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NMDA-antagonists reverse increased hypoxic tolerance by preceding chemical hypoxia
K Kasischke1, A C Ludolph, M W Riepe
1Department of Neurology, Humboldt University, Berlin, Germany.
Neuroscience Letters
|August 23, 1996
Summary
Mild chemical hypoxia enhances brain tolerance to oxygen deprivation. However, NMDA-antagonists, but not non-NMDA-antagonists, abolish this protective effect, suggesting a role for NMDA receptors.
Area of Science:
- Neuroscience
- Cellular Physiology
- Neuropharmacology
Background:
- Glutamate excitotoxicity contributes to hypoxic brain damage.
- Energy metabolism inhibition can induce tolerance to subsequent hypoxic insults.
- N-methyl-D-aspartate (NMDA) and non-NMDA receptors mediate excitatory neurotransmission.
Purpose of the Study:
- To investigate the role of NMDA and non-NMDA receptors in hypoxia-induced tolerance.
- To determine if glutamate antagonists affect the enhanced hypoxic tolerance conferred by prior energy metabolism inhibition.
Main Methods:
- Preparation of rat hippocampal slices.
- Induction of mild chemical hypoxia in vivo using 3-nitropropionic acid (3-NP).
- Assessment of population spike amplitude recovery after hypoxic exposure.
- Perfusion of slices with NMDA-antagonist D(-)-2-amino-5-phosphonopentanoic acid (APV) or non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX).
Main Results:
- Slices from 3-NP treated rats (p-slices) showed >90% recovery of population spike amplitude after hypoxia, compared to 30% in controls.
- APV treatment of p-slices reduced hypoxic recovery to 42%.
- CNQX treatment of p-slices resulted in 72% recovery, indicating partial preservation of tolerance.
Conclusions:
- Enhanced hypoxic tolerance induced by mild chemical hypoxia is abolished by NMDA receptor antagonism.
- Non-NMDA receptor antagonism does not abolish this tolerance.
- NMDA receptors play a critical role in the neuroprotective mechanisms underlying hypoxia-induced tolerance.