Acidosis mediates recurrent hypoglycemia-induced increase in ischemic brain injury in treated diabetic rats

Ashish K. Rehni, Vibha Shukla, Miguel Perez-Pinzon, Kunjan R Dave

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)192-201
Number of pages10
JournalNeuropharmacology
Volume135
DOIs
StatePublished - Jun 1 2018

Keywords

  • CA1 hippocampus
  • Global cerebral ischemia
  • Glucose transporter
  • Ischemic acidosis
  • Lactate

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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