Acrolein‐mediated mechanisms of neuronal death

Abstract

It is well known that traumatic injury in the central nervous system can be viewed as a primary injury and a secondary injury. Increases in oxidative stress lead to breakdown of membrane lipids (lipid peroxidation) during secondary injury. Acrolein, an alpha,beta-unsaturated aldehyde, together with other aldehydes, increases as a result of self-propagating lipid peroxidation. Historically, most research on the pathology of secondary injury has focused on reactive oxygen species (ROS) rather than lipid peroxidation products. Little is known about the toxicology and cell death mediated by these aldehydes. In this study, we investigated and characterized certain features of cell death induced by acrolein on PC12 cells as well as cells from dorsal root ganglion (DRG) and sympathetic ganglion in vitro. In the companion paper, we evaluated a possible means to interfere with this toxicity by application of a compound that can bind to and inactivate acrolein. Here we use both light and atomic force microscopy to study cell morphology after exposure to acrolein. Administration of 100 microM acrolein caused a dramatic change in cell morphology as early as 4 hr. Cytoskeletal structures significantly deteriorated after exposure to 100 microM acrolein as demonstrated by fluorescence microscopy, whereas calpain activity increased significantly at this concentration. Cell viability assays indicated significant cell death with 100 microM acrolein by 4 hr. Caspase 3 activity and DNA fragmentation assays were performed and supported the notion that 100 microM acrolein induced PC12 cell death by the mechanism of necrosis, not apoptosis.

Morphological changes in peri-prostatic sympathetic ganglion cells in aging males

“…The effects of Acrolein on various cells including the sympathetic ganglia were examined by Liu-Snyder et al (14). They found cell death was induced by Acrolein 12 h after its application.…”

Nanomedicine strategies for treatment of secondary spinal cord injury

“…3,32,38,[75][76][77] In particu lar, the drug will scavenge and react with acrolein that has reacted with proteins. 38 As mentioned earlier, the carbonyl group in acrolein is free for nucleophilic attack. Once acrolein reacts with a protein, the carbonyl is free, and hydralazine can attack it.…”

“…37 Later studies explored the various biochemical changes caused by acrolein in neuronal tissues, includ ing lipid peroxidation, myelin damage, and mitochondrial damage. [38][39][40] The primary carbon of acrolein can undergo nucleophilic ("nucleusloving") attack, but contributing to its destructive nature, the electrophilic ("electronloving" or electrondeficient) carbons of the πbond (second bond of C=C) can undergo attack by nucleophiles in the cell. Specifi cally, acrolein reacts with aminecontaining lysine residues, histidines, and electrophilic unsaturated fatty acids.…”

“…In this way, acrolein can increase stress and damage healthy tissues surrounding the injury site. 32,38,45 The large amount of oxidative stress overwhelms the body's natural antioxidant, glutathione. 46 Normally, glutathione is oxidized, which stops reactive oxygen species and reactive nitrogen species from oxidizing proteins and structures in the cell.…”

The Nervous System Cytoskeleton under Oxidative Stress

“…Differentiated cells are less susceptible to this form of attack than undifferentiated cells [32]. Another product of lipid peroxidation, acrolein, disrupts microtubules in PC12 cells, as well as sympathetic ganglion cells in vitro [33], and this may be due in part to increased phosphorylation of Tau protein [34]. In a model system of microtubule degradation by lipid-derived free radicals, it was shown that the kinetics of this process is determined by the level of lipid saturation and the presence of free radical scavengers [35].…”