Ashish K Rehni1, Vibha Shukla1, Miguel A Perez-Pinzon2, Kunjan R Dave3. 1. Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA. 2. Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, 33136, USA. 3. Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, 33136, USA. Electronic address: KDave@med.miami.edu.
Abstract
OBJECTIVES: Cerebral ischemia is a serious possible manifestation of diabetic vascular disease. Recurrent hypoglycemia (RH) enhances ischemic brain injury in insulin-treated diabetic (ITD) rats. In the present study, we determined the role of ischemic acidosis in enhanced ischemic brain damage in RH-exposed ITD rats. METHODS: Diabetic rats were treated with insulin and mild/moderate RH was induced for 5 days. Three sets of experiments were performed. The first set evaluated the effects of RH exposure on global cerebral ischemia-induced acidosis in ITD rats. The second set evaluated the effect of an alkalizing agent (Tris-(hydroxymethyl)-aminomethane: THAM) on ischemic acidosis-induced brain injury in RH-exposed ITD rats. The third experiment evaluated the effect of the glucose transporter (GLUT) inhibitor on ischemic acidosis-induced brain injury in RH-exposed ITD rats. Hippocampal pH and lactate were measured during ischemia and early reperfusion for all three experiments. Neuronal survival in Cornu Ammonis 1 (CA1) hippocampus served as a measure of ischemic brain injury. FINDINGS: Prior RH exposure increases lactate concentration and decreases pH during ischemia and early reperfusion when compared to controls. THAM and GLUT inhibitor treatments attenuated RH-induced increase in ischemic acidosis. GLUT inhibitor treatment reduced the RH-induced increase in lactate levels. Both THAM and GLUT inhibitor treatments significantly decreased ischemic damage in RH-exposed ITD rats. CONCLUSIONS: Ischemia causes increased acidosis in RH-exposed ITD rats via a GLUT-sensitive mechanism. Exploring downstream pathways may help understand mechanisms by which prior exposure to RH increases cerebral ischemic damage.
OBJECTIVES:Cerebral ischemia is a serious possible manifestation of diabetic vascular disease. Recurrent hypoglycemia (RH) enhances ischemic brain injury in insulin-treated diabetic (ITD) rats. In the present study, we determined the role of ischemic acidosis in enhanced ischemic brain damage in RH-exposed ITD rats. METHODS:Diabeticrats were treated with insulin and mild/moderate RH was induced for 5 days. Three sets of experiments were performed. The first set evaluated the effects of RH exposure on global cerebral ischemia-induced acidosis in ITD rats. The second set evaluated the effect of an alkalizing agent (Tris-(hydroxymethyl)-aminomethane: THAM) on ischemic acidosis-induced brain injury in RH-exposed ITD rats. The third experiment evaluated the effect of the glucose transporter (GLUT) inhibitor on ischemic acidosis-induced brain injury in RH-exposed ITD rats. Hippocampal pH and lactate were measured during ischemia and early reperfusion for all three experiments. Neuronal survival in Cornu Ammonis 1 (CA1) hippocampus served as a measure of ischemic brain injury. FINDINGS: Prior RH exposure increases lactate concentration and decreases pH during ischemia and early reperfusion when compared to controls. THAM and GLUT inhibitor treatments attenuated RH-induced increase in ischemic acidosis. GLUT inhibitor treatment reduced the RH-induced increase in lactate levels. Both THAM and GLUT inhibitor treatments significantly decreased ischemic damage in RH-exposed ITD rats. CONCLUSIONS:Ischemia causes increased acidosis in RH-exposed ITD rats via a GLUT-sensitive mechanism. Exploring downstream pathways may help understand mechanisms by which prior exposure to RHincreases cerebral ischemic damage.
Authors: Raimund I Herzog; Owen Chan; Sunkyung Yu; James Dziura; Ewan C McNay; Robert S Sherwin Journal: Endocrinology Date: 2008-01-10 Impact factor: 4.736