Multiple pathways of neuroprotection against oxidative stress and excitotoxic injury in immature primary hippocampal neurons.
In the immature brain hydrogen peroxide accumulates after excitotoxic hypoxia-ischemia and is neurotoxic. Immature hippocampal neurons were exposed to N-methyl-D-aspartate (NMDA), a glutamate agonist, and hydrogen peroxide (H(2)O(2)) and the effects of free radical scavenging and transition metal chelation on neurotoxicity were studied. alpha-Phenyl-N-tert.-butylnitrone (PBN), a known superoxide scavenger, attenuated both H(2)O(2) and NMDA mediated toxicity. Treatment with desferrioxamine (DFX), an iron chelator, at the time of exposure to H(2)O(2) was ineffective, but pretreatment was protective. DFX also protected against NMDA toxicity. TPEN, a metal chelator with higher affinities for a broad spectrum of transition metal ions, also protected against H(2)O(2) toxicity but was ineffective against NMDA induced toxicity. These data suggest that during exposure to free radical and glutamate agonists, the presence of iron and other free metal ions contribute to neuronal cell death. In the immature nervous system this neuronal injury can be attenuated by free radical scavengers and metal chelators.
Almli
L M
LM
Departments of Neurology and Pediatrics, University of California San Francisco, Box 0114, San Francisco, CA 94143-0114, USA.
Hamrick
S E
SE
Koshy
A A
AA
Täuber
M G
MG
Ferriero
D M
DM
D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D003497:Cyclic N-Oxides; D003676:Deferoxamine / Q000494:pharmacology; D005029:Ethylenediamines / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D016166:Free Radical Scavengers / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology* / Q000254:growth & development*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D009589:Nitrogen Oxides / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
D002614:Chelating Agents; D003497:Cyclic N-Oxides; D005029:Ethylenediamines; D018690:Excitatory Amino Acid Agonists; D016166:Free Radical Scavengers; D007502:Iron Chelating Agents; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; D016877:Oxidants; D017382:Reactive Oxygen Species; C029217:phenyl-N-tert-butylnitrone; D016202:N-Methylaspartate; D006861:Hydrogen Peroxide; D007501:Iron; D003676:Deferoxamine; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine