Experimental stroke research commonly employs focal cerebral ischemic rat models (Bederson et al., 1986a; Longa et al., 1989). In human patients, ischemic stroke typically results from thrombotic or embolic occlusio...Experimental stroke research commonly employs focal cerebral ischemic rat models (Bederson et al., 1986a; Longa et al., 1989). In human patients, ischemic stroke typically results from thrombotic or embolic occlusion of a major cerebral artery, usually the mid- dle cerebral artery (MCA). Experimental focal cerebral ischemia models have been employed to mimic human stroke (Durukan and Tatlisumak, 2007). Rodent models of focal cerebral ischemia that do not require craniotomy have been developed using intraluminal suture occlusion of the MCA (MCA occlusion, MCAO) (Rosamond et al., 2008). Furthermore, mouse MCAO models have been wide- ly used and extended to genetic studies of cell death or recovery mechanisms (Liu and McCullough, 2011). Genetically engineered mouse stroke models are particularly useful for evaluation of isch- emic pathophysiology and the design of new prophylactic, neuro- protective, and therapeutic agents and interventions (Armstead et al., 2010). During the past two decades, MCAO surgical techniques have been developed that do not reveal surgical techniques for mouse MCAO model engineering. Therefore, we compared MCAO surgical methods in rats and mice.展开更多
Endovascular surgery is advantageous in experimentally induced ischemic stroke because it causes fewer cranial traumatic lesions than invasive surgery and can closely mimic the pathophysiology in stroke patients. Howe...Endovascular surgery is advantageous in experimentally induced ischemic stroke because it causes fewer cranial traumatic lesions than invasive surgery and can closely mimic the pathophysiology in stroke patients. However, the outcomes are highly variable, which limits the accuracy of evaluations of ischemic stroke studies. In this study, eight healthy adult rhesus monkeys were randomized into two groups with four monkeys in each group: middle cerebral artery occlusion at origin segment (M1) and middle cerebral artery occlusion at M2 segment. The blood flow in the middle cerebral artery was blocked completely for 2 hours using the endovascular microcoil placement technique (1 mm × 10 cm) (undetachable), to establish a model of cerebral ischemia. The microcoil was withdrawn and the middle cerebral artery blood flow was restored. A reversible middle cerebral artery occlusion model was identified by hematoxylin-eosin staining, digital subtraction angiography, magnetic resonance angiography, magnetic resonance imaging, and neurological evaluation. The results showed that the middle cerebral artery occlusion model was successfully established in eight adult healthy rhesus monkeys, and ischemic lesions were apparent in the brain tissue of rhesus monkeys at 24 hours after occlusion. The rhesus monkeys had symptoms of neurological deficits. Compared with the M1 occlusion group, the M2 occlusion group had lower infarction volume and higher neurological scores. These experimental findings indicate that reversible middle cerebral artery occlusion can be produced with the endovascular microcoil technique in rhesus monkeys. The M2 occluded model had less infarction and less neurological impairment, which offers the potential for application in the field of brain injury research.展开更多
Rodents have been widely used in the production of cerebral ischemia models. However, successful therapies have been proven on experimental rodent stroke model, and they have often failed to be effective when tested c...Rodents have been widely used in the production of cerebral ischemia models. However, successful therapies have been proven on experimental rodent stroke model, and they have often failed to be effective when tested clinically. Therefore, nonhuman primates were recommended as the ideal alternatives, owing to their similarities with the human cerebrovascular system, brain metabolism, grey to white matter ratio and even their rich behavioral repertoire. The present review is a thorough summary of ten methods that establish nonhuman primate models of focal cerebral ischemia; electrocoagulation, endothelin-1-induced occlusion, microvascular clip occlusion, autologous blood clot embolization, balloon inflation, microcatheter embolization, coil embolization, surgical suture embolization, suture, and photochemical induction methods. This review addresses the advantages and disadvantages of each method, as well as precautions for each model, compared nonhuman primates with rodents, different species of nonhuman primates and different modeling methods. Finally it discusses various factors that need to be considered when modelling and the method of evaluation after modelling. These are critical for understanding their respective strengths and weaknesses and underlie the selection of the optimum model.展开更多
The purpose of this work was to demonstrate the feasibility of neurite orientation dispersion and density imaging(NODDI)in characterizing the brain tissue microstructural changes of middle cerebral artery occlusion(MC...The purpose of this work was to demonstrate the feasibility of neurite orientation dispersion and density imaging(NODDI)in characterizing the brain tissue microstructural changes of middle cerebral artery occlusion(MCAO)in rats at 3T MRI,and to validate NODDI metrics with histology.A multi-shell diffusion MRI protocol was performed on 11 MCAO rats and 10 control rats at different post-operation time points of 0.5,2,6,12,24 and 72 h.NODDI orientation dispersion index(ODI)and intracellular volume fraction(V_(ic))metrics were compared between MCAO group and control group.The evolution of NODDI metrics was characterized and validated by histology.Infarction was consistent with significantly increased ODI and V_(ic)in comparison to control tissues at all time points(P<0.001).Lesion ODI increased gradually from 0.5 to 72 h,while its V_(ic)showed a more complicated and fluctuated evolution.ODI and V_(ic)were significantly different between hyperacute and acute stroke periods(P<0.001).The NODDI metrics were found to be consistent with the histological findings.In conclusion,NODDI can reflect microstructural changes of brain tissues in MCAO rats at 3T MRI and the metrics are consistent with histology.This study helps to prepare NODDI for the diagnosis and management of ischemic stroke in translational research and clinical practice.展开更多
Angiopoietin-1/tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 (Tie-2) is a newly discovered signaling pathway of angiogenesis. Angiogenesis benefits recovery of neurological funct...Angiopoietin-1/tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 (Tie-2) is a newly discovered signaling pathway of angiogenesis. Angiogenesis benefits recovery of neurological functions such as swallowing. In the present study, a rat model of dysphagia following stroke was induced by middle cerebral artery occlusion to investigate the influence of low frequency electrical stimulus with bidirectional square waves and triangular waves on angiopoietin-1/-13e-2 mRNA expression. Reverse transcription-polymerase chain reaction results showed that low frequency electrical stimulus significantly improved the neurological scores of the model rats, and increased angiopoietin-1/'13e-2 mRNA expression. This demonstrates that low frequency electrical stimulation can ameliorate neurological function in rats with focal brain ischemia, potentially through regulation of angiopoietin-1/-13e-2 expression in the angiogenesis pathway.展开更多
Salidroside,the main active ingredient extracted from Rhodiola crenulata,has been shown to be neuroprotective in ischemic cerebral injury,but the underlying mechanism for this neuroprotection is poorly understood.In t...Salidroside,the main active ingredient extracted from Rhodiola crenulata,has been shown to be neuroprotective in ischemic cerebral injury,but the underlying mechanism for this neuroprotection is poorly understood.In the current study,the neuroprotective effect of salidroside on cerebral ischemia-induced oxidative stress and the role of the nuclear factor erythroid 2-related factor 2(Nrf2)pathway was investigated in a rat model of middle cerebral artery occlusion.Salidroside(30 mg/kg)reduced infarct size,improved neurological function and histological changes,increased activity of superoxide dismutase and glutathione-S-transferase,and reduced malon-dialdehyde levels after cerebral ischemia and reperfusion.Furthermore,salidroside apparently increased Nrf2 and heme oxygenase-1 expression.These results suggest that salidroside exerts its neuroprotective effect against cerebral ischemia through anti-oxidant mechanisms and that activation of the Nrf2 pathway is involved.The Nrf2/antioxidant response element pathway may become a new therapeutic target for the treatment of ischemic stroke.展开更多
Objectives: To study the acupoint specificity through the comprehensive evaluation of the acupuncture effect on rat model with the middle cerebral artery occlusion (MCAO). Methods: Duplicated MCAO model by Zea-lo...Objectives: To study the acupoint specificity through the comprehensive evaluation of the acupuncture effect on rat model with the middle cerebral artery occlusion (MCAO). Methods: Duplicated MCAO model by Zea-longa's thread ligation was assessed by Zausinger's six-point method, and rats with 1-3 scores were chosen to be grouped. According to the randomized and controlled principle, rats were divided into 6 basic control groups (including normal group, sham group, model control group, model group without intervention, Nimodipine group, lateral-to-Renzhong group) and 6 acupuncture groups [including Neiguan (PC6) group, Weizhong (BL40) group, Chize (LU5) group, Sanyinjiao (SP6) group, Renzhong (DU6) group and non-acupoint group]; in each acupoint or non-acupoint 9 different parameter combinations were respectively set by orthogonal intersection method. There were in total 60 groups, and each group had 12 rats. The rats were treated by acupuncture with the lifting-thrusting manipulation every 12 h, in total 6 times. Indices of neurobehavioral scores, cerebral blood flow, infarction rate, microcirculation, and light microscope, etc. were measured. In order to comprehensively evaluate the acupuncture effect to research the specificity of acupoint, a cluster analysis was made with SPSS17.0 for the comprehensive effect scores of the samples computed according to the comprehensive evaluation models, and then sorting and classification were made for the comprehensive effect scores. Results: In the acupuncture groups every acupoint had different therapeutic effect due to different acupuncture parameter combinations; among the acupuncture groups the orders of curative effect were as followings: Neiguan group was of exceptional result, Weizhong group and Sanyinjiao group were of valid results in upper level, Chize group and Renzhong group were of valid results in lower level, and non-acupoint group was of invalid result; the therapeutic result of acupoint group was superior to non-acupoint group; and the curative effect of acupuncture group was also superior to basic control group. Conclusion: The acupoint has the specificity of acupuncture effect, and the acupoint specificity is relative.展开更多
Background To date murine models of permanent focal cerebral ischemia have not been well characterized. The purposes of this paper were to compare three different permanent middle cerebral artery occlusion (MCAo) mode...Background To date murine models of permanent focal cerebral ischemia have not been well characterized. The purposes of this paper were to compare three different permanent middle cerebral artery occlusion (MCAo) models with or without cra niectomy, and to identify an ideal mouse model of permanent focal cerebral ischemia. Methods Experiments were performed on 45 healthy adult male Kunming mice, weighing 28 to 42 g. The animals were randomly assigned to three groups (n=15 in every group) based on surgical procedure: MCAo via the external carotid artery (ECA), MCAo via the common carotid artery (CCA), and direct ligation of the middle cerebral artery (MCA). Each day post-ischemia, the animals were scored using an eight-grade n eurological function scale, and mortality was also recorded. Seven days post-ischemia, the brains were removed for lesion size determination using triphenyltetrazoli um chloride staining. Correlation analysis of lesion volume and neurological score was carried out. Results Mortality in the group receiving direct MCA ligation was lowest among the three groups, and there was a significant difference between the direct MCA ligation group and the two intraluminal occlusion groups (P<0.05). In all groups, neurological scores gradually increased with prolongation of ischemic duration, peaking after two days, then gradually decreasing. In the direct MCA ligation group, however, neurological scores were relatively stable. There was a significant correlation between infarct volume and neurological score 7 days after MCAo in every group (all r>0.7, P<0.05), suggesting good reproducibility of lesion volume in the three groups, but the infarct volume was more constant in the direct MCA ligation group. Conclusion The direct ligation model of MCAo provides an optimal means of studying permanent focal cerebral ischemia, and is preferable to the models using intraluminal sutures.展开更多
基金supported by the 2013 Inje University Research Grant
文摘Experimental stroke research commonly employs focal cerebral ischemic rat models (Bederson et al., 1986a; Longa et al., 1989). In human patients, ischemic stroke typically results from thrombotic or embolic occlusion of a major cerebral artery, usually the mid- dle cerebral artery (MCA). Experimental focal cerebral ischemia models have been employed to mimic human stroke (Durukan and Tatlisumak, 2007). Rodent models of focal cerebral ischemia that do not require craniotomy have been developed using intraluminal suture occlusion of the MCA (MCA occlusion, MCAO) (Rosamond et al., 2008). Furthermore, mouse MCAO models have been wide- ly used and extended to genetic studies of cell death or recovery mechanisms (Liu and McCullough, 2011). Genetically engineered mouse stroke models are particularly useful for evaluation of isch- emic pathophysiology and the design of new prophylactic, neuro- protective, and therapeutic agents and interventions (Armstead et al., 2010). During the past two decades, MCAO surgical techniques have been developed that do not reveal surgical techniques for mouse MCAO model engineering. Therefore, we compared MCAO surgical methods in rats and mice.
基金supported by grants from the National Key Basic Research Program(973 Program)of China,No.2011CB707804Beijing Municipal Science and Technology Project,No.2121100005312016
文摘Endovascular surgery is advantageous in experimentally induced ischemic stroke because it causes fewer cranial traumatic lesions than invasive surgery and can closely mimic the pathophysiology in stroke patients. However, the outcomes are highly variable, which limits the accuracy of evaluations of ischemic stroke studies. In this study, eight healthy adult rhesus monkeys were randomized into two groups with four monkeys in each group: middle cerebral artery occlusion at origin segment (M1) and middle cerebral artery occlusion at M2 segment. The blood flow in the middle cerebral artery was blocked completely for 2 hours using the endovascular microcoil placement technique (1 mm × 10 cm) (undetachable), to establish a model of cerebral ischemia. The microcoil was withdrawn and the middle cerebral artery blood flow was restored. A reversible middle cerebral artery occlusion model was identified by hematoxylin-eosin staining, digital subtraction angiography, magnetic resonance angiography, magnetic resonance imaging, and neurological evaluation. The results showed that the middle cerebral artery occlusion model was successfully established in eight adult healthy rhesus monkeys, and ischemic lesions were apparent in the brain tissue of rhesus monkeys at 24 hours after occlusion. The rhesus monkeys had symptoms of neurological deficits. Compared with the M1 occlusion group, the M2 occlusion group had lower infarction volume and higher neurological scores. These experimental findings indicate that reversible middle cerebral artery occlusion can be produced with the endovascular microcoil technique in rhesus monkeys. The M2 occluded model had less infarction and less neurological impairment, which offers the potential for application in the field of brain injury research.
基金supported by the National Natural Science Foundation of China,No.81000852 and 81301677the AHA Award,No.17POST32530004+1 种基金the Supporting Project of Science & Technology of Sichuan Province of China,No.2012SZ0140the Research Foundation of Zhejiang Province of China,No.201022896
文摘Rodents have been widely used in the production of cerebral ischemia models. However, successful therapies have been proven on experimental rodent stroke model, and they have often failed to be effective when tested clinically. Therefore, nonhuman primates were recommended as the ideal alternatives, owing to their similarities with the human cerebrovascular system, brain metabolism, grey to white matter ratio and even their rich behavioral repertoire. The present review is a thorough summary of ten methods that establish nonhuman primate models of focal cerebral ischemia; electrocoagulation, endothelin-1-induced occlusion, microvascular clip occlusion, autologous blood clot embolization, balloon inflation, microcatheter embolization, coil embolization, surgical suture embolization, suture, and photochemical induction methods. This review addresses the advantages and disadvantages of each method, as well as precautions for each model, compared nonhuman primates with rodents, different species of nonhuman primates and different modeling methods. Finally it discusses various factors that need to be considered when modelling and the method of evaluation after modelling. These are critical for understanding their respective strengths and weaknesses and underlie the selection of the optimum model.
基金National Natural Science Foundation of China(No.81570462,No.81730049,and No.81801666).
文摘The purpose of this work was to demonstrate the feasibility of neurite orientation dispersion and density imaging(NODDI)in characterizing the brain tissue microstructural changes of middle cerebral artery occlusion(MCAO)in rats at 3T MRI,and to validate NODDI metrics with histology.A multi-shell diffusion MRI protocol was performed on 11 MCAO rats and 10 control rats at different post-operation time points of 0.5,2,6,12,24 and 72 h.NODDI orientation dispersion index(ODI)and intracellular volume fraction(V_(ic))metrics were compared between MCAO group and control group.The evolution of NODDI metrics was characterized and validated by histology.Infarction was consistent with significantly increased ODI and V_(ic)in comparison to control tissues at all time points(P<0.001).Lesion ODI increased gradually from 0.5 to 72 h,while its V_(ic)showed a more complicated and fluctuated evolution.ODI and V_(ic)were significantly different between hyperacute and acute stroke periods(P<0.001).The NODDI metrics were found to be consistent with the histological findings.In conclusion,NODDI can reflect microstructural changes of brain tissues in MCAO rats at 3T MRI and the metrics are consistent with histology.This study helps to prepare NODDI for the diagnosis and management of ischemic stroke in translational research and clinical practice.
基金the National High-Tech R&D Program of China (863 Program), No.2007AA022Z482
文摘Angiopoietin-1/tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 (Tie-2) is a newly discovered signaling pathway of angiogenesis. Angiogenesis benefits recovery of neurological functions such as swallowing. In the present study, a rat model of dysphagia following stroke was induced by middle cerebral artery occlusion to investigate the influence of low frequency electrical stimulus with bidirectional square waves and triangular waves on angiopoietin-1/-13e-2 mRNA expression. Reverse transcription-polymerase chain reaction results showed that low frequency electrical stimulus significantly improved the neurological scores of the model rats, and increased angiopoietin-1/'13e-2 mRNA expression. This demonstrates that low frequency electrical stimulation can ameliorate neurological function in rats with focal brain ischemia, potentially through regulation of angiopoietin-1/-13e-2 expression in the angiogenesis pathway.
基金supported by the Independent Research Project of Fujian Academy of Traditional Chinese Medicine in China,No.2012fjzyyk-4the Natural Science Foundation of Fujian Province in China,No.2014J01340+1 种基金the Research Project of Fujian Provincial Health and Family Planning Commission,No.2014-ZQN-JC-32a grant from the Platform for Preclinical Studies of Traditional Chinese Medicine and Quality Control Engineering Technology Research Center of Fujian Province in China,No.2009Y2003
文摘Salidroside,the main active ingredient extracted from Rhodiola crenulata,has been shown to be neuroprotective in ischemic cerebral injury,but the underlying mechanism for this neuroprotection is poorly understood.In the current study,the neuroprotective effect of salidroside on cerebral ischemia-induced oxidative stress and the role of the nuclear factor erythroid 2-related factor 2(Nrf2)pathway was investigated in a rat model of middle cerebral artery occlusion.Salidroside(30 mg/kg)reduced infarct size,improved neurological function and histological changes,increased activity of superoxide dismutase and glutathione-S-transferase,and reduced malon-dialdehyde levels after cerebral ischemia and reperfusion.Furthermore,salidroside apparently increased Nrf2 and heme oxygenase-1 expression.These results suggest that salidroside exerts its neuroprotective effect against cerebral ischemia through anti-oxidant mechanisms and that activation of the Nrf2 pathway is involved.The Nrf2/antioxidant response element pathway may become a new therapeutic target for the treatment of ischemic stroke.
基金Supported by the National Program on Key Basic Research Project(973 Program,No.2006CB504504,2010CB530500 and2012 CB 518505)
文摘Objectives: To study the acupoint specificity through the comprehensive evaluation of the acupuncture effect on rat model with the middle cerebral artery occlusion (MCAO). Methods: Duplicated MCAO model by Zea-longa's thread ligation was assessed by Zausinger's six-point method, and rats with 1-3 scores were chosen to be grouped. According to the randomized and controlled principle, rats were divided into 6 basic control groups (including normal group, sham group, model control group, model group without intervention, Nimodipine group, lateral-to-Renzhong group) and 6 acupuncture groups [including Neiguan (PC6) group, Weizhong (BL40) group, Chize (LU5) group, Sanyinjiao (SP6) group, Renzhong (DU6) group and non-acupoint group]; in each acupoint or non-acupoint 9 different parameter combinations were respectively set by orthogonal intersection method. There were in total 60 groups, and each group had 12 rats. The rats were treated by acupuncture with the lifting-thrusting manipulation every 12 h, in total 6 times. Indices of neurobehavioral scores, cerebral blood flow, infarction rate, microcirculation, and light microscope, etc. were measured. In order to comprehensively evaluate the acupuncture effect to research the specificity of acupoint, a cluster analysis was made with SPSS17.0 for the comprehensive effect scores of the samples computed according to the comprehensive evaluation models, and then sorting and classification were made for the comprehensive effect scores. Results: In the acupuncture groups every acupoint had different therapeutic effect due to different acupuncture parameter combinations; among the acupuncture groups the orders of curative effect were as followings: Neiguan group was of exceptional result, Weizhong group and Sanyinjiao group were of valid results in upper level, Chize group and Renzhong group were of valid results in lower level, and non-acupoint group was of invalid result; the therapeutic result of acupoint group was superior to non-acupoint group; and the curative effect of acupuncture group was also superior to basic control group. Conclusion: The acupoint has the specificity of acupuncture effect, and the acupoint specificity is relative.
文摘Background To date murine models of permanent focal cerebral ischemia have not been well characterized. The purposes of this paper were to compare three different permanent middle cerebral artery occlusion (MCAo) models with or without cra niectomy, and to identify an ideal mouse model of permanent focal cerebral ischemia. Methods Experiments were performed on 45 healthy adult male Kunming mice, weighing 28 to 42 g. The animals were randomly assigned to three groups (n=15 in every group) based on surgical procedure: MCAo via the external carotid artery (ECA), MCAo via the common carotid artery (CCA), and direct ligation of the middle cerebral artery (MCA). Each day post-ischemia, the animals were scored using an eight-grade n eurological function scale, and mortality was also recorded. Seven days post-ischemia, the brains were removed for lesion size determination using triphenyltetrazoli um chloride staining. Correlation analysis of lesion volume and neurological score was carried out. Results Mortality in the group receiving direct MCA ligation was lowest among the three groups, and there was a significant difference between the direct MCA ligation group and the two intraluminal occlusion groups (P<0.05). In all groups, neurological scores gradually increased with prolongation of ischemic duration, peaking after two days, then gradually decreasing. In the direct MCA ligation group, however, neurological scores were relatively stable. There was a significant correlation between infarct volume and neurological score 7 days after MCAo in every group (all r>0.7, P<0.05), suggesting good reproducibility of lesion volume in the three groups, but the infarct volume was more constant in the direct MCA ligation group. Conclusion The direct ligation model of MCAo provides an optimal means of studying permanent focal cerebral ischemia, and is preferable to the models using intraluminal sutures.