NMDA receptor modification in the fetal guinea pig brain during hypoxia

Mishra, O.P.; Delivoria-Papadopoulos, M.

Neurochemical Research 17(12): 1211-1216


ISSN/ISBN: 0364-3190
PMID: 1361030
DOI: 10.1007/bf00968402
Accession: 009074375

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The effect of maternal hypoxia on the modification of the fetal brain cell membrane N-methyl-D-aspartate (NMDA) receptor and its modulatory sites was investigated. Experiments were conducted in pregnant guinea pigs of 60 days of gestation. Guinea pig fetuses were exposed to maternal hypoxia (FiO-2 = 7%) for 60 minutes. Tissue hypoxia in the fetal brain was documented biochemically by decreased levels of ATP and phosphocreatine (91.3% and 88.6% lower than normoxia, respectively)/ MK-801 binding characteristics (Bmax = number of receptors, Kd = affinity of receptor) were used as an index of NMDA receptor modification. P2 membrane fraction was prepared from the cortex of normoxic and hypoxic fetal brain and washed thoroughly before carrying out the binding assay. In hypoxic brains, Bmax decreased from the normoxic control level 0.79 +- 0.03 pmol/mg protein to 0.58 +- 0.03 pmol/mg protein (P lt 0.005) and Kd value decreased (increased affinity) from 8.54 +- 0.27 nM to 4.01 +- 0.23 nM (P lt 0.005) respectively. The MK-801 binding in the absence of added glutamate and glycine in hypoxic brain was 100% higher as compared to controls, indicating an increased sensitivity of the NMDA receptor to activation. The spermine dependent maximum activation of the NMDA receptor increased to 44% in the hypoxic animals as compare to 25% in controls. The Mg-2+ response of the NMDA receptor was not affected by hypoxia. The increased affinity and increased basal activation (tone) of the NMDA receptor during hypoxia, as well as its increased activation by spermine, would hyperstimulate the NMDA receptor-ion channel complex function which could increase the susceptibility of the fetal brain to hypoxia. The results of this study indicate that hypoxia causes differential and selective modification of specific sites (recognition, co-activator, and modulatory) of the NMDA receptor ion channel complex. The hypoxia-induced modification of the NMDA receptor modulatory sites appears to be the potential mechanism of neuroexcitotoxicity.

NMDA receptor modification in the fetal guinea pig brain during hypoxia