4-hydroxynonenal increases neuronal susceptibility to oxidative stress

Abstract

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.

The 2013 SFRBM discovery award: Selected discoveries from the butterfield laboratory of oxidative stress and its sequela in brain in cognitive disorders exemplified by Alzheimer disease and chemotherapy induced cognitive impairment

“…Subsequently, we, showed that elevated protein-bound HNE was observed in AD brain [4, 23-25], complementing research by Markesbery and colleagues, who showed that free HNE was elevated in AD brain [26]. We also demonstrated that 3-NT was elevated in AD brain in the same regions in which protein carbonyls were elevated [27, 28].…”

Oxidative stress causes ERK phosphorylation and cell death in cultured retinal pigment epithelium: Prevention of cell death by AG126 and 15-deoxy-delta 12, 14-PGJ2

“…4-HNE can impair synaptosomal membrane proteins, glutamate transport and importantly, mitochondrial functions [58,59]. Evidence indicates that 4-HNE increases neuronal susceptibility to oxidative stress [60] and serves as a mediator of oxidative stress that leads to neuronal apoptosis [61]. As indicated in the Introduction, 4-HNE has been implicated in some ocular pathological conditions [19,20].…”

Toll‐like receptor 4 in CNS pathologies

“…Neurons and oligodendroglia are especially fragile under inflammatory conditions (Lehnardt et al 2003). Neurological stress provokes NF‐κB induced release of reactive oxygen species, which in turn cause neuronal vulnerability (Keller et al 1999; Hua et al 2007). A comprehensive review of microglia‐mediated inflammation and chronic excitation highlights TLR4’s contribution to neurotoxicity (Block et al 2007).…”