Hydroxylase inhibition reduces synaptic transmission and protects against a glutamate-induced ischemia in the CA1 region of the rat hippocampus.

Abstract

The discovery of hydroxylases as oxygen sensors and key regulators of hypoxia-induced gene expression has made them a novel target for manipulating the transcriptional response to hypoxia for therapeutic benefit. In this study we have investigated the effect of prolyl hydroxylase inhibition on synaptic activity in hippocampal slices and compared this to the changes occurring following exposure to hypoxia. Furthermore, we investigated a potentially protective role for hydroxylase inhibition against a glutamate-induced ischemic insult in the CA1 region of organotypic hippocampal cultures. Application of the hydroxylase inhibitor, dimethyloxallyl glycine (DMOG), depressed synaptic transmission. Both hypoxia and DMOG induced a reversible reduction in synaptic transmission, enhanced paired pulse facilitation (P<0.05) and inhibited N-methyl d-aspartate receptor (NMDAR) activity (P<0.01). However the effects of DMOG were adenosine A(1) receptor independent. Our results also suggest a potential therapeutic application for prolyl 4-hydroxylase (PHD) inhibitors in cerebral ischemia, since DMOG protected the CA1 region in organotypic hippocampal slices against a glutamate-induced ischemic insult.

• Authors: L Batti, C T Taylor, J J O'Connor
• Journal: Neuroscience (Neuroscience) Vol. 167 Issue 4 Pg. 1014-24 (Jun 02 2010) ISSN: 1873-7544 [Electronic] United States
• PMID: 20298762 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Amino Acids, Dicarboxylic
• Hif1a protein, rat
• Hypoxia-Inducible Factor 1, alpha Subunit
• Receptors, N-Methyl-D-Aspartate
• Glutamic Acid
• Procollagen-Proline Dioxygenase
• oxalylglycine

Topics

• Amino Acids, Dicarboxylic (pharmacology)
• Animals
• Brain Ischemia (metabolism, pathology, physiopathology)
• CA1 Region, Hippocampal (drug effects, pathology, physiopathology)
• Cell Death
• Cell Hypoxia
• Excitatory Postsynaptic Potentials
• Glutamic Acid (pharmacology)
• Hypoxia-Inducible Factor 1, alpha Subunit (biosynthesis)
• Male
• Procollagen-Proline Dioxygenase (antagonists & inhibitors)
• Rats
• Rats, Wistar
• Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors, physiology)
• Synaptic Transmission (drug effects)