Accumulation of Calcium and Loss of Potassium in the Hippocampus following Transient Cerebral Ischemia: A Proton Microprobe Study

Martins, E.; Inamura, Keiji; Themner, K.; Malmqvist, Klas; Siesjö, Bo K.

doi:10.1038/jcbfm.1988.93

Cited by 69 publications

(19 citation statements)

References 40 publications

(33 reference statements)

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“…These observations are in basic agreement with earlier studies that have shown that the net calcium content of globally ischemic normoglycemic rat brain does not show an increase during the first 24 h of recirculation (Dienel, 1984;Deshpande et aI., 1987;Martins et al, 1988). The data further indicate that glucose loading, with hyperlactic acidosis, does not augment or alter the calcium content profile of the ischemic brain over the initial 24 h period of recirculation.…”

Section: Discussionsupporting

confidence: 92%

Influence of Lactate Accumulation on Calcium Content of Ischemic and Postischemic Brain

MacMillan

1989

J Cereb Blood Flow Metab

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Summary: In this study, the cerebral hemisphere content of calcium as well as selected parameters of oxidative metabolism and electro physiological function were as sessed in normoglycemic and hyperglycemic rats that were exposed to ischemia produced by electrocautery of the vertebral arteries and reversible occlusion of the ca rotid arteries. In hyperglycemic animals, 0.5 h of isch emia was associated with large accumulations of lactate (27 mmol!kg), whereas normoglycemic animals showed lesser lactate accumulation (17 mmollkg). At this sam pling time (0.5 h of ischemia), both groups of ischemic animals showed tissue calcium contents that were un changed from preischemic control levels. In normoglyce mic animals, release of the carotid clamps and recircula tion for 1.5-24 h was associated with normalization of Animals administered glucose prior to the induc tion of cerebral ischemia show a greater degree of metabolic, electrophysiologic, and histologic dam age when compared to fasted animals exposed to an equivalent degree and duration of ischemia (Myers and Yamaguchi, 1976; Welsh et aI. , 1980; Rehn crona et aI. , 1981; Kalimo et aI. , 1981; Pulsinelli et aI., 1982). It has also been established that these indices of tissue damage are best correlated to the excessive accumulation of lactic acid in the brain of the glucose-loaded animal (Myers, 1979). Although it has been shown that direct injection of N a lactate, sufficient to lower brain pH to about 5, can cause neuronal damage and astrocytic swelling (Petito et aI., 1987), the precise mechanism by which exces sive lactic acidosis accentuates ischemic brain dam age is as yet undefined. The possibilities discussed 640lactate, ATP and phosphocreatine, clinical behavior, and EEG. During this 24 h of recirculation, cerebral calcium levels showed no changes. Hyperglycemic ischemic ani mals recirculated for 1.5-24 h showed a persistent lactic acidosis, depressed ATP and phosphocreatine, gross EEG abnormalities, seizures, and a high mortality rate. Again, during this 24 h period, cerebral calcium content showed no changes from preischemic control or from the matched saline-treated group. These data suggest that sig nificant accumulation of calcium in brain tissue is not an early event in ischemic-hyperglycemic brain damage, and thus does not provide support for a role of calcium in the production of this form of ischemic damage.

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Section: Discussionsupporting

confidence: 92%

Influence of Lactate Accumulation on Calcium Content of Ischemic and Postischemic Brain

MacMillan

1989

J Cereb Blood Flow Metab

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“…An ischemia-induced rise in intracellular calcium concentration will eventually lead to mitochondrial calcium overload, resulting in delayed neuronal death (32,33). In a rat model of transient 10-min forebrain ischemia, the total calcium content in the CA1 region of the hippocampus was found to be unchanged at 24 hr after ischemia, but increased significantly between 48 -72 hr after ischemia (25,26). It has also been demonstrated in this model that calcium deposition precedes marked necrosis and is probably related to membrane dysfunction (25).…”

Section: Discussionmentioning

confidence: 99%

Delayed changes in T₁‐weighted signal intensity in a rat model of 15‐minute transient focal ischemia studied by magnetic resonance imaging/spectroscopy and synchrotron radiation X‐ray fluorescence

Wang

Qian

et al. 2006

Magnetic Resonance in Med

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Previous studies have found that rats subjected to 15-min transient middle cerebral artery occlusion (MCAO) show neurodegeneration in the dorsolateral striatum only, and the resulting striatal lesion is associated with increased T 1 -weighted (T 1 W) signal intensity (SI) and decreased T 2 -weighted (T 2 W) SI at 2-8 weeks after the initial ischemia. It has been shown that the delayed increase in T 1 W SI in the ischemic region is associated with deposition of paramagnetic manganese ions. However, it has been suggested that other mechanisms, such as tissue calcification and lipid accumulation, also contribute to the relaxation time changes. To clarify this issue, we measured changes in relaxation times, lipid accumulation, and elemental distributions in the brain of rats subjected to 15-min MCAO using MRI, in vivo The time course and outcome of brain lesion development after cerebral ischemia can be monitored and characterized by magnetic resonance imaging (MRI) (1-3). For example, it has been shown in numerous studies that T 2 of water protons in ischemic tissue increases significantly between 1-4 days after ischemia, followed by gradual recovery to its normal level and, in many cases, subsequent secondary changes (1-3). Relaxation time changes that occur during the acute/subacute phases of cerebral ischemia can be explained by such mechanisms as reductions in cerebral blood flow (CBF) and blood oxygenation, alterations in cerebral energy metabolism, tissue edema, and selective neuronal loss (1-3). In comparison, the metabolic and molecular events underlying the relaxation time changes during the chronic phase of ischemia are often more complex, and have been shown to depend on the duration and severity of the initial ischemia. For instance, transient focal ischemia with a duration of 15 min results exclusively in subcortical (CP) lesions, which show normal T 1 and elevated T 2 at 3 days, but have elevated T 1 -weighted (T 1 W) signal intensity (SI) and reduced T 2 -weighted (T 2 W) SI at 2 weeks after ischemia, likely due to simultaneous decreases in both T 1 and T 2 in the ischemic lesion (4,5). On the other hand, transient focal ischemia with a duration of 60 min induces brain lesions of two distinct types (CP lesions and cortico-subcortical (CP ϩ ) lesions), which develop and mature with different time courses reflecting different mechanisms of neurodegeneration (6,7). At 2 weeks after ischemia, CP lesions resulting from 60-min focal ischemia are characterized by normal T 1 and T 2 , while the CP ϩ lesions are frequently associated with elevated T 1 and T 2 (6).Delayed T 2 decreases observed in the chronic stage of cerebral ischemia have been attributed to iron deposition associated with hemorrhagic transformation, vascular degradation, or chronic inflammation (6,8 -10). Delayed increases in T 1 W SI observed in the 15-min transient focal ischemia model is associated with deposition of paramagnetic manganese ions (5). It has been proposed that other mechanisms, such as tissue calcification and lipid accumul...

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“…The results, which are illustrated in Fig 5, were subsequently confirmed by measurements with proton-intensified x-ray emission (PIXE), allowing analyses of the different layers of the CA1 and CA3 sectors. 87 Based on these results and on the theory proposed by Alkon and Rasmussen, 88 we advanced the hypothesis of delayed calcium-related cell death. This hypothesis predicts that the initial ischemic transient gives rise to a sustained perturbation of plasma membrane handling of Ca 2ϩ , resulting in a gradual rise in [Ca 2ϩ ] i .…”

Section: Calcium and Delayed Neuronal Deathmentioning

confidence: 99%

Calcium in Ischemic Cell Death

Kristián

Siesjö

1998

Stroke

724

428

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Background-This review article deals with the role of calcium in ischemic cell death. A calcium-related mechanism was proposed more than two decades ago to explain cell necrosis incurred in cardiac ischemia and muscular dystrophy. In fact, an excitotoxic hypothesis was advanced to explain the acetylcholine-related death of muscle end plates. A similar hypothesis was proposed to explain selective neuronal damage in the brain in ischemia, hypoglycemic coma, and status epilepticus. Summary of Review-The original concepts encompass the hypothesis that cell damage in ischemia-reperfusion is due to enhanced activity of phospholipases and proteases, leading to release of free fatty acids and their breakdown products and to degradation of cytoskeletal proteins. It is equally clear that a coupling exists between influx of calcium into cells and their production of reactive oxygen species, such as ⅐O 2 Ϫ , H 2 O 2 , and ⅐OH. Recent results have underscored the role of calcium in ischemic cell death. A coupling has been demonstrated among glutamate release, calcium influx, and enhanced production of reactive metabolites such as ⅐O 2 Ϫ , ⅐OH, and nitric oxide. It has become equally clear that the combination of ⅐O 2 Ϫ and nitric oxide can yield peroxynitrate, a metabolite with potentially devastating effects. The mitochondria have again come into the focus of interest. This is because certain conditions, notably mitochondrial calcium accumulation and oxidative stress, can trigger the assembly (opening) of a high-conductance pore in the inner mitochondrial membrane. The mitochondrial permeability transition (MPT) pore leads to a collapse of the electrochemical potential for H ϩ , thereby arresting ATP production and triggering production of reactive oxygen species. The occurrence of an MPT in vivo is suggested by the dramatic anti-ischemic effect of cyclosporin A, a virtually specific blocker of the MPT in vitro in transient forebrain ischemia. However, cyclosporin A has limited effect on the cell damage incurred as a result of 2 hours of focal cerebral ischemia, suggesting that factors other than MPT play a role. It is discussed whether this could reflect the operation of phospholipase A 2 activity and degradation of the lipid skeleton of the inner mitochondrial membrane. Conclusions-Calcium is one of the triggers involved in ischemic cell death, whatever the mechanism. (Stroke.1998;29:705-718.)Key Words: calcium Ⅲ cerebral ischemia Ⅲ free radicals Ⅲ mitochondria T he calcium hypothesis of ischemic cell death was originally launched to explain the relationship between excessive calcium influx and the cell damage that is incurred in myocardial ischemia 1 as well as in muscle dystrophy. 2 In fact, studies conducted at that time led to the formulation of an excitotoxic hypothesis, predicting that excessive release of acetylcholine at the motor end plate was what caused damage to skeletal muscle. 3,4 The work performed at that time on ischemic muscle damage was almost visionary since it forestalled the pivotal role of release o...

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Accumulation of Calcium and Loss of Potassium in the Hippocampus following Transient Cerebral Ischemia: A Proton Microprobe Study

Cited by 69 publications

References 40 publications

Influence of Lactate Accumulation on Calcium Content of Ischemic and Postischemic Brain

Influence of Lactate Accumulation on Calcium Content of Ischemic and Postischemic Brain

Delayed changes in T₁‐weighted signal intensity in a rat model of 15‐minute transient focal ischemia studied by magnetic resonance imaging/spectroscopy and synchrotron radiation X‐ray fluorescence

Calcium in Ischemic Cell Death

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Accumulation of Calcium and Loss of Potassium in the Hippocampus following Transient Cerebral Ischemia: A Proton Microprobe Study

Cited by 69 publications

References 40 publications

Influence of Lactate Accumulation on Calcium Content of Ischemic and Postischemic Brain

Influence of Lactate Accumulation on Calcium Content of Ischemic and Postischemic Brain

Delayed changes in T1‐weighted signal intensity in a rat model of 15‐minute transient focal ischemia studied by magnetic resonance imaging/spectroscopy and synchrotron radiation X‐ray fluorescence

Calcium in Ischemic Cell Death

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Delayed changes in T₁‐weighted signal intensity in a rat model of 15‐minute transient focal ischemia studied by magnetic resonance imaging/spectroscopy and synchrotron radiation X‐ray fluorescence