Effects of Hyperglycemia on the Time Course of Changes in Energy Metabolism and pH during Global Cerebral Ischemia and Reperfusion in Rats: Correlation of<sup>1</sup>H and<sup>31</sup>P NMR Spectroscopy with Fatty Acid and Excitatory Amino Acid Levels

Widmer, HR; Abiko, Hisashi; Faden, Alan I.; James, Thomas Leroy; Weinstein, Philip

doi:10.1038/jcbfm.1992.63

Cited by 55 publications

(35 citation statements)

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“…The degree and extent of tissue damage is correlated with the content of lactic acid (Graham et al, 1993;Widmer et al,1992), and an increase in morbidity and mortality in hyperglycemia has been linked to excessive lactate production and the resulting acidosis (Pulsinelli et al, 1982;Siemkowicz and Gjedde, 1980). Our previous reports (Huang et al, 1996;Quast et al, 1995Quast et al, , 1997Wei et al, 1997;Wei and Quast, 1998) are consistent with this concept.…”

Section: Figsupporting

confidence: 78%

Effects of 2-Deoxy-D-Glucose on Focal Cerebral Ischemia in Hyperglycemic Rats

Wei

Cohen

Quast

2003

J Cereb Blood Flow Metab

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Summary:The authors examined the effects of pretreatment with 2-deoxy-D-glucose (2DG) on the middle cerebral artery occlusion-reperfusion (MCAO/R) model in hyperglycemic rats. Proton magnetic resonance imaging and spectroscopy were used to measure the lesion size, the level of cerebral perfusion deficit, and ratio of lactate to N-acetyl aspartate (NAA) in brain regions. By performing sequential diffusion weighted imaging, gradient echo bolus tracking, steady-state spin echo imaging, and water-suppressed proton magnetic resonance spectroscopy techniques, the time course of the early changes of the lactate/NAA peak ratio and perfusion deficit was examined in hyperglycemic rats undergoing 90-minute MCAO followed by 24-h reperfusion. Compared with the saline-treated hyperglycemic rats, 2DG treatment at 10 minutes before MCAO significantly reduced diffusion weighted imaging hyperintensity by ∼60% and the lactate/NAA peak ratio by ∼70% at 4 h after MCAO/R. Both spin echo-measured cerebral blood volume and dynamic gradient echo-relative cerebral blood flow showed that the restoration of blood supply recovered and remained at ∼80% of baseline during reperfusion in 2DG-treated hyperglycemic rats. These data suggest that inhibition of glucose metabolism by 2DG has a beneficial effect in reducing brain injury and minimizing the production of brain lactate during MCAO/R in hyperglycemic rats. Key Words: Cerebral ischemia-Magnetic resonance imaging-NMR spectroscopy-Hyperglycemia-2-Deoxy-D-glucose-Lactate.The cerebral concentration and supply of glucose influence the outcome of cerebral ischemia. Elevated blood glucose at the onset of brain ischemia is well known to be associated with a worsened neurologic outcome (David and Bell,1994;Huang et al.,1996; Li and Siesjo,1997; Nedergaard and Diemer,1987;Yip et al., 1991; ). The detrimental effect of hyperglycemia on cerebral ischemia is considered to be mediated by the release of excitatory amino acids, additional formation of free radicals and enhanced accumulation of lactic acid, followed by a further decrease in intracellular and extracellular pH (Li and Siesjo,1997;Li et al., 1999Li et al., , 2000Siesjo et al., 1990Siesjo et al., , 1993Wei et al., 1997;Wei and Quast, 1998). By using 31 P MRS, we observed that the preexisting hyperglycemic rat brain intracellular pH values were 6.14 ± 0.18 and 6.08 ± 0.19 during MCAO and reperfusion (Quast MJ, Wei J, Sell S, unpublished data, 1996), which is consistent with previous studies (Haraldseth et al.,1992;Suttle et al., 1992;Widmer et al., 1992) that showed hyperglycemia-related acidosis aggravates ischemic brain damage due to decreased intracellular and extracellular pH. It is assumed that lactate production in ischemic brain is a result of anaerobic metabolism of the higher concentration of available glucose (Li et al., 1994;Siesjo et al., 1993;Tyson et al.,1993). It has been reported that pretreatment with 2DG reduces brain damage and improves behavioral outcome in a normoglycemic rat focal ischemia model (Yu and Mattson, 1999)...

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Section: Figsupporting

confidence: 78%

Effects of 2-Deoxy-D-Glucose on Focal Cerebral Ischemia in Hyperglycemic Rats

Wei

Cohen

Quast

2003

J Cereb Blood Flow Metab

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“…These results in vehicle-treated dogs con firm previous work in this experimental model (Hum et aI., 1991a). Metabolic deterioration during reperfusion has also been reported in other models of global hyperglycemic ischemia (Welsh et aI., 1980;Rehncrona et aI., 1981;Kozuka et aI., 1989;Wagner et aI., 1989;Widmer et aI., 1992). The ma jor finding of the present study is that administra tion of the 21-aminosteroid tirilazad improved re covery of high energy phosphates, tissue acidosis, and ICP as early as 30-45 min of reperfusion, pre vented the delayed reduction in CBF and CMR0 2 , and partially restored synaptic transmission and the ability to conduct action potentials in the somato sensory pathway.…”

Section: Discussionmentioning

confidence: 84%

Tirilazad Pretreatment Improves Early Cerebral Metabolic and Blood Flow Recovery from Hyperglycemic Ischemia

Maruki

Koehler

Kirsch

et al. 1995

J Cereb Blood Flow Metab

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Summary: Acidosis may augment cerebral ischemic in jury by promoting lipid peroxidation. We tested the hy pothesis that when acidosis is augmented by hyperglyce mia, pretreatment with the 21-aminosteroid tirilazad mes ylate (U74006F), a potent inhibitor of lipid peroxidation in vitro, improves early cerebral metabolic recovery. In a randomized, blinded study, anesthetized dogs received either tirilazad mesylate (1 mg/kg plus 0.2 mg/kg/h; n = 8) or vehicle (n = 8). Hyperglycemia (400-500 mg/dl) was produced prior to 30 min of global incomplete cerebral ischemia. Intracellular pH and high energy phosphates were measured by phosphorus magnetic resonance spec troscopy. During ischemia, microsphere-determined CBF decreased to 8 ± 4 ml min -I 100 g-I and intracellular pH decreased to 5.6 ± 0.2 in both groups. During the first 20 min of reperfusion, ATP partially recovered in the vehicle group to 57 ± 21% of baseline, but then declined progresAcidosis is one of several mechanisms thought to contribute to ischemic injury (Siesj6 et aI., 1993). The precise molecular mechanism whereby acidosis augments injury has not been elucidated. By alter ing protein charge, pH is expected to alter protein function. However, severe acidosis induced by ex treme hypercapnia does not produce irreversible in jury (Xu et aI., 1991), suggesting that pH-induced changes in protein charge per se are insufficient to cause injury. Even in the presence of ischemia and ATP depletion, augmenting acidosis by hypercap nia does not produce the same impairment of met- 88sively in association with elevated intracranial pressure. By 30 min, ATP recovery was greater in the tirilazad group (77 ± 35 vs. 36 ± 19%), although postischemic hyperemia was similar. By 45 min, the tirilazad group had a higher intracellular pH (6.5 ± 0.5 vs. 5.9 ± 0.6) and a lower intracranial pressure (18 ± 6 vs. 52 ± 24 mm Hg). By 180 min, blood flow and ATP were undetectable in seven of eight vehicle-treated dogs, whereas ATP was >67% and pH was >6.7 in six of eight tirilazad-treated dogs. Thus, tirilazad acts during early reperfusion to pre vent secondary metabolic decay associated with severe acidotic ischemia. If tirilazad acts by inhibiting lipid per oxidation, then these data are consistent with extreme acidosis limiting recovery by a mechanism involving lipid peroxidation.

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“…The development of stroke is related to lifestyle diseases, such as hypertension, dyslipidemia, and obesity (3). Most notably, diabetes mellitus and impaired glucose metabolism are the most important risk factors for stroke (4,5). Clinically, cerebral ischemic neuronal damage is exacerbated in patients with a history of glucose intolerance or diabetes mellitus (6).…”

Section: Introductionmentioning

confidence: 99%

Effect of Orexin-A on Post-ischemic Glucose Intolerance and Neuronal Damage

2011

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Abstract. Orexin-A is a newly identified neuropeptide expressed in the lateral areas of the hypothalamus that plays a role in various physiological functions, including regulation of glucose metabolism. We have previously reported that the development of post-ischemic glucose intolerance is one of the triggers of ischemic neuronal damage. Therefore, the aim of this study was to determine the effects of orexin-A on the development of post-ischemic glucose intolerance and ischemic neuronal damage. Male ddY mice were subjected to middle cerebral artery occlusion (MCAO) for 2 h. Neuronal damage was estimated by histological and behavioral analysis after MCAO. Intracerebroventricular administration of orexin-A (2.5, 25, or 250 pmol/mouse) significantly and dose-dependently suppressed the development of post-ischemic glucose intolerance on day 1 after MCAO and neuronal damage on day 3 after MCAO. In the liver and skeletal muscle, the expression levels of insulin receptor were decreased, whereas those of gluconeogenic enzymes were increased on day 1 after MCAO. Furthermore, these expressions were completely recovered to normal levels by orexin-A and were reversed by the administration of SB334867, a specific orexin-1 receptor antagonist. These results suggest that regulation of post-ischemic glucose intolerance by orexin-A suppressed cerebral ischemic neuronal damage.

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Effects of Hyperglycemia on the Time Course of Changes in Energy Metabolism and pH during Global Cerebral Ischemia and Reperfusion in Rats: Correlation of¹H and³¹P NMR Spectroscopy with Fatty Acid and Excitatory Amino Acid Levels

Cited by 55 publications

References 56 publications

Effects of 2-Deoxy-D-Glucose on Focal Cerebral Ischemia in Hyperglycemic Rats

Effects of 2-Deoxy-D-Glucose on Focal Cerebral Ischemia in Hyperglycemic Rats

Tirilazad Pretreatment Improves Early Cerebral Metabolic and Blood Flow Recovery from Hyperglycemic Ischemia

Effect of Orexin-A on Post-ischemic Glucose Intolerance and Neuronal Damage

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Effects of Hyperglycemia on the Time Course of Changes in Energy Metabolism and pH during Global Cerebral Ischemia and Reperfusion in Rats: Correlation of1H and31P NMR Spectroscopy with Fatty Acid and Excitatory Amino Acid Levels

Cited by 55 publications

References 56 publications

Effects of 2-Deoxy-D-Glucose on Focal Cerebral Ischemia in Hyperglycemic Rats

Effects of 2-Deoxy-D-Glucose on Focal Cerebral Ischemia in Hyperglycemic Rats

Tirilazad Pretreatment Improves Early Cerebral Metabolic and Blood Flow Recovery from Hyperglycemic Ischemia

Effect of Orexin-A on Post-ischemic Glucose Intolerance and Neuronal Damage

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Effects of Hyperglycemia on the Time Course of Changes in Energy Metabolism and pH during Global Cerebral Ischemia and Reperfusion in Rats: Correlation of¹H and³¹P NMR Spectroscopy with Fatty Acid and Excitatory Amino Acid Levels