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 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 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 Ischemic Preconditioning Preserves Mitochondrial Function after Global Cerebral Ischemia in Rat Hippocampus

2001 ◽  
Vol 21 (12) ◽  
pp. 1401-1410 ◽  
Author(s):  
Kunjan R. Dave ◽  
Isabel Saul ◽  
Raul Busto ◽  
Myron D. Ginsberg ◽  
Thomas J. Sick ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Cerebral Ischemia ◽  
Oxidative Phosphorylation ◽  
Ischemic Preconditioning ◽  
Global Cerebral Ischemia ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Ischemic Insult ◽  
Bilateral Carotid ◽  
Consumption Rates ◽  
Induction Of Tolerance

Ischemic tolerance in brain develops when sublethal ischemic insults occur before “lethal” cerebral ischemia. Two windows for the induction of tolerance by ischemic preconditioning (IPC) have been proposed: one that occurs within 1 hour after IPC, and another that occurs 1 or 2 days after IPC. The authors tested the hypotheses that IPC would reduce or prevent ischemia-induced mitochondrial dysfunction. IPC and ischemia were produced by bilateral carotid occlusions and systemic hypotension (50 mm Hg) for 2 and 10 minutes, respectively. Nonsynaptosomal mitochondria were harvested 24 hours after the 10-minute “test” ischemic insult. No significant changes were observed in the oxygen consumption rates and activities for hippocampal mitochondrial complexes I to IV between the IPC and sham groups. Twenty-four hours of reperfusion after 10 minutes of global ischemia (without IPC) promoted significant decreases in the oxygen consumption rates in presence of substrates for complexes I and II compared with the IPC and sham groups. These data suggest that IPC protects the integrity of mitochondrial oxidative phosphorylation after cerebral ischemia.

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 Intraischemic but Not Postischemic Brain Hypothermia Protects Chronically following Global Forebrain Ischemia in Rats

1993 ◽  
Vol 13 (4) ◽  
pp. 541-549 ◽  
Author(s):  
W. Dalton Dietrich ◽  
Raul Busto ◽  
Ofelia Alonso ◽  
Mordecai Y.-T. Globus ◽  
Myron D. Ginsberg
Keyword(s):  
Pyramidal Neurons ◽  
Brain Temperature ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Global Cerebral Ischemia ◽  
Forebrain Ischemia ◽  
Ischemic Insult ◽  
Treatment Protocols ◽  
Secondary Insult ◽  
Bilateral Carotid

We investigated whether postischemic brain hypothermia (30°C) would permanently protect the hippocampus following global forebrain ischemia. Global ischemia was produced in anesthetized rats by bilateral carotid artery occlusion plus hypotension (50 mm Hg). In the postischemic hypothermic group, brain temperature was maintained at 37°C during the 10-min ischemic insult but reduced to 30°C starting 3 min into the recirculation period and maintained at 30°C for 3 h. In normothermic animals, intra- and postischemic brain temperature was maintained at 37°C. After recovery for 3 days, 7 days, or 2 months, the extent of CA1 hippocampal histologic injury was quantitated. At 3 days after ischemia, postischemic hypothermia significantly protected the hippocampal CA1 sector compared with normothermic animals. For example, within the medial, middle, and lateral CA1 subsectors, the numbers of normal neurons were increased 20-, 13-, and 9-fold by postischemic hypothermia (p < 0.01). At 7 days after the ischemic insult, however, the degree of postischemic hypothermic protection was significantly reduced. In this case, the numbers of normal neurons were increased an average of only threefold compared with normothermia. Ultrastructural analysis of 7-day postischemic hypothermic rats demonstrated CA1 pyramidal neurons showing variable degrees of injury surrounded by reactive astrocytes and microglial cells. At 2 months after the ischemic insult, no trend for protection was demonstrated. In contrast to postischemic hypothermia, significant protection was seen at 2 months following intraischemic hypothermia. These data indicate that intraischemic, but not postischemic, brain hypothermia provides chronic protection to the hippocampus after transient brain ischemia. The inability of postischemic hypothermia to protect chronically after 3 days could indicate that (a) postischemic hypothermia merely delays ischemic cell death and/or (b) the postischemic brain undergoes a secondary insult. In postischemic treatment protocols, chronic survival studies are required to determine accurately the ultimate histopathological outcome following global cerebral ischemia.

scholarly journals Neuroprotectionby MK-801 following cerebral ischemia in Mongolian gerbils

2008 ◽  
Vol 60 (3) ◽  
pp. 341-346 ◽  
Author(s):  
Lidija Radenovic ◽  
Vesna Selakovic ◽  
P.R. Andjus
Keyword(s):  
Cerebral Ischemia ◽  
Neuronal Damage ◽  
Neuronal Loss ◽  
Brain Structures ◽  
Cell Loss ◽  
Global Cerebral Ischemia ◽  
Mongolian Gerbils ◽  
Nissl Staining ◽  
Neuroprotective Effects ◽  
Mk 801

Global cerebral ischemia in Mongolian gerbils is an established model in experimental research on cerebral ischemia, which is characterized morphologically by selective neuronal damage in the hippocampus, striatum, and cortex. Elevated glutamate levels are thought to be a primary cause of neuronal death after global cerebral ischemia. The purpose of this study was to investigate the potential neuroprotective effects of dizocilpine malate (MK-801), a non-competitive glutamate antagonist, in the model of 10-min gerbil cerebral ischemia. Gerbils were given MK-801(3 mg/kg i.p.)or saline immediately after the occlusion. On day 4 after reperfusion, neuronal damage was examined in the hippocampus (30 ?m)and striatum slices (5 ?m)stained with hematoxylin/eosin, fluorescent Nissl staining and membrane tracer DiI. The striatum and C3 regions of the hippocampus were analyzed by confocal microscopy. Neuroprotection was determined by quantifying the degree of cell loss, reduction of morphologically damaged cells, and the degree of preservation of recog?nizable neuroanatomical pathways after the ischemic insult. Our results demonstrate that the neuronal damage induced by sustained ischemia is related to abnormalities in glutamatergic function associated with NMDA receptors. MK-801significantly prevented neuronal loss in the tested brain structures. All of this contributes to a better understanding of the given pathophysiological process causing ischemic neuronal damage. <br><br><font color="red"><b> This article has been corrected. Link to the correction <u><a href="http://dx.doi.org/10.2298/ABS160524054E">10.2298/ABS160524054E</a><u></b></font>

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.

Incomplete global cerebral ischemia alters platelet biology in neonatal and adult sheep

1998 ◽  
Vol 274 (4) ◽  
pp. H1293-H1300 ◽  
Author(s):  
Marguerite T. Littleton-Kearney ◽  
Patricia D. Hurn ◽  
Thomas S. Kickler ◽  
Richard J. Traystman
Keyword(s):  
Platelet Aggregation ◽  
Cerebral Ischemia ◽  
Global Cerebral Ischemia ◽  
Ischemic Insult ◽  
Aggregation Response ◽  
Etiologic Agents ◽  
Platelet Deposition ◽  
Incomplete Global Cerebral Ischemia ◽  
Indium 111 ◽  
Neonatal Lambs

Platelets are implicated as etiologic agents in cerebral ischemia and as modulators of neural injury following an ischemic insult. We examined the effects of severe, transient global ischemia on platelet aggregation during 45-min ischemia and 30-, 60-, and 120-min reperfusion in adult and neonatal lambs. We also examined postischemic platelet deposition in brain and other tissues (120-min reperfusion) using indium-111-labeled platelets. Ischemic cerebral blood flow fell to 5 ± 1 and 5 ± 2 ml ⋅ min−1⋅ 100 g−1in lambs and sheep, respectively. During ischemia, platelet counts fell to 47.5 ± 5.1% of control ( P < 0.05) in lambs and 59 ± 4.9% of control in sheep ( P < 0.05). Ischemia depressed platelet aggregation response ( P < 0.01) to 4 μg collagen in lambs and sheep (20.4 ± 29.2 and 26 ± 44.7% of control, respectively). Marked platelet deposition occurred in brain and spleen in sheep, whereas significant platelet entrapment occurred only in brain in lambs. Our findings suggest that ischemia causes platelet activation and deposition in brain and noncerebral tissues.

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