scholarly journals A Model of Global Cerebral Ischemia in C57 BL/6 Mice

2004 ◽  
Vol 24 (2) ◽  
pp. 151-158 ◽  
Author(s):  
Ichiro Yonekura ◽  
Nobutaka Kawahara ◽  
Hirofumi Nakatomi ◽  
Kazuhide Furuya ◽  
Takaaki Kirino
Keyword(s):  
Cerebral Ischemia ◽  
Genetic Background ◽  
Neuronal Degeneration ◽  
Neuronal Damage ◽  
Neuronal Injury ◽  
Genetically Engineered ◽  
Global Cerebral Ischemia ◽  
Vessel Occlusion ◽  
Bilateral Carotid ◽  
The Mean

A reproducible model of global cerebral ischemia in mice is essential for elucidating the molecular mechanism of ischemic neuronal injury. Such a model is particularly important in the mouse because many genetically engineered mutant animals are available. In C57BL/6 and SV129/EMS mice, we evaluated a three-vessel occlusion model. Occlusion of the basilar artery with a miniature clip was followed by bilateral carotid occlusion. The mean cortical cerebral blood flow was reduced to less than 10% of the preischemic value, and the mean anoxic depolarization was attained within 1 minute. In C57BL/6 mice, there was CA1 hippocampal neuronal degeneration 4 days after ischemia. Neuronal damage depended upon ischemic duration: the surviving neuronal count was 78.5 ± 8.5% after 8-minute ischemia and 8.4 ± 12.7% after 14-minute ischemia. In SV129/EMS mice, similar neuronal degeneration was not observed after 14-minute ischemia. The global ischemia model in C57BL/6 mice showed high reproducibility and consistent neuronal injury in the CA1 sector, indicating that comparison of ischemic outcome between wild-type and mutant mice could provide meaningful data using the C57BL/6 genetic background. Strain differences in this study highlight the need for consideration of genetic background when evaluating ischemia experiments in mice.

scholarly journals MK-801 (Dizocilpine) Protects the Brain from Repeated Normothermic Global Ischemic Insults in the Rat

1993 ◽  
Vol 13 (6) ◽  
pp. 925-932 ◽  
Author(s):  
Baowan Lin ◽  
W. Dalton Dietrich ◽  
Myron D. Ginsberg ◽  
Mordecai Y.-T. Globus ◽  
Raul Busto
Keyword(s):  
Cerebral Ischemia ◽  
Repeated Measures ◽  
Neuronal Damage ◽  
Brain Temperature ◽  
Global Cerebral Ischemia ◽  
Striatal Neurons ◽  
Ischemic Insult ◽  
Mk 801 ◽  
Bilateral Carotid ◽  
Ventrolateral Thalamus

We investigated the neuroprotective potential of MK-801 (dizocilpine), a noncompetitive N-methyl-d-aspartate (NMDA) antagonist, in the setting of three 5-min periods of global cerebral ischemia separated by 1-h intervals in halothane-anesthetized rats. Each ischemic insult was produced by bilateral carotid artery occlusions plus hypotension (50 mm Hg). Brain temperature was maintained at normothermic levels (36.5–37.0°C) throughout the experiment. MK-801 (3 mg/kg) (n = 6) or saline (n = 6) was injected intraperitoneally 45 min following the end of the first ischemic insult. Following 7-day survival, quantitative neuronal counts of perfusion-fixed brains revealed severe ischemic damage in hippocampal CA1 area, neocortex, ventrolateral thalamus, and striatum of untreated rats. By contrast, significant protection was observed in MK-801-treated rats. In area CA1 of the hippocampus, numbers of normal neurons were increased 11- to 14-fold by MK-801 treatment (p < 0.01). The ventrolateral thalamus of MK-801-treated rats showed almost complete histologic protection, and neocortical damage was reduced by 71% (p < 0.01). The degree of MK-801 protection of striatal neurons was less complete than that seen in other vulnerable structures, amounting to 63% for central striatum (p = 0.02, Mann–Whitney U test) and 48% in the dorsolateral striatum (NS). A repeated-measures analysis of variance demonstrated a highly significant overall protective effect of MK-801 treatment ( F1,10 = 37.2, p = 0.0001). These findings indicate that excitotoxic mechanisms play a major role in neuronal damage produced by repeated ischemic insults and that striking cerebroprotection is conferred by MK-801 administered following the first insult in animals with cerebral normothermia. NMDA antagonists may prove useful in patients at risk of repeated episodes of cerebral ischemia.

scholarly journals Neuroprotection after Transient Global Cerebral Ischemia in Wlds Mutant Mice

2004 ◽  
Vol 24 (1) ◽  
pp. 62-66 ◽  
Author(s):  
Thomas H. Gillingwater ◽  
Jane E. Haley ◽  
Richard R. Ribchester ◽  
Karen Horsburgh
Keyword(s):  
Cerebral Ischemia ◽  
Caudate Nucleus ◽  
Pyramidal Cell ◽  
Cell Layer ◽  
Neuronal Degeneration ◽  
Neuronal Damage ◽  
Global Cerebral Ischemia ◽  
Nerve Lesion ◽  
Wild Type ◽  
Pyramidal Cell Layer

The Wlds mouse mutant demonstrates a remarkable phenotype of delayed axonal and synaptic degeneration after nerve lesion. In this study, the authors tested the hypothesis that expression of Wld protein is neuroprotective in an in vivo mouse model of global cerebral ischemia. This model is associated with selective neuronal degeneration in specific brain regions such as the caudate nucleus and CA2 hippocampal pyramidal cell layer. The extent of neuronal damage was quantified in Wlds compared to wild-type mice after an identical episode of global cerebral ischemia. The results demonstrated a significant and marked reduction in the extent of neuronal damage in Wlds as compared to wild-type C57Bl/6 mice. In the caudate nucleus, Wld expression significantly reduced the percentage of ischemic neuronal damage after global ischemia (Wlds, 27.7 ± 16.8%; wild-type mice, 58.7 ± 32.3%; P = 0.036). Similarly, in the CA2 pyramidal cell layer, there was a significant reduction of neuronal damage in the Wlds mice as compared to wild-type mice after ischemia (Wlds, 17.7 ± 23.0%; wild-type mice, 41.9 ± 28.0%; P < 0.023). Thus, these results clearly demonstrate that the Wld gene confers substantial neuroprotection after cerebral ischemia, and suggest a new role to that previously described for Wlds.

scholarly journals Targeting Expression of hsp70i to Discrete Neuronal Populations Using the Lmo-1 Promoter: Assessment of the Neuroprotective Effects of hsp70i In vivo and In vitro

2001 ◽  
Vol 21 (8) ◽  
pp. 972-981 ◽  
Author(s):  
Stephen Kelly ◽  
Alison Bieneman ◽  
Karen Horsburgh ◽  
David Hughes ◽  
Michael V. Sofroniew ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Transgenic Mice ◽  
Caudate Nucleus ◽  
Neuronal Damage ◽  
Global Cerebral Ischemia ◽  
Specific Gene ◽  
Wild Type ◽  
Neuroprotective Effects ◽  
Bilateral Carotid

Transgenic technology provides a powerful means of studying gene regulation and specific gene function with complex mammalian systems. In this study, the authors exploited the specific and discrete neuronal expression pattern mediated by promoter 1 of the Lmo-1 gene to study the neuroprotective effects of the inducible form of heat shock protein 70kD (hsp70i) in primary hippocampal cultures in a mouse model of global cerebral ischemia. Targeting expression of hsp70i to hippocampal neurons protected these cells significantly from toxic levels of glutamate and oxidative stress (for example, exposure to 10 μmol/L free iron produced a 26% increase in lactate dehydrogenase release from neurons cultured from wild-type mice, but a 7% increase in neurons cultured from hsp70i transgenic mice). Bilateral carotid occlusion (25 minutes) produced significantly less neuronal damage in the caudate nucleus and posterior thalamus in hsp70i transgenic mice than in wild-type littermates (for example, 21% ± 9.3% and 12.5% ± 9.0% neuronal damage in lateral caudate nucleus of wild-type and hsp70i transgenic mice, respectively, P < 0.05). The current study highlights the utility of targeted expression of transgenes of interest in cerebral ischemia and demonstrates that expression of hsp70i alone is sufficient to mediate the protection of primary neurons from denaturing stress and that expression of human hsp70i in vivo plays crucial role in determining the fate of neurons after ischemic challenge.

scholarly journals Rapid Preconditioning Protects Rats against Ischemic Neuronal Damage after 3 but Not 7 Days of Reperfusion following Global Cerebral Ischemia

1997 ◽  
Vol 17 (2) ◽  
pp. 175-182 ◽  
Author(s):  
Miguel A. Pérez-Pinzón ◽  
Guang-Ping Xu ◽  
W. Dalton Dietrich ◽  
Myron Rosenthal ◽  
Thomas J. Sick
Keyword(s):  
Cerebral Ischemia ◽  
Neuronal Damage ◽  
Systemic Blood Pressure ◽  
Global Cerebral Ischemia ◽  
Extracellular Potassium ◽  
Artery Ligation ◽  
Clear Trend ◽  
Maximal Increase ◽  
Hippocampal Ca1 ◽  
Bilateral Carotid

Earlier studies indicated that sublethal ischemic insults separated by many hours may “precondition” and, thereby, protect tissues from subsequent insults. In Wistar rats, we examined the hypothesis that ischemic preconditioning (IPC) can improve histopathological outcome even if the “conditioning” and “test” ischemic insults are separated by only 30 min. Normothermic (36.5–37°C) global cerebral ischemia was produced by bilateral carotid artery ligation after lowering mean systemic blood pressure. The conditioning ischemic insult lasted 2 min and was associated with a time sufficient to provoke “anoxic depolarization” (AD) (i.e., the abrupt maximal increase in extracellular potassium ion activity). After 30 min of reperfusion, 10-min test ischemia was produced, and histopathology was assessed 3 and 7 days later. After 3 days of reperfusion, neuroprotection was most robust in the left lateral, middle and medial subsections of the hippocampal CA1 subfield and in the cortex, where protection was 91, 76, 70 and 86%, respectively. IPC also protected the right lateral, middle and medial subsections of the hippocampal CA1 region. These data demonstrate that neuroprotection against acute neuronal injury can be achieved by conditioning insults followed by only short (30 min) periods of reperfusion. However, neuroprotection almost disappeared when reperfusion was continued for 7 days. When test ischemia was decreased to 7 min, a clear trend of neuroprotection by IPC was observed. These data suggest that subsequent rescue of neuronal populations could be achieved with better understanding of the neuroprotective mechanisms involved in this rapid IPC model.

scholarly journals Functional, Behavioral, and Histological Changes Induced by Transient Global Cerebral Ischemia in Rats: Effects of Cinnarizine and Flunarizine

1989 ◽  
Vol 9 (5) ◽  
pp. 646-654 ◽  
Author(s):  
H. Poignet ◽  
M. Beaughard ◽  
G. Lecoin ◽  
R. Massingham
Keyword(s):  
Cerebral Ischemia ◽  
Neuronal Damage ◽  
Global Cerebral Ischemia ◽  
Experimental Conditions ◽  
Vessel Occlusion ◽  
Transient Global Cerebral Ischemia ◽  
Behavioral Parameters ◽  
Ischemic Episode ◽  
Cerebral Ischemic ◽  
Positive Effect

Temporary cerebral ischemia (15 min) produced by “four-vessel occlusion” in the rat causes neurological disorders, changes in behavior (locomotor hyperactivity), and neuronal damage in the neocortex, striatum, and especially the CA1 zone of the hippocampus. We have studied the effects of two calcium overload blockers, flunarizine (50 mg/kg p.o. twice a day) and cinnarizine (100 mg/kg p.o. twice a day), on these alterations. Cinnarizine markedly improved the functional abnormalities of ischemia but had little or no effect upon the neuronal damage. In contrast, flunarizine provided far greater neuronal protection but with less obvious effects upon behavioral parameters. However, there was evidence of sedation 2 h after treating animals with this dose of flunarizine that might have masked any positive effect of the drug on behavior. We conclude that under the present experimental conditions, there is no correlation between the early and late behavioral changes observed following a temporary cerebral ischemic episode and the histological damage observed in certain vulnerable neurons, particularly in the hippocampus, 72 h after the insult.

scholarly journals Inhibition of MLKL-dependent necroptosis via downregulating interleukin-1R1 contributes to neuroprotection of hypoxic preconditioning in transient global cerebral ischemic rats

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Lixuan Zhan ◽  
Xiaomei Lu ◽  
Wensheng Xu ◽  
Weiwen Sun ◽  
En Xu
Keyword(s):  
Plasma Membrane ◽  
Cerebral Ischemia ◽  
Neuronal Death ◽  
Interleukin 1 ◽  
Hypoxic Preconditioning ◽  
Global Cerebral Ischemia ◽  
Free Calcium ◽  
Membrane Translocation ◽  
Vessel Occlusion ◽  
Transient Global Cerebral Ischemia

Abstract Background Our previous study indicated that hypoxic preconditioning reduced receptor interacting protein (RIP) 3-mediated necroptotic neuronal death in hippocampal CA1 of adult rats after transient global cerebral ischemia (tGCI). Although mixed lineage kinase domain-like (MLKL) has emerged as a crucial molecule for necroptosis induction downstream of RIP3, how MLKL executes necroptosis is not yet well understood. In this study, we aim to elucidate the molecular mechanism underlying hypoxic preconditioning that inactivates MLKL-dependent neuronal necroptosis after tGCI. Methods Transient global cerebral ischemia was induced by the four-vessel occlusion method. Twenty-four hours before ischemia, rats were exposed to systemic hypoxia with 8% O2 for 30 min. Western blotting was used to detect the expression of MLKL and interleukin-1 type 1 receptor (IL-1R1) in CA1. Immunoprecipitation was used to assess the interactions among IL-1R1, RIP3, and phosphorylated MLKL (p-MLKL). The concentration of intracellular free calcium ion (Ca2+) was measured using Fluo-4 AM. Silencing and overexpression studies were used to study the role of p-MLKL in tGCI-induced neuronal death. Results Hypoxic preconditioning decreased the phosphorylation of MLKL both in neurons and microglia of CA1 after tGCI. The knockdown of MLKL with siRNA decreased the expression of p-MLKL and exerted neuroprotective effects after tGCI, whereas treatment with lentiviral delivery of MLKL showed opposite results. Mechanistically, hypoxic preconditioning or MLKL siRNA attenuated the RIP3-p-MLKL interaction, reduced the plasma membrane translocation of p-MLKL, and blocked Ca2+ influx after tGCI. Furthermore, hypoxic preconditioning downregulated the expression of IL-1R1 in CA1 after tGCI. Additionally, neutralizing IL-1R1 with its antagonist disrupted the interaction between IL-1R1 and the necrosome, attenuated the expression and the plasma membrane translocation of p-MLKL, thus alleviating neuronal death after tGCI. Conclusions These data support that the inhibition of MLKL-dependent neuronal necroptosis through downregulating IL-1R1 contributes to neuroprotection of hypoxic preconditioning against tGCI.

A modified four vessel occlusion model of global cerebral ischemia in rats

2021 ◽  
Vol 352 ◽  
pp. 109090
Author(s):  
Wei Sun ◽  
Yeting Chen ◽  
Yongjie Zhang ◽  
Yue Geng ◽  
Xiaohang Tang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Global Cerebral Ischemia ◽  
Vessel Occlusion ◽  
Occlusion Model

scholarly journals Assessment of Postischemic Neurogenesis in Rats with Cerebral Ischemia and Propofol Anesthesia

2009 ◽  
Vol 110 (3) ◽  
pp. 529-537 ◽  
Author(s):  
Irina Lasarzik ◽  
Uta Winkelheide ◽  
Sonja Stallmann ◽  
Christian Orth ◽  
Astrid Schneider ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Spatial Learning ◽  
Neuronal Damage ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
High Dose ◽  
Sprague Dawley ◽  
Bilateral Carotid ◽  
Significant Difference ◽  
Treatment Naïve

Background Postischemic endogenous neurogenesis can be dose-dependently modulated by volatile anesthetics. The intravenous anesthetic propofol is used during operations with a risk of cerebral ischemia, such as neurosurgery, cardiac surgery, and vascular surgery. The effects of propofol on neurogenesis are unknown and, therefore, the object of this study. Methods Eighty male Sprague-Dawley rats were randomly assigned to treatment groups with propofol administration for 3 h: 36 mg x kg(-1) x h(-1) propofol with or without cerebral ischemia and 72 mg x kg(-1) x h(-1) propofol with or without cerebral ischemia. In addition, 7 rats with propofol administration for 6 h and 14 treatment-naive rats were investigated. Forebrain ischemia was induced by bilateral carotid artery occlusion and hemorrhagic hypotension. Animals received 5-bromo-2-deoxyuridine for 7 days. 5-Bromo-2-deoxyuridine-positive neurons were counted in the dentate gyrus after 9 and 28 days. Spatial learning in the Barnes maze and histopathologic damage of the hippocampus were analyzed. Results Propofol revealed no impact on basal neurogenesis. Cerebral ischemia increased the amount of new neurons. After 28 days, neurogenesis significantly increased in animals with low-dose propofol administered during cerebral ischemia compared with naive animals, whereas no significant difference was observed in animals with high-dose propofol during ischemia. Neuronal damage in the CA3 region was increased at 28 days with high-dose propofol. Postischemic deficits in spatial learning were not affected by propofol. Conclusions Independent effects of propofol are difficult to ascertain. Peri-ischemic propofol administration may exert secondary effects on neurogenesis by modulating the severity of histopathologic injury and thereby regenerative capacity of the hippocampus.

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