Isoflurane neurotoxicity involves activation of hypoxia inducible factor-1α via intracellular calcium in neonatal rodents.

Abstract

OBJECTIVE:

Previously, we found that the inhaled anesthetic isoflurane up-regulated the transcriptional factor hypoxia inducible factor (HIF)-1α protein levels during induction of neurodegeneration in the brain of neonatal rats. Here, we investigated the role of HIF-1α and the underlying signaling pathway in the neurodegenration induced by isoflurane in rodent developing brain.

METHODS:

Primary hippocampal neurons were exposed to isoflurane (0.4mM) for 12h. Neuron injury was analyzed by 3-(4,5-dimethyithiazol-2-yl)-2,5-diphenyl-tetra-zolium bromide (MTT) test and quantification of lactate dehydrogenaserelease. HIF-1α gene expression and transcriptional activity, cleaved caspase-3 and phosphoinositide phospholipase C (PLC)-γ gene expression were quantified. Cytosolic calcium concentration was measured by calcium imagining. The role of HIF-1α on juvenile learning and memory impairment induced by isoflurane was studied by fear conditioning and extinction test and Morris water maze test.

RESULTS:

Isoflurane induced HIF-1α gene expression and transcriptional activity in vitro. Furthermore, pharmacological inhibition of HIF-1α or knockdown of HIF-1α by shRNA counteracted the neurotoxicity of isoflurane. Ca2+ signaling pathways involving PLC-γ activation are required for isoflurane-evoked HIF-1α accumulation. Finally, partial deficiency of HIF-1α attenuated isoflurane-induced neurodegeneration in developing brain, and alleviated juvenile learning and memory impairment induced by isoflurane.

CONCLUSION:

HIF-1α activation via cytosolic Ca2+ signaling pathway play a role in the mechanism of isoflurane-induced neurodegeneration in neonatal rodents, suggesting HIF-1α as a potential therapeutic target for the prevention of the deleterious effects of prolonged exposures to anesthetics.

• Authors: Dongdong Chai, Hong Jiang, Qifang Li
• Journal: Brain research (Brain Res) Vol. 1653 Pg. 39-50 (12 15 2016) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 27769790 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier B.V. All rights reserved.

Chemical References

• Anesthetics, Inhalation
• Hif1a protein, mouse
• Hif1a protein, rat
• Hypoxia-Inducible Factor 1, alpha Subunit
• Isoflurane
• Phospholipase C gamma
• Calcium

Topics

• Anesthetics, Inhalation (toxicity)
• Animals
• Animals, Newborn
• Apoptosis (drug effects, physiology)
• Calcium (metabolism)
• Calcium Signaling (drug effects, physiology)
• Cells, Cultured
• Disease Models, Animal
• Hippocampus (drug effects, growth & development, metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (deficiency, genetics, metabolism)
• Intracellular Space (drug effects, metabolism)
• Isoflurane (toxicity)
• Learning Disabilities (chemically induced, metabolism)
• Memory Disorders (chemically induced, metabolism)
• Mice, 129 Strain
• Mice, Inbred C57BL
• Mice, Transgenic
• Nerve Degeneration (chemically induced, metabolism)
• Neurons (drug effects, metabolism)
• Neurotoxicity Syndromes (metabolism)
• Phospholipase C gamma (metabolism)
• Rats, Sprague-Dawley