the three groups: Times of passing through platform were remarkably less in the ischemia/reperfusion group than those in the sham-operation group [(1.79±0.39), (4.30±0.73) times/minute, P < 0.01], and those were markedly more in the treatment group than the ischemia/reperfusion group [(3.16±1.03), (1.79±0.39) times/minute, P < 0.01]. CONCLUSION: CGRP and NGF are capable of ameliorating the abilities of spatial learning and memory in MCAO rats, which indicates that CGRP and NGF can protect ischemic neurons.展开更多
BACKGROUND： Tetramethylpyrazine （TMP） presents the effect of anti-platelet aggregation, reduces arteria resistance, increases cerebral blood flow, and improves microcirculation. OBJECTIVE： To observe the effects o...BACKGROUND： Tetramethylpyrazine （TMP） presents the effect of anti-platelet aggregation, reduces arteria resistance, increases cerebral blood flow, and improves microcirculation. OBJECTIVE： To observe the effects of TMP on the learning and memory abilities and the number of neurons in cortex and hippocampus after focal cerebral ischemia in rats DESIGN： A randomized controlled tria SETTING： Department of Human Anatomy and Histological Embryology, School of Medicine, Xi＇an Jiaotong University. MATERIALS： Fifty adult male Sprague-Dawley rats, weighing 250-300 g were supplied by the Experimental Animal Center, School of Medicine, Xi＇an Jiaotong University. TMP was purchased from Wuxi Seventh Pharmaceutical Co.Ltd （Lot Number： 2004051106, Specification： 2 mL/piece）. METHODS ： The experiments were carried out in School of Medicine of Xi＇an Jiaotong University from June 2004 to May 2005. The 50 rats were randomly divided into five groups according to the random number table method： sham-operated group, cerebral ischemia control group, low-dose TMP group, middle-dose TMP group and high-dose TMP group, 10 rats in each group. Rats in the TMP groups were immediately treated with intraperitoneal injection of TMP of 40, 80 and 120 mg/kg respectively, and those in the sham-operated group and cerebral ischemia control group were injected intraperitoneally by isovolume saline, once a day for 14 days successively. On the 15^th day, the spatial learning and memory abilities of the rats were assessed with the Morris water maze test, and then the changes of neuron numbers in cortex and hippocampus were observed by Nissl staining of brain sections. MAIN OUTCOME MEASURES ： The results of Morris water maze test and the changes of neuron numbers in cortex and hippocampus by Nissl staining of brain sections were observed. RESULTS： Finally 39 rats were involved in the analysis of results, and the other 11 died of excessive anesthesia or failure in model establishment. ① The rats in the cerebral ischemia control group manifested obvious spatial cognitive deficits in the place navigation trial and spatial probe trial. The mean values of escape latency in the sham-operated group, low, middle and high-dose TMP groups were obviously shorter than that in the cerebral ischemia control group [（23.92±2.21）, （41.84±3.74）, （39.50 ±3.80）, （31.38_±3.72）, （61.60±3.61） s, P 〈 0.05-0.01]. In the spatial probe trial, significant differences in the percentage of time spending in the former platform quadrant and frequency of crossing the former platform site in the sham-operated group, lose, middle and high-dose TMP groups were obviously higher or more than those in the cerebral ischemia control group [（36.27±3.42） %, （35.84±2.54）%, （38.43±3.08）%, （36.51±1.96）%, （22.24±3.46）%; （11 ±1 ）, （10±1）, （8_±1）, （8±1）, （4±1） times, P 〈 0.01]. ② In the morphological observation, the numbers of neurons in ipsilateral （left） parietal cortex in the sham-operated group, low, middle and high-dose TMP groups were obviously more than that in the cerebral ischemia control group [（98±8）, （65±5）, （53±6）, （57±6）, （37±6）/0.625 mm^2, P 〈 0.01], but the number of neurons in left hippocampus had no obvious differences among the groups （P 〉 0.05）. CONCLUSION ： TMP can improve obviously the spatial learning and memory function after permanent focal cerebral ischemia in rats, and the neuroprotective role of the drug in cortex may be involved in its mechanism.展开更多
Rutaecarpine, an active component of the traditional Chinese medicine Tetradium ruticarpum, has been shown to improve myocardial ischemia repeffusion injury. Because both cardiovascular and cerebrovascular diseases ar...Rutaecarpine, an active component of the traditional Chinese medicine Tetradium ruticarpum, has been shown to improve myocardial ischemia repeffusion injury. Because both cardiovascular and cerebrovascular diseases are forms of ischemic vascular disease, they are closely related. We hypothesized that rutaecarpine also has neuroprotective effects on cerebral ischemia reperfusion injury. A cerebral ischemia reperfusion model was established after 84, 252 and 504 pg/kg rutae- carpine were given to mice via intrapedtoneal injection, daily for 7 days. Results of the step through test, 2,3,5-triphenyl tetrazolium chloride dyeing and oxidative stress indicators showed that rutae- carpine could improve learning and memory ability, neurological symptoms and reduce infarction volume and cerebral water content in mice with cerebral ischemia reperfusion injury. Rutaecarpine could significantly decrease the malondialdehyde content and increase the activities of superoxide dismutase and glutathione peroxidase in mouse brain. Therefore, rutaecarpine could improve neu- rological function following injury induced by cerebral ischemia reperfusion, and the mechanism of this improvement may be associated with oxidative stress. These results verify that rutaecarpine has neuroprotective effects on cerebral ischemia reperfusion in mice.展开更多
OBJECTIVE Learning and memory impairment is one of the common sequelae of stroke patients,which is called"post-stroke dementia"and seriously affects the quality of life of the patients.For post-stroke dement...OBJECTIVE Learning and memory impairment is one of the common sequelae of stroke patients,which is called"post-stroke dementia"and seriously affects the quality of life of the patients.For post-stroke dementia,there is still no effective clinical treatment.In the present study,we aim to investigate the effect of the active ingredient of Ferula sinkiangensis,AW09,on global cerebral ischemia-reperfusion mice.METHODS The bilateral common carotid artery occlusion(BCCAO)reperfusion model was used to investigate the protective effect of AW09 on cognitive dysfunction in mice with global cerebral ischemia reperfusion.Y-maze and Morris water maze were used to test the learning and memory ability of mice.RESULTS Y-maze test showed that AW09 treatment significantly increased the spontaneous alternation rate of BCCAO model animals and had no significant effect on the total number of arm entries.The results of Morris water maze showed that AW09 significantly reduced the escape latency of BCCAO mice during the training period.During the probe test phase,AW09 significantly increased the swimming time in target quadrant,distance in target quadrant and number of platform crossings and decreased the swimming time in the quadrant opposite the target quadrant of BCCAO mice.CONCLUSION AW09,the active ingredient of Ferula sinkiangensis,can improve working memory impairment and spatial memory impairment in animals with global cerebral ischemia-reperfusion,suggesting that AW09 has poten⁃tial therapeutic value for cognitive dysfunction caused by global cerebral ischemia.展开更多
Objective:To observe the effect of puerarin on the learning-memory disorder after global cerebral ischemia-reperfusion injury in rats,and to explore its mechanism of action.Methods:The global cerebral ischemia-reperfu...Objective:To observe the effect of puerarin on the learning-memory disorder after global cerebral ischemia-reperfusion injury in rats,and to explore its mechanism of action.Methods:The global cerebral ischemia-reperfusion injury model was established using the modified Pulsinelli four-vessel occlusion in Sprague-Dawley rats.Rats were intraperitoneally injected with puerarin(100 mg/kg) 1 h before ischemia and once every 6 h afterwards.The learning-memory ability was evaluated by the passive avoidance test.Th...展开更多
基金supported by the National Natural Science Foundation of China,No.82101567Doctoral Start-up Foundation of Liaoning Province,No.2021-BS-111345 Talent Project of Shengjing Hospital of China Medical University,No.M0673(all to XYF)。
文摘Cerebral ischemia/reperfusion injury impairs learning and memory in patients.Studies have shown that synaptic function is involved in the formation and development of memory,and that DNA methylation plays a key role in the regulation of learning and memory.To investigate the role of DNA hypomethylation in cerebral ischemia/reperfusion injury,in this study,we established a rat model of cerebral ischemia/reperfusion injury by occlusion of the middle cerebral artery and then treated the rats with intraperitoneal 5-aza-2′-deoxycytidine,an inhibitor of DNA methylation.Our results showed that 5-aza-2′-deoxycytidine markedly improved the neurological function,and cognitive,social and spatial memory abilities,and dose-dependently increased the synaptic density and the expression of SYP and SHANK2 proteins in the hippocampus in a dose-dependent manner in rats with cerebral ischemia/reperfusion injury.The effects of 5-aza-2′-deoxycytidine were closely related to its reduction of genomic DNA methylation and DNA methylation at specific sites of the Syp and Shank2 genes in rats with cerebral ischemia/reperfusion injury.These findings suggest that inhibition of DNA methylation by 5-aza-2′-deoxycytidine promotes the recovery of learning and memory impairment in a rat model of cerebral ischemia/reperfusion injury.These results provide theoretical evidence for stroke treatment using epigenetic methods.
文摘BACKGROUND: Calcitonin gene-related peptide (CGRP) and nerve growth actor (NGF) cam improve spatial learning and memory abilities of rats with cerebral ischemia/reperfusion; however, the effect of combination of them on relieving learning and memory injury following cerebral ischemia/reperfusion should be further studied. OBJECTIVE: To study the effects of exogenous CGRP and NGF on learning and memory abilities of rats with focal cerebral ischemia/reperfusion. DESIGN: Randomized controlled animal study. SETTING: Department of Neurosurgery, the Second Hospital of Xiamen; Department of Neurosurgery, the Second Affiliated Hospital of China Medical University; Department of Neurobiology, Basic Medical College of China Medical University. MATERIALS: A total of 30 healthy male SD rats, aged 8 weeks, of clean grade, weighing 250-300 g, were provided by Experimental Animal Department of China Medical University. All rats were randomly divided into sham-operation group, ischemia/reperfusion group and treatment group with 10 in each group. The main reagents were detailed as the follows: 100 g/L chloral hydrate, 0.5 mL CGRP (2 mg/L, Sigma Company, USA), and NGF (1× 106 U/L, 0.5 mL, Siweite Company, Dalian). METHODS: The experiment was carried out in the Department of Neurobiology, Basic Medical College of China Medical University from February to July 2005. Rat models of middle cerebral artery occlusion were established by method of occlusion, 2 hours after that rats were anesthetized and the thread was slightly drawn out for 10 mm under direct staring to perform reperfusion. Rats in the ischemia/reperfusion group received intraperitoneal injection of 1 mL saline via the abdomen at two hours later, while rats in the treatment group at 2 hours later received intraperitoneal injection of 2 mg/L CGRP (0.5 mL) and 1×106 U/L NGF (0.5 mL) once a day for 10 successive days. First administration was accomplished within 15 minutes after ischemia/reperfusion. Rats in the sham-operation group were separated of the vessels without occlusion or administration. The neural function was evaluated with Zea Longa 5-grade scale. Animals with the score of one, two and three points received Morris water-maze test to measure searching time on platform (omitting platform-escaping latency). Meanwhile, leaning and memory abilities of animals were reflected through testing times of passing through platform per minute. MAIN OUTCOME MEASURES: Experimental results of omitting platform-escaping latency and spatial probe. RESULTS: Three and two rats in the ischemia/reperfusion group and treatment group respectively were not in accordance with the criteria in the process, and the rest were involved in the final analysis. ① Comparisons of platform-escaping latency during Morris water-maze test in all the three groups: Ten days after modeling, the platform-escaping latency in the ischemia/reperfusion group was obviously longer than that in sham-operation group (P < 0.01), and was significantly shorter than that in the treatment group (P < 0.01). ② Comparisons of times of passing through platform in all the three groups: Times of passing through platform were remarkably less in the ischemia/reperfusion group than those in the sham-operation group [(1.79±0.39), (4.30±0.73) times/minute, P < 0.01], and those were markedly more in the treatment group than the ischemia/reperfusion group [(3.16±1.03), (1.79±0.39) times/minute, P < 0.01]. CONCLUSION: CGRP and NGF are capable of ameliorating the abilities of spatial learning and memory in MCAO rats, which indicates that CGRP and NGF can protect ischemic neurons.
基金the National Natural Science Foundation of China, No. 30170300 30300109
文摘BACKGROUND： Tetramethylpyrazine （TMP） presents the effect of anti-platelet aggregation, reduces arteria resistance, increases cerebral blood flow, and improves microcirculation. OBJECTIVE： To observe the effects of TMP on the learning and memory abilities and the number of neurons in cortex and hippocampus after focal cerebral ischemia in rats DESIGN： A randomized controlled tria SETTING： Department of Human Anatomy and Histological Embryology, School of Medicine, Xi＇an Jiaotong University. MATERIALS： Fifty adult male Sprague-Dawley rats, weighing 250-300 g were supplied by the Experimental Animal Center, School of Medicine, Xi＇an Jiaotong University. TMP was purchased from Wuxi Seventh Pharmaceutical Co.Ltd （Lot Number： 2004051106, Specification： 2 mL/piece）. METHODS ： The experiments were carried out in School of Medicine of Xi＇an Jiaotong University from June 2004 to May 2005. The 50 rats were randomly divided into five groups according to the random number table method： sham-operated group, cerebral ischemia control group, low-dose TMP group, middle-dose TMP group and high-dose TMP group, 10 rats in each group. Rats in the TMP groups were immediately treated with intraperitoneal injection of TMP of 40, 80 and 120 mg/kg respectively, and those in the sham-operated group and cerebral ischemia control group were injected intraperitoneally by isovolume saline, once a day for 14 days successively. On the 15^th day, the spatial learning and memory abilities of the rats were assessed with the Morris water maze test, and then the changes of neuron numbers in cortex and hippocampus were observed by Nissl staining of brain sections. MAIN OUTCOME MEASURES ： The results of Morris water maze test and the changes of neuron numbers in cortex and hippocampus by Nissl staining of brain sections were observed. RESULTS： Finally 39 rats were involved in the analysis of results, and the other 11 died of excessive anesthesia or failure in model establishment. ① The rats in the cerebral ischemia control group manifested obvious spatial cognitive deficits in the place navigation trial and spatial probe trial. The mean values of escape latency in the sham-operated group, low, middle and high-dose TMP groups were obviously shorter than that in the cerebral ischemia control group [（23.92±2.21）, （41.84±3.74）, （39.50 ±3.80）, （31.38_±3.72）, （61.60±3.61） s, P 〈 0.05-0.01]. In the spatial probe trial, significant differences in the percentage of time spending in the former platform quadrant and frequency of crossing the former platform site in the sham-operated group, lose, middle and high-dose TMP groups were obviously higher or more than those in the cerebral ischemia control group [（36.27±3.42） %, （35.84±2.54）%, （38.43±3.08）%, （36.51±1.96）%, （22.24±3.46）%; （11 ±1 ）, （10±1）, （8_±1）, （8±1）, （4±1） times, P 〈 0.01]. ② In the morphological observation, the numbers of neurons in ipsilateral （left） parietal cortex in the sham-operated group, low, middle and high-dose TMP groups were obviously more than that in the cerebral ischemia control group [（98±8）, （65±5）, （53±6）, （57±6）, （37±6）/0.625 mm^2, P 〈 0.01], but the number of neurons in left hippocampus had no obvious differences among the groups （P 〉 0.05）. CONCLUSION ： TMP can improve obviously the spatial learning and memory function after permanent focal cerebral ischemia in rats, and the neuroprotective role of the drug in cortex may be involved in its mechanism.
基金financially supported by Zhangjiakou Science and Technology Commission Foundation,No.1021095Dthe Hebei North University Foundation,No.Q2010018
文摘Rutaecarpine, an active component of the traditional Chinese medicine Tetradium ruticarpum, has been shown to improve myocardial ischemia repeffusion injury. Because both cardiovascular and cerebrovascular diseases are forms of ischemic vascular disease, they are closely related. We hypothesized that rutaecarpine also has neuroprotective effects on cerebral ischemia reperfusion injury. A cerebral ischemia reperfusion model was established after 84, 252 and 504 pg/kg rutae- carpine were given to mice via intrapedtoneal injection, daily for 7 days. Results of the step through test, 2,3,5-triphenyl tetrazolium chloride dyeing and oxidative stress indicators showed that rutae- carpine could improve learning and memory ability, neurological symptoms and reduce infarction volume and cerebral water content in mice with cerebral ischemia reperfusion injury. Rutaecarpine could significantly decrease the malondialdehyde content and increase the activities of superoxide dismutase and glutathione peroxidase in mouse brain. Therefore, rutaecarpine could improve neu- rological function following injury induced by cerebral ischemia reperfusion, and the mechanism of this improvement may be associated with oxidative stress. These results verify that rutaecarpine has neuroprotective effects on cerebral ischemia reperfusion in mice.
基金National Natural Science Foundation of China(U160312581473330+5 种基金8187276881673323)Fundamental Research Funds for the Central Universities of China(N182008004N182006001)Liaoning Revitalization Talents Program(XLYC1807118)Liaoning BaiQianWan Talents Program(2018)
文摘OBJECTIVE Learning and memory impairment is one of the common sequelae of stroke patients,which is called"post-stroke dementia"and seriously affects the quality of life of the patients.For post-stroke dementia,there is still no effective clinical treatment.In the present study,we aim to investigate the effect of the active ingredient of Ferula sinkiangensis,AW09,on global cerebral ischemia-reperfusion mice.METHODS The bilateral common carotid artery occlusion(BCCAO)reperfusion model was used to investigate the protective effect of AW09 on cognitive dysfunction in mice with global cerebral ischemia reperfusion.Y-maze and Morris water maze were used to test the learning and memory ability of mice.RESULTS Y-maze test showed that AW09 treatment significantly increased the spontaneous alternation rate of BCCAO model animals and had no significant effect on the total number of arm entries.The results of Morris water maze showed that AW09 significantly reduced the escape latency of BCCAO mice during the training period.During the probe test phase,AW09 significantly increased the swimming time in target quadrant,distance in target quadrant and number of platform crossings and decreased the swimming time in the quadrant opposite the target quadrant of BCCAO mice.CONCLUSION AW09,the active ingredient of Ferula sinkiangensis,can improve working memory impairment and spatial memory impairment in animals with global cerebral ischemia-reperfusion,suggesting that AW09 has poten⁃tial therapeutic value for cognitive dysfunction caused by global cerebral ischemia.
基金Supported by the Key Technologies Research and Development Program of Shaanxi Province(No.2002k10-G2)
文摘Objective:To observe the effect of puerarin on the learning-memory disorder after global cerebral ischemia-reperfusion injury in rats,and to explore its mechanism of action.Methods:The global cerebral ischemia-reperfusion injury model was established using the modified Pulsinelli four-vessel occlusion in Sprague-Dawley rats.Rats were intraperitoneally injected with puerarin(100 mg/kg) 1 h before ischemia and once every 6 h afterwards.The learning-memory ability was evaluated by the passive avoidance test.Th...
