Prenatal infection obliterates glutamate-related protection against free hydroxyl radicals in neonatal rat brain.
Prenatal infection constitutes an important risk factor for brain injury, in both premature and full-term infants. Unfortunately, as the mechanisms involved are far from understood, no therapeutic strategy emerges to prevent the damage. We tested the hypothesis that administration of lipopolysaccharide (LPS) to gravid female rats enhanced glutamate-induced oxidative stress in brain of pups. A microdialysis probe was implanted into the striatum of 14-day-old animals and the release of hydroxyl radicals (.OH) in the perfusion medium was evaluated. Glutamate promoted a delayed.OH release in the offspring of dams given LPS, contrasting with the.OH decreases observed in control animals. A similar response occurred after infusion of (R,S)-3,5-dihydroxyphenylglycine (DHPG), a Group I metabotropic glutamate receptor (mGluR) agonist. This response was not consecutive to a remote activation of N-methyl-D-aspartate (NMDA) receptors, as it was unaffected by an NMDA receptor antagonist. Furthermore, the response to NMDA itself decreased in the offspring of dams given LPS. Massive amounts of DHPG, however, likely internalizing the mGlu receptor, still blunted the response to NMDA, as in controls. No quantitative variation occurred in mGluR1, mGluR5, or the NR1 subunit of the NMDA receptor between controls and neonates born from LPS-treated dams. Direct LPS injection into age-matched pups, by contrast, affected the response to neither glutamate nor DHPG. These results confirm that normally during perinatal development, the brain is protected from any oxidative stress resulting from excess glutamate, and the results support the hypothesis that maternal infection before delivery may lead to critical brain damage via the release of toxic free radicals.
Cambonie
Gilles
G
CRBM, CNRS UPR 1086, Medicinal Chemistry Laboratory, ENSCM, Montpellier, France.
Hirbec
Hélène
H
Michaud
Martine
M
Kamenka
Jean-Marc
JM
Barbanel
Gérard
G
D015083:2,3-Diketogulonic Acid / Q000378:metabolism; D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003510:Cyclohexanes / Q000494:pharmacology; D053138:Cyclohexenes; D005260:Female; D005315:Fetal Diseases / Q000378:metabolism*; D007839:Functional Laterality; D018698:Glutamic Acid / Q000378:metabolism*; D017665:Hydroxyl Radical / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives* / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress; D010880:Piperidines / Q000494:pharmacology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
D003510:Cyclohexanes; D053138:Cyclohexenes; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D010880:Piperidines; D018094:Receptors, Metabotropic Glutamate; D017665:Hydroxyl Radical; D015083:2,3-Diketogulonic Acid; D018698:Glutamic Acid; D008734:Methoxyhydroxyphenylglycol; C070707:gacyclidine; C010117:3,4-dihydroxyphenylglycol