Glutamate-mediated excitotoxicity in neonatal hippocampal neurons is mediated by mGluR-induced release of Ca++ from intracellular stores and is prevented by estradiol.
Hypoxic/ischemic (HI) brain injury in newborn full-term and premature infants is a common and pervasive source of life time disabilities in cognitive and locomotor function. In the adult, HI induces glutamate release and excitotoxic cell death dependent on NMDA receptor activation. In animal models of the premature human infant, glutamate is also released following HI, but neurons are largely insensitive to NMDA or AMPA/kainic acid (KA) receptor-mediated damage. Using primary cultured hippocampal neurons we have determined that glutamate increases intracellular calcium much more than kainic acid. Moreover, glutamate induces cell death by activating Type I metabotropic glutamate receptors (mGluRs). Pretreatment of neurons with the gonadal steroid estradiol reduces the level of the Type I metabotropic glutamate receptors and completely prevents cell death, suggesting a novel therapeutic approach to excitotoxic brain damage in the neonate.
Hilton
Genell D
GD
Department of Physiology, University of Maryland, Baltimore, Maryland 21201, USA. Gdh4@georgetown.edu
Nunez
Joseph L
JL
Bambrick
Linda
L
Thompson
Scott M
SM
McCarthy
Margaret M
MM
D000818:Animals; D001238:Asphyxia Neonatorum / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D018698:Glutamic Acid / Q000633:toxicity*; D006624:Hippocampus / Q000196:embryology / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D007231:Infant, Newborn; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000378:metabolism*
D018696:Neuroprotective Agents; D009498:Neurotoxins; D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid; D004958:Estradiol; D002118:Calcium