Rescuing neurons from necrotic death
It is widely accepted that various secondary injury mechanisms such as glutamate mediated excitotoxicity, calcium influx and oxidative stress are actively involved in the progression of CNS trauma. However the therapeutic strategies that targeted those biochemical mechanisms have failed to be of clinical benefit in human trials due to various reasons. These failures add even more incentive for alternative strategies that slow down or stop the cascades of biochemical events we call "secondary injury". Lately a growing body of evidence has showed the involvement of another injury mechanism, called carbonyl stress, critical to CNS trauma and cell death. Carbonyls come from lipid peroxidation of cell and organelle membranes, glycolation, and consequent protein carbonylation. Acrolein, a pollutant from automobile exhaust or from cigarette, is also an endogenous toxin produced by the lipid peroxidation process. Among the several end products of lipid peroxidation, acrolein has the longest half-life in tissues and highest toxic reactivity with cells. So the understanding of the pathology of acrolein-mediated injury and neuronal cell death are very important and useful for the treatment of carbonyl stress. We have used PC12 cells as an in vitro model to examine the cytotoxicity of acrolein and to test for a potential protective effect derived from polyethylene glycol (PEG) and hydralazine. We have found that acrolein broke down membrane integrity, disrupted cytoskeletonal structure and mitochondrial functioning, and reduced intracellular ATP and glutathione level eventually leading to necrotic cell death. Polyethylene glycol, a membrane fusogen failed to improve cellular functioning via its ability to repair damaged cell membrane. In contrast, hydralazine, a carbonyl scavenger effectively blocked acrolein-mediated injury processes and rescued PC12 cells from the death. Taken together, these data indicate that the "scavenging" property of hydralazine is very effective in reducing, even eliminating, the cytotoxicity of acrolein. Further studies using in vivo animal models of CNS trauma are planned to examine the effect of hydralazine on functional recovery from CNS trauma in spinal cord injury, traumatic brain injury and stroke.
Borgens, Purdue University.
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