4-hydroxynonenal increases neuronal susceptibility to oxidative stress.
Increased levels of reactive oxygen species occur in neurodegenerative disorders and may promote neuron death. The lipid peroxidation product 4-hydroxynonenal (HNE) is increased in neurons following oxidative stress and promotes neuron death in vitro and in vivo. The present study examined the possibility that HNE can increase neuron vulnerability to oxidative stress. Application of low concentrations of HNE (50-500 nM) increased neuron death induced by beta-amyloid or glutamate when added within 3 hr of injury. In addition, treatment with HNE exacerbated mitochondrial reactive oxygen species formation and loss of mitochondrial membrane potential in response to beta-amyloid and glutamate. The ability to exacerbate oxidative stress, mitochondrial dysfunction, and neuron death appears to be specific to HNE, because application of other lipid peroxidation products had no effect. These data indicate a role for low levels of HNE in promoting reactive oxygen species accumulation and neuron degeneration by altering mitochondrial homeostasis. In addition, the present study indicates a possible mechanism for reactive oxygen species and lipid peroxidation toxicity in neurodegenerative conditions.
Keller
J N
JN
Sanders-Brown Center on Aging, University of Kentucky, Lexington 40536-0230, USA. Jnkello@pop.uky.edu
Hanni
K B
KB
Markesbery
W R
WR
D000447:Aldehydes / Q000009:adverse effects* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000009:adverse effects; D000818:Animals; D018929:Cell Culture Techniques; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000009:adverse effects / Q000378:metabolism; D018698:Glutamic Acid / Q000009:adverse effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000447:Aldehydes; D016229:Amyloid beta-Peptides; D015853:Cysteine Proteinase Inhibitors; D018698:Glutamic Acid; C027576:4-hydroxy-2-nonenal