Development Of Ischemic Neuronal Damage Research Articles

Neuroprotective effect through the cerebral sodium–glucose transporter on the development of ischemic damage in global ischemia

Diabetes mellitus and impaired glucose metabolism are the most important risk factors for stroke. We recently demonstrated that cerebral ischemic stress causes hyperglycemia (i.e., post-ischemic hyperglycemia) and may worsen ischemic neuronal damage in a mouse model of focal ischemia. However, the detailed mechanisms are still unknown. The sodium–glucose transporter (SGLT) generates inward currents in the process of transporting glucose into cells, resulting in depolarization and increased excitability, which is well known to be caused by cerebral ischemia. Hence, we focused on the role of SGLT on the development of neuronal damage using a global ischemic model.Male ddY mice were subjected to 30min of bilateral carotid artery occlusion (BCAO). The neuronal damage was estimated by histological analysis using HE staining on day 3 after BCAO.Intraperitoneal (i.p.) administration of phlorizin (a specific and competitive inhibitor of SGLT, 200mg/kg immediately after reperfusion) suppressed the development of post-ischemic hyperglycemia on day 1 after BCAO. In contrast, intracerebroventricular (i.c.v.) administration of phlorizin (40μg/mouse immediately and 6h after reperfusion) had no effect on day 1 after BCAO. Interestingly, the development of ischemic neuronal damage was significantly suppressed by i.p. and i.c.v. administration of phlorizin on day 3 after BCAO. In addition, BCAO-induced spasticity was significantly suppressed by PHZ (40μg/mouse, i.c.v.) from using gait analysis.Our results indicated that cerebral SGLT was involved in the development of ischemic neuronal damage in global ischemia.

ChemInform Abstract: Effectiveness of Metformin in Prevention of Development of Hyperglycemia and Neuronal Damage Caused by Ischemic Stress

AbstractReview: 13 refs.

Involvement of Matrix Metalloproteinase-Mediated Proteolysis of Neural Cell Adhesion Molecule in the Development of Cerebral Ischemic Neuronal Damage

Neural cell adhesion molecule (NCAM) is a membrane protein abundantly expressed in the central nervous system. Recently, it has been reported that dysfunction of NCAM is linked to human brain disorders. Furthermore, NCAM is one of the proteolysis targets of matrix metalloproteinase (MMP), whose activation is implicated in neuronal damage. The aim of this study was to elucidate the involvement of MMP-mediated proteolysis of NCAM in the development of ischemic neuronal damage. Male ddY and MMP-9 knockout (KO) C57BL/6J mice were subjected to 2 h of middle cerebral artery occlusion (MCAO). In MCAO model mice, development of infarction and behavioral abnormality were clearly observed on days 1 and 3 after MCAO. Protein levels of MMP-2 and MMP-9 were significantly increased on days 1 and 3 after MCAO. In addition, full-length NCAM (180 kDa) was significantly decreased, but its metabolite levels increased on day 1 by ischemic stress per se. NCAM small interfering RNA significantly increased the neuronal damage induced by MCAO. MMP inhibition or MMP-9 gene KO attenuated the infarction, behavioral abnormalities, and decrease of NCAM (180 kDa) observed after MCAO in mice. The present findings clearly suggest that MMP-2/MMP-9-mediated NCAM proteolysis is implicated in the exacerbation of ischemic neuronal damage.

Effectiveness of Metformin in Prevention of Development of Hyperglycemia and Neuronal Damage Caused by Ischemic Stress

Hyperglycemia is a known exacerbating factor in ischemic stroke. It has been reported that hyperglycemia and post-ischemic glucose intolerance can develop after stroke and be involved in the development of neuronal damage, as we described previously. Here, we focus on the effectiveness of metformin, a hypoglycemic drug, in preventing the development of neuronal damage using the middle cerebral artery occlusion (MCAO) model mice. 5'-AMP-activated protein kinase (AMPK) is a serine/threonine kinase that plays a key role in the hypoglycemic effects of metformin. Recently, it has been reported that centrally activated AMPK is involved in the development of ischemic neuronal damage, while the effect of peripherally activated AMPK on ischemic neuronal damage is not known. In the liver, AMPK activity was not affected by MCAO, while the administration of intraperitoneal metformin (250 mg/kg), an AMPK activator, significantly activated hepatic AMPK and suppressed both the development of post-ischemic glucose intolerance and ischemic neuronal damage without alteration of central AMPK activity. On the other hand, the administration of intracerebroventricular metformin (100 µg/mouse) significantly exacerbated the development of neuronal damage observed on day 1 after MCAO. These effects were significantly blocked by compound C, a specific AMPK inhibitor. These results suggest that central AMPK is activated by ischemic stress per se, although peripheral AMPK is not altered. Furthermore, the regulation of post-ischemic glucose intolerance by metformin-induced activation of peripheral AMPK contributes to the reduction of cerebral ischemic neuronal damage.

MK 801: A Possible Neuroprotective Agent by Poststroke Depression?

Back to table of contents Previous article Next article LETTERFull AccessMK 801: A Possible Neuroprotective Agent by Poststroke Depression?Ertugrul Cam Ph.D.,Burak Yulug M.D.,Erol Ozan M.D.,Ertugrul Cam Ph.D.Search for more papers by this author,Burak Yulug M.D.Search for more papers by this author,Erol Ozan M.D.Search for more papers by this author,Published Online:1 Jul 2008AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Stroke is the third leading cause of death and adult morbidity in developed countries. 1 Many deleterious cellular pathways have been proposed to explain the molecular pathogenesis of this clinically devastating disease. 2 Interest in the role of neurotransmitters in the pathogenesis of ischemic stroke resulted in studies establishing that the release of glutamate and its excitotoxic actions through the N -methyl- D -aspartic acid (NMDA) receptors are significant in the development of ischemic neuronal damage. 2 It is widely known that the occurrence of poststroke mood disorders, especially depression, is one of the most frequent complications of stroke. 3 It affects approximately 20% to 40% of all patients and the definitive treatment includes various antidepressant agents. 3 Interestingly, the evidence regarding antidepressant activity of NMDA receptor antagonists (especially MK 801) is rapidly replicating. 4 , 5 In light of these findings, we wanted to evaluate whether this novel antidepressant agent also has a neuroprotective effect by cerebral ischemia. To examine this matter, we evaluated the neuroprotective effect of MK 801 (dizocilpine), a noncompetitive NMDA receptor antagonist, after transient focal cerebral ischemia, a relevant model for the thrombolyzed stroke in humans. Anesthetized Wistar rats (330–370 g) were submitted to transient thread occlusion of the middle cerebral artery using an intraluminal filament technique. 6 The rectal temperature was maintained between 36.5°C and 37.0°C using a feedback-controlled heating system. The cerebral blood flow, measured by laser Doppler flowmetry, was reduced to ∼15% of preischemic control levels immediately after thread insertion in all animal groups. MK 801 or vehicle was applied intraperitoneally (3 mg/kg) just after transient ischemia. Twenty-four hours after reperfusion, the area of infarction was measured by toluidine blue staining. This study was interesting with regard to poststroke depression by which a mood stabilizer with neuroprotective properties would be preferable. MK 801 showed a significant neuroprotection (p<0.05, analysis of variance followed by least significant difference tests) after transient focal cerebral ischemia (73.12±23.2 versus 23.12+21.1) ( Figure 1 ). In summary, this study indicates that even with a serious brain injury, MK 801 could exert a significant neuroprotective effect. However, further experiments to evaluate the long-term clinical reflections of such neuroprotective effects of MK 801 in poststroke depression patients via MRI and spectroscopy studies, would be logical future steps in the field of psychiatric research. FIGURE 1. Infarct Volumes of Rats Subjected to Transient Cerebral IschemiaData are given as means±SDAnimals treated with MK 801 (3 mg/kg) led to a decrease in infarct size.*Significantly different from vehicle-treated control animals (p≤0.05).The first two authors contributed equally to this work.Department of Neurology, University Hospital Zurich, Zurich, SwitzerlandDepartment of Neurology, University Hospital Uludag, Bursa, TurkeyDepartment of Psychiatry, University of Atatürk, Erzurum, TurkeyReferences1 . Rothwell PM: The high cost of nonfunding stroke research: a comparison with heart disease and cancer. Lancet 2001; 357:1612–1616.Google Scholar2 . Dirnagl U, Iadecola C, Moskowitz MA: Pathobiology of ischemic stroke: an integrated view. Trends Neurosci 1999; 22:391–397Google Scholar3 . Whyte EM, Mulsant BH: Poststroke depression: epidemiology, pathophysiology and biological treatment. Biol Psychiatry 2002; 52:253–264Google Scholar4 . Zomkowski AD, Hammes L, Lin J, et al: Agmatine produces antidepressant-like effects in two models of depression in mice. Neuroreport 2002; 25:387–391Google Scholar5 . Chaturvedi HK, Bapna JS, Chandra D: Effect of fluvoxamine and N -methyl- D -aspartate receptor antagonists on shock-induced depression in mice. Indian J Physiol Pharmacol 2001; 45:199–207. Google Scholar6 . Koizumi J, Yoshida Y, Nakazawa T, et al: Experimental studies of ischemic brain edema. Part I: a new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischemic area. Jpn J Stroke 1986; 8:1–8 (Japanese)Google Scholar FiguresReferencesCited byDetailsCited ByNone Volume 20Issue 3 Summer, 2008Pages 367-368 Metrics PDF download History Published online 1 July 2008 Published in print 1 July 2008

Rethinking the excitotoxic ionic milieu: the emerging role of Zn(2+) in ischemic neuronal injury.

Zn(2+) plays an important role in diverse physiological processes, but when released in excess amounts it is potently neurotoxic. In vivo trans-synaptic movement and subsequent post-synaptic accumulation of intracellular Zn(2+) contributes to the neuronal injury observed in some forms of cerebral ischemia. Zn(2+) may enter neurons through NMDA channels, voltage-sensitive calcium channels, Ca(2+)-permeable AMPA/kainate (Ca-A/K) channels, or Zn(2+)-sensitive membrane transporters. Furthermore, Zn(2+) is also released from intracellular sites such as metallothioneins and mitochondria. The mechanisms by which Zn(2+) exerts its potent neurotoxic effects involve many signaling pathways, including mitochondrial and extra-mitochondrial generation of reactive oxygen species (ROS) and disruption of metabolic enzyme activity, ultimately leading to activation of apoptotic and/or necrotic processes. As is the case with Ca(2+), neuronal mitochondria take up Zn(2+) as a way of modulating cellular Zn(2+) homeostasis. However, excessive mitochondrial Zn(2+) sequestration leads to a marked dysfunction of these organelles, characterized by prolonged ROS generation. Intriguingly, in direct comparison to Ca(2+), Zn(2+) appears to induce these changes with a considerably greater degree of potency. These effects are particularly evident upon large (i.e., micromolar) rises in intracellular Zn(2+) concentration ([Zn(2+)](i)), and likely hasten necrotic neuronal death. In contrast, sub-micromolar [Zn(2+)](i) increases promote release of pro-apoptotic factors, suggesting that different intensities of [Zn(2+)](i) load may activate distinct pathways of injury. Finally, Zn(2+) homeostasis seems particularly sensitive to the environmental changes observed in ischemia, such as acidosis and oxidative stress, indicating that alterations in [Zn(2+)](i) may play a very significant role in the development of ischemic neuronal damage.

Blockade of central histaminergic H 2 receptors facilitates catecholaminergic metabolism and aggravates ischemic brain damage in the rat telencephalon

Blockade of central H 2 receptors aggravates ischemic neuronal damage. Since changes in the activity of the monoaminergic system are contributing factors in the development of ischemic neuronal damage, the authors evaluated the effects of ranitidine on the monoaminergic system and ischemic neuronal damage in the middle cerebral artery (MCA) occlusion model of rats. Wistar rats pretreated with saline or ranitidine (3 and 30 nmol, i.c.v.) were subjected to reversible occlusion of MCA for 2 h. The total infarct volume was determined 24 h after reperfusion. The relationship between dopaminergic activity and the histologic outcome was estimated by lesioning the substantia nigra 2 days before MCA occlusion. In a second experiment, the animals were subjected to 15 min of MCA occlusion, and the effects of ranitidine on the histologic outcome was evaluated 7 days after ischemia. In a third experiment, the tissue concentrations of monoamines and their metabolites were determined in the cerebral cortex and striatum 2 h after reperfusion following MCA occlusion for 2 h. The turnover of norepinephrine and dopamine was compared between animals treated with saline and those treated with ranitidine by estimating the α-methyl- p-tyrosine-induced depletion of norepinephrine and dopamine, respectively. The turnover of 5-hydroxytryptamine was evaluated by the probenecid-induced accumulation of 5-hydroxyindoleacetic acid. Treatments with ranitidine markedly increased the infarct volume 24 h after reperfusion. Ranitidine also aggravated delayed neuronal death 7 days after ischemia. The aggravation was abolished by the lesion of the substantia nigra before MCA occlusion. The MCA occlusion increased the turnover of cortical norepinephrine and striatal dopamine. The turnover was further facilitated by ranitidine. Although ranitidine suppressed the 5-hydroxytryptamine turnover in the cerebral cortex, the extent of this effect was similar in both the ischemic and non-ischemic sides. These results suggest that facilitation of the catecholaminergic systems is involved in the aggravation of ischemic neuronal damage by H 2 blockade.

Cell cycle protein expression in proliferating microglia and astrocytes following transient global cerebral ischemia in the rat

Cerebral ischemia induces microglial and astroglial activation, which may play a crucial role in the development of ischemic neuronal damage. In this study, we examined the role of cell cycle proteins in glial proliferation in the hippocampus following 10 min of global cerebral ischemia in the rat. Proliferating cells were identified with immunostaining for proliferating cell nuclear antigen (PCNA), and glial cells were visualized with immunostaining for microglial response factor-1 (microglia/macrophages) and glial fibrillary acidic protein (astrocytes). Expression of cyclin D1 and cyclin-dependent kinase-4 was also examined with double label immunohistochemistry. Proliferating cells in the CA1 region after ischemia consisted of microglia and much fewer astrocytes. Microglial activation and proliferation (7.6-fold increase in number after 7 days) were preceded by an increase in PCNA-positive microglia; 83% of microglia were PCNA-positive after 2 days. Astrocytes increased by 1.8-fold after 7 days, and only 6% of astrocytes became PCNA-positive by day 7. Cyclin D1 and cyclin-dependent kinase-4 immunoreactivity appeared in these glial cells in parallel with the expression of PCNA. The findings suggest that the accumulation of brain macrophages elicited by transient cerebral ischemia is caused predominantly by activation and proliferation of resident microglia through the upregulation of cell cycle proteins.

Characteristics of hippocampal glycine release in cell-damaging conditions in the adult and developing mouse.

The release of preloaded [3H]glycine from hippocampal slices from 7-day-old and 3-month-old (adult) mice was studied in different cell-damaging conditions, including hypoxia, hypoglycemia, ischemia, oxidative stress and the presence of free radicals and metabolic poisons, using a superfusion system. Glycine release was greatly enhanced in all the above conditions in both age groups, with the exception of hypoxia in developing mice. This coincides with the increased susceptibility to seizures and excitotoxicity during postnatal development. The ischemia-induced release of glycine was Ca2+-independent at both ages. The release was potentiated by exogenously applied glycine but not in Na+-free conditions, indicating the involvement of Na+-dependent transporters operating outwards. The Cl- channel blockers 4-acetamido-4'-isothiocyanostilbene-2,2'-disulphonate and diisothiocyanostilbene-2,2'-disulphonate generally reduced the ischemia-induced release, suggesting that this occurs through anion channels in both developing and adult mice. Furthermore, in the adult hippocampus riluzole and amiloride inhibited the release, indicating that Na+ channels also contribute to the ischemia-evoked release. Since glycine is an essential factor in glutamate-induced Ca2+ channel opening at the N-methyl-D-aspartate receptor, the elevated levels of glycine, together with the increased release of excitatory amino acids, must obviously collaborate in the development of ischemic neuronal damage.

Regional alterations of protein kinase C activity following transient cerebral ischemia: effects of intraischemic brain temperature modulation.

It is well established that ischemia-induced release of glutamate and the subsequent activation of post-synaptic glutamate receptors are important processes involved in the development of ischemic neuronal damage. Moderate intraischemic hypothermia attenuates glutamate release and confers protection from ischemic damage, whereas mild intraischemic hyperthermia increases glutamate release and augments ischemic pathology. As protein kinase C (PKC) is implicated in neurotransmitter release and glutamate receptor-mediated events, we evaluated the relationship between intraischemic brain temperature and PKC activity in brain regions known to be vulnerable or nonvulnerable to transient global ischemia. Twenty minutes of bilateral carotid artery occlusion plus hypotension were induced in rats in which intraischemic brain temperature was maintained at 30 degrees C, 37 degrees C, or 39 degrees C. Prior to and following ischemia, brain temperature was 37 degrees C in all groups. Cytosolic, membrane-bound, and total PKC activities were determined in hippocampal, striatal, cortical, and thalamic homogenates at the end of ischemia and at 0.25-24 h of recirculation. PKC activity of control rats varied by region and were affected by altered brain temperature. For both membrane-bound and cytosolic PKC, there was a significant temperature effect, and for membrane-bound PKC there was also a significant effect of region. Rats with normothermic ischemia (37 degrees C) showed extensive depressions of all PKC fractions. Hippocampus and striatum were noteworthy for depressions in PKC activity extending from the earliest (15 min) to the latest (24 h) recirculation times studied, whereas cortex showed PKC depressions chiefly during the first hour of recirculation, and the thalamic pattern was inconsistent.(ABSTRACT TRUNCATED AT 250 WORDS)

Dantrolene protects against ischemic, delayed neuronal death in gerbil brain

The effect was examined of dantrolene, a drug for malignant hyperthermia acting through preventing release of Ca from the ryanodine-type intracellular stores in muscle cells, on ischemic delayed neuronal death in field CA1 of gerbil hippocampus. Dantrolene (1.6 mM in concentration, 3 μl each in volume), when administered bilaterally in the lateral ventricles 30 min after reperfusion after transient forebrain ischemia for 3 min at 37°C, significantly protected against the neuronal death. It is proposed that the dantrolene-sensitive (most likely, the ryanodine-type) intracellular Ca stores in CA1 pyramidal cells play a pivotal role in the development of ischemic neuronal damage.

Ischemia-induced changes in extracellular levels of striatal cyclic AMP: role of dopamine neurotransmission.

Dopamine has been demonstrated to be involved in the development of ischemic neuronal damage in the striatum. This detrimental effect of dopamine may involve activation of second messenger systems, such as the cyclic AMP (cAMP) cascade, which may enhance the susceptibility of striatal neurons to ischemia. In the present study, we have evaluated the relationship between ischemia-induced changes in cAMP and dopamine neurotransmission. Microdialysis probes were implanted in both striata, and a D1 antagonist (SCH-23390, 100 microM) was administered through one probe and modified Ringer's solution through the other. After a stabilization period, rats (n = 6) were subjected to 20 min of ischemia by two-vessel occlusion plus hypotension. Extracellular samples were collected from both striata, before, during, and after ischemia, and analyzed for cAMP by radioimmunoassay. Ischemia induced a significant increase in extracellular cAMP (means +/- SE, fmol/microliter; baseline: 4.35 +/- 1.1, ischemia: 12.2 +/- 1.98), which was also observed at 4 h of recirculation (mean level of 8.45 +/- 1.14). Treatment with the D1 antagonist significantly inhibited the rise in extracellular cAMP during ischemia and recirculation. These results indicate that an ischemia-induced surge in dopamine and activation of D1 receptors are involved in the generation of cAMP during ischemia and recirculation. Because activation of the adenylate cyclase cascade may modulate the effects of glutamate, generation of cAMP through this pathway may play a role in facilitating the injurious effects of dopamine during ischemia.

Changes in the Activity of Protein Kinase C and the Differential Subcellular Redistribution of Its Isozymes in the Rat Striatum During and Following Transient Forebrain Ischemia

The changes in the levels of protein kinase C [PKC(alpha, beta II, gamma)] were studied in cytosolic and particulate fractions of striatal homogenates from rats subjected to 15 min of cerebral ischemia induced by bilateral occlusion of the common carotid arteries and following 1 h, 6 h, and 48 h of reperfusion. During ischemia the levels of PKC(beta II) and -(gamma) increased in the particulate fraction to 390% and 590% of control levels, respectively, concomitant with a decrease in the cytosolic fraction to 36% and 20% of control, respectively, suggesting that PKC is redistributed from the cytosol to cell membranes. During reperfusion the PKC(beta II) levels in the particulate fraction remained elevated at 1 h postischemia and decreased to below control levels after 48 h reperfusion, whereas PKC(gamma) rapidly decreased to subnormal levels. In the cytosol PKC(beta II) and -(gamma) decreased to 25% and 15% of control levels at 48 h, respectively. The distribution of PKC(alpha) did not change significantly during ischemia and early reperfusion. The PKC activity in the particulate fraction measured in vitro by histone IIIS phosphorylation in the presence of calcium, 4 beta-phorbol 13-myristate 12-acetate, and phosphatidylserine (PS) significantly decreased by 52% during ischemia, and remained depressed over the 48-h reperfusion period. In the cytosolic fraction PKC activity was unchanged at the end of ischemia, and decreased by 47% after 6 h of reperfusion. The appearance of a stable cytosolic 50-kDa PKC-immunoreactive peptide or an increase in the calcium- and PS-independent histone IIIS phosphorylation was not observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Protein kinase C is translocated to cell membranes during cerebral ischemia

The subcellular distribution of PKC(α) and PKC(γ) was studied in homogenates of cerebral cortex from rats subjected to 10 and 15 min of ischemia and 15 min of ischemia followed by 1 h, 6 h, 24 h, 48 h, and 7 days of reperfusion. During ischemia no significant changes in the levels of PKC (α) were seen. During the first hour of reperfusion, a transient 2.5-fold ( P < 0.05) increase in PKC(α) levels was observed in the particulate fraction. In contrast, a three-fold increase of PKC(γ) in the particulate fraction concomitant with a 40% decrease in the cytosol was noted during ischemia. In the postischemic phase the levels in the cytosol decreased to 35% of control values at 2 days following ischemia, with a concomitant decrease in the particulate fraction to control levels. The redistribution of PKC to the cell membranes during and following ischemia could be due to ischemia induced receptor activation, increased levels of diacylglycerols, arachidonate and intracellular calcium, and may be of importance for the development of ischemic neuronal damage.

Direct Evidence for Acute and Massive Norepinephrine Release in the Hippocampus during Transient Ischemia

Recent studies suggest the norepinephrine (NE) may play a regulatory role in neuronal cell death in the hippocampus after transient ischemia. However, ischemia-induced changes in extracellular NE release have not been demonstrated. In the present study, we utilized the microdialysis technique to measure extracellular NE levels in the hippocampus before, during, and after 20 min of global ischemia induced by two-vessel occlusion combined with systemic hypotension in the rat. Stable basal concentrations of extracellular NE were detected in three consecutive samples collected prior to ischemia (1.86 +/- 1.21 pmol/ml of perfusate mean +/- SEM). During ischemia, NE levels increased to 30.1 +/- 5.5 pmol/ml, representing an 18-fold increase. The levels gradually returned to baseline by 40 min of reperfusion. These results are the first to demonstrate that acute and massive extracellular release of NE occurs in the hippocampus during ischemia and early recirculation. These results support the hypothesis that the activation of the noradrenergic system may play a significant role in modulating the development of ischemic neuronal damage.

Chronic dexamethasone pretreatment aggravates ischemic neuronal necrosis.

This study addresses the question of whether the cyclooxygenase inhibitors indomethacin and diclofenac and the glucocorticosteroid dexamethasone ameliorate neuronal necrosis following cerebral ischemia. In addition, since these drugs inhibit the production of prostaglandins and depress phospholipase A2 activity, respectively, the importance of free fatty acids (FFAs) on the development of ischemic neuronal damage was assessed. Neuronal damage was determined in the rat brain at 1 week following 10 min of forebrain ischemia. The cyclooxygenase inhibitors, whether given before or after ischemia, failed to alter the brain damage incurred. Animals given dexamethasone were divided into three groups and the drug was administered at a constant dosage of 2 mg/kg: (a) 2 days, 1 day, and 3 h intraperitoneally before (chronic pretreatment), (b) 3 h intraperitoneally before (acute pretreatment), and (c) 5 min intravenously and 6 h and 1 day intraperitoneally after (chronic posttreatment) induction of ischemia. Acute pretreatment did not affect the histopathological outcome. Chronic posttreatment of animals with dexamethasone ameliorated the damage inflicted on the caudate nucleus, but had no effect on other brain areas investigated. Unexpectedly, the chronic pretreatment aggravated the brain damage and caused seizures following ischemia. Histopathological data showed massive neuronal damage in these brains. The accumulation of FFA levels during ischemia was markedly suppressed, and the decrease in the energy charge was curtailed by chronic pretreatment with dexamethasone. However, brain glucose levels in control animals and lactic acid concentrations following 10 min of ischemia were significantly higher both in the cerebral cortex and in the hippocampus of dexamethasone-treated animals. These results suggest that aggravation of neuronal necrosis by chronic dexamethasone pretreatment could be ascribed to lactic acidosis due to hyperglycemia in combination with an action of dexamethasone on glucocorticoid receptors in the brain.