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

Abstract

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)...

Citalopram attenuated neurobehavioral, biochemical, and metabolic alterations in transient middle cerebral artery occlusion model of stroke in male Wistar rats

“…The extent of neuronal death associated with cerebral ischemic‐reperfusion injury is also correlated with Lac levels (Graham et al, ). In hyperglycemic MCAo rats, infarct area increased with elevation in Lac and reduction in NAA levels (Wei, Cohen, & Quast, ). In MCAo model, the Cr‐normalized Lac‐lipid levels ([Lac + Lip]/Cr) negatively correlated with Cr‐normalized NAA levels (NAA/Cr), while positively correlated with TUNEL‐positive cell numbers up to 24 h post‐reperfusion (Woo, Lee, Kim ST, & Kim, ).…”

Regulation of Mct1 by cAMP-dependent internalization in rat brain endothelial cells

“…For example, in ischemic stroke, hyperglycemic stroke, and brain injury, the severity of lactic acidosis is a principle indicator of outcomes (Coon et al, 2006; Frykholm et al, 2005; Schnaberth et al, 1981; Wagner et al, 1992; Wass and Lanier, 1996; Siesjo et al, 1993; Wei et al, 2003; Clausen et al, 2005; DeSalles et al, 1986; Unterberg et al, 2004). MCT1 is ideally positioned in the cerebrovascular endothelial cells of the blood-brain barrier to counter lactic acidosis; however, lactic acid fails to flow readily from brain to blood during stroke and brain injury indicating that Mct1 is an ideal pharmacological target for modulating lactic acidosis in a novel therapeutic approach.…”

Radial glia express aromatase in the injured zebra finch brain

“…Transient global ischemic insults that normally cause selective neuronal death, can cause infarction in hyperglycemic animals (Pulsinelli et al, 1982c), and, after focal ischemia, hyperglycemia in rabbit brain leads to enhanced acidity, less effective reoxidation of NADH, and larger infarcts; conversely moderate hypoglycemia can decrease infarct size (Anderson et al, 1999). Nutritional restriction prior to ischemia or inhibition of glucose utilization with 2‐deoxy‐ D ‐glucose (DG), a competitive inhibitor of glucose transport and metabolism, are also associated with reduced infarct volume in vivo and better outcome, suggesting that reduced glucose utilization and suppression of lactate formation during ischemia might be beneficial (Yu and Mattson, 1999; Wei et al, 2003).…”